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Cannabinoids and Pain: Sites and Mechanisms of Action
Abstract
The endocannabinoid system, consisting of the cannabinoid1 receptor (CB1R) and cannabinoid2 receptor (CB2R), endogenous cannabinoid ligands (endocannabinoids), and metabolizing enzymes, is present throughout the pain pathways. Endocannabinoids, phytocannabinoids, and synthetic cannabinoid receptor agonists have antinociceptive effects in animal models of acute, inflammatory, and neuropathic pain. CB1R and CB2R located at peripheral, spinal, or supraspinal sites are important targets mediating these antinociceptive effects. The mechanisms underlying the analgesic effects of cannabinoids likely include inhibition of presynaptic neurotransmitter and neuropeptide release, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pain pathway, and reductions in neuroinflammatory signaling. Strategies to dissociate the psychoactive effects of cannabinoids from their analgesic effects have focused on peripherally restricted CB1R agonists, CB2R agonists, inhibitors of endocannabinoid catabolism or uptake, and modulation of other non-CB1R/non-CB2R targets of cannabinoids including TRPV1, GPR55, and PPARs. The large body of preclinical evidence in support of cannabinoids as potential analgesic agents is supported by clinical studies demonstrating their efficacy across a variety of pain disorders.
... Consequently, immune and neural system crosstalk and regulate each other, by means of glial, epithelial, and mesenchymal, and mast cells. Recent literature on this topic highlights the role of cannabinoid receptors (CB1 and CB2), which are expressed by glia and neurons at peripheral, spinal, and supraspinal sites (32). They bind different endogenous lipid ligands (i.e., endocannabinoids) and modulate pain, mood, appetite, and emesis. ...
... They bind different endogenous lipid ligands (i.e., endocannabinoids) and modulate pain, mood, appetite, and emesis. Their antinociceptive activity is exerted through inhibition of presynaptic neurotransmitter release, reduction of neuronal excitability at the postsynaptic level, and activation of descending inhibitory pathways (32). ...
... In this context, HT serves both for pain relief and function improvement. Indeed, exercise combined with HT works on nociceptors and favour the production of endorphins (19,32). When proposing HT in a multimodal approach, it is indicated to let the patient think that there will be an improvement, favouring both pain and functional benefit. ...
Background
Among children and adolescents, up to 40% will experience musculoskeletal pain (MP), which can significantly impair functional ability, reduce quality of life, cause emotional distress, and lead to sleeping disorders for both patients and their families. The first-line treatment often involves pharmacological interventions, even though there is a lack of evidence supporting the efficacy or the safety of this approach in this specific age group. Recent guidelines recommend the implementation of preventative strategies and physical tools as the first option to minimize the use of medications. We aimed to provide an expert opinion on the use of heat therapy for MP management in young patients.
Methods
This paper is the result of a virtual advisory board held by the authors in order to discuss and provide an expert opinion about the use of heat therapy in MP in children and adolescents.
Results
MP is a significant burden affecting children and adolescents. While non-steroidal anti-inflammatory drugs are currently the first-choice treatment of acute and chronic MP in children and adolescents, avoiding or reducing them in such patients is advisable, to reduce side effects and to prevent the development of chronic pain and medication overuse headaches. Heat therapy can be an additional treatment option due to its ability to promote muscle relaxation, enhance blood circulation, and modulate nociceptors with a good safety profile.
Conclusions
MP in children and adolescents is a common condition that should be approached multidisciplinary, including information, therapeutic exercise and physical therapies like hot or cold therapies. Future studies should be conducted to evaluate the safety, efficacy and indications of each treatment in MP.
... The high expression of the CB2R in tissues of the immune system including the spleen and thymus as well as on specific immune cells including B lymphocytes, natural killer cells, monocytes, neutrophils, and T lymphocytes has focused research on the viability of the CB2R as a therapeutic target in inflammatory pain conditions in particular, but also neuropathic pain which can have a neuroinflammatory/neuroimmune component [18]. Recent in vivo microdialysis experiments demonstrated that intraplantar injection of the chemical irritant formalin evokes the release of AEA in the midbrain periaqueductal gray (PAG) [19]. The endocannabinoids and N-acylethanolamines also have affinity for, and activity at, a number of non-CB1/non-CB2 receptors, including TRPV1, GPR55 (putative CB3 receptor), and the peroxisome proliferator-activated receptors (PPARs)-all of which are also expressed throughout the pain pathways and likely play important roles in endocannabinoid-mediated regulation of pain. ...
... The chemical heterogeneity of the cannabis plant constituents extends to terpenes and flavonoids, which hold their own distinct mechanisms of action and pharmacological profiles. It has been advanced that there may be synergy among some constituents of the plant in what is broadly referred to as an "entourage" effect, a concept which will be later described [19]. ...
... Significant decreased levels of salivary 2-AG were identified in patients with trigeminal neuralgia and tension-type headache, while patients with burning mouth syndrome had significantly elevated AEA levels compared to pain-free control patients [20 ••]. Genetic polymorphisms are correlated with the state of the eCB system and have been associated with pain intensity, opioid-related side effects, and adverse outcomes [19]. On a subjective level, preoperative pressure pain thresholds have been shown to be predictive in various surgical populations [26,27]. ...
Purpose of the Review
Acute pain management remains a challenge and postoperative pain is often undermanaged despite many available treatment options, also including cannabinoids.
Recent Findings
In the light of the opioid epidemic, there has been growing interest in alternative care bundles for pain management, including cannabinoids as potential treatment to decrease opioid prescribing. Despite the lack of solid evidence on the efficacy of cannabinoids, their use among patients with pain, including those using opioids, is currently increasing. This use is supported by data suggesting that cannabinoids could potentially contribute to a better pain management and to a reduction in opioid doses while maintaining effective analgesia with minimum side effects.
Summary
The scientific basis for supporting the use of cannabis is extensive, although it does not necessarily translate into relevant clinical outcomes. The use of cannabinoids in acute pain did not always consistently show statistically significant results in improving acute pain. Large randomized, controlled trials evaluating diverse cannabis extracts are needed in different clinical pain populations to determine safety and efficacy.
... NeuN and MAP2 regulate neuronal growth and regeneration (11)(12)(13). These are closely related to analgesic effects by the inhibition of presynaptic neurotransmitter and neuropeptide release, modulation of postsynaptic neuron, and reductions in neuroinflammatory signaling (14). ...
... This therefore suggests a longer-lasting analgesic effect in the 830LA + EA group, which exhibited significantly lower FAAH protein levels than the other groups. The endocannabinoid system to which CB1R belongs is involved in the pain pathway and is composed of CB1R, CB2R, endocannabinoids such as transient receptor potential subfamily V member (TRPV) 1 and peroxisome proliferator-activated receptors (PPAR), and metabolizing enzymes (14). The endocannabinoid signaling system is regulated by synthesis and release of anandamide and 2-arachidonoylglycerol, uptake and degradation at supraspinal, spinal, and peripheral levels (8,14,35). ...
... The endocannabinoid system to which CB1R belongs is involved in the pain pathway and is composed of CB1R, CB2R, endocannabinoids such as transient receptor potential subfamily V member (TRPV) 1 and peroxisome proliferator-activated receptors (PPAR), and metabolizing enzymes (14). The endocannabinoid signaling system is regulated by synthesis and release of anandamide and 2-arachidonoylglycerol, uptake and degradation at supraspinal, spinal, and peripheral levels (8,14,35). Endocannabinoids are released activating CB1R, CB2R, and non-cannabinoid receptors including TRPV1 and PPAR (35). Released endocannabinoids are degraded by the hydrolyzing enzymes including FAAH and monoacylglycerol lipase, and by oxidative metabolism through cyclooxygenase, lipoxygenase and cytochrome P450 enzymes (8,35). ...
Introduction
Allodynia, which can be induced by paclitaxel administration, is the presence of pain as a result of a stimulus that does not usually provoke pain. Many studies have investigated the analgesic efficacy of acupuncture, including laser acupuncture (LA) and electroacupuncture (EA). Although pain-related diseases are relatively common, few studies have analyzed the analgesic effects and mechanisms of LA combined with EA. The purpose of this study was to investigate the therapeutic effect and mechanism of manual acupuncture (MA), EA, LA, and combined therapy (LA + EA) in a paclitaxel-induced allodynia rat model.
Methods
A total of 56 rats were classified into eight groups: a normal (Nor, n = 7), a control (Con, n = 7), an MA (n = 7), an EA (n = 7), a 650-nm LA (650LA, n = 7), an 830-nm LA (830LA, n = 7), a 650-nm LA combined with EA (650LA + EA, n = 7), and an 830-nm LA combined with EA group (830LA + EA, n = 7). Allodynia was induced by intraperitoneal injection of 2 mg/kg of paclitaxel every other day for a total of four times except the Nor group. Acupuncture treatments were conducted at the points of Jungwan (CV12) and Joksamni (ST36) once every other day for 6 min, for a total of nine times. Withdrawal response reaction times and force intensity of the foot were measured before the start of the experiment, after the 4th paclitaxel administration (day 8), and after the 9th and last treatment (day 15). On the 16th day, mRNA and protein expression in the spinal nerves was assessed, and a metabolome analysis of the animals’ feces was performed.
Results and discussion
Our analyses show that 650LA + EA treatment resulted in an upregulation of protein expression related to pain relief and nerve regeneration, whereas 830LA + EA treatment led to significant changes in metabolomes. This study demonstrates that a combination treatment of EA and LA can suppress allodynia and promote upregulation of protein expression related to nerve regeneration and is effective in changing the intestinal microbiome. Further large-scale research is required to assess the exact mechanism underlying the therapeutic effect of this combination treatment in pain-related diseases.
... Endocannabinoids are lipid agents that act on cannabinoid receptors, which are expressed widely in the CNS and the PNS. Endocannabinoid signaling is important in multiple physiological and neurological processes, including pain modulation 47,48 . Whereas cannabinoid receptor 1 (CB1) is expressed in the nervous system, CB2 is enriched in the immune compartment. ...
... Whereas cannabinoid receptor 1 (CB1) is expressed in the nervous system, CB2 is enriched in the immune compartment. Cannabinoids suppress acute responses to noxious stimuli in the dorsal horn [47][48][49] . Activation of CB2 attenuates mechanical allodynia in a rat model of complex regional pain syndrome 50 , indicating CB2 receptors on spinal microglia are implicated in analgesia. ...
Immune cells are involved in the pathogenesis of pain by directly activating or sensitizing nociceptor sensory neurons. However, because the immune system also has the capacity to self-regulate through anti-inflammatory mechanisms that drive the resolution of inflammation, it might promote pain resolution and prevention. Here, we describe how immune cell-derived cytokines can act directly on sensory neurons to inhibit pain hypersensitivity and how immune-derived endogenous opioids promote analgesia. We also discuss how immune cells support healthy tissue innervation by clearing debris after nerve injury, protecting against axon retraction from target tissues and enhancing regeneration, preventing the development of chronic neuropathic pain. Finally, we review the accumulating evidence that manipulating immune activity positively alters somatosensation, albeit with currently unclear molecular and cellular mechanisms. Exploration of immune-mediated analgesia and pain prevention could, therefore, be important for the development of novel immune therapies for the treatment of clinical pain states.
... Cannabis contains numerous biologically active components, with Δ 9 -tetrahydrocannabinol (THC) being the most abundant and most extensively studied (Finn et al., 2021;McDonagh et al., 2022). THC produces its pharmacological effects by hijacking the endocannabinoid signaling system , a critical regulator of nociception and pain, through its 5 interaction with CB 1 and CB 2 cannabinoid receptors (Starowicz & Finn, 2017). Nonetheless, THC's activation of CB 1 receptors in brain regions involved in mood, reward, and cognition produces a distinctive set of physiological and psychotropic effects which may limit cannabis application in the management of SCD pain. ...
... While our study did not directly investigate the mechanism by which THC elicits its antinociceptive effects in HbSS mice, it is plausible that this may involve the activation of CB 1 and/or CB 2 cannabinoid receptors. Most, if not all pharmacological properties of THC are ascribed to its ability to engage these receptors, whose role in pain regulation is well established Starowicz & Finn, 2017;Vincent et al., 2016). However, it is important to acknowledge that THC may ligate other receptor systems, such as transient receptor potential vanilloid 2 (TRPV2) (De Petrocellis et al., 2011;Qin et al., 2008), which might also contribute to its antinociceptive activity (Frederick et al., 2007;Shimosato et al., 2005). ...
People with sickle cell disease (SCD) often experience chronic pain as well as unpredictable episodes of acute pain, which significantly affect their quality of life and life expectancy. Current treatment strategies for SCD-associated pain primarily rely on opioid analgesics, which have limited efficacy and cause serious adverse effects. Cannabis has emerged as a potential alternative, yet its efficacy remains uncertain. In this study, we investigated the antinociceptive effects of Δ9-tetrahydrocannabinol (THC), cannabis' intoxicating constituent, in male HbSS mice, which express >99% human sickle hemoglobin, and male HbAA mice, which express normal human hemoglobin A, as a control. Acute THC administration (0.1-3 mg-kg-1, intraperitoneal, i.p.) dose-dependently reduced mechanical and cold hypersensitivity in HbSS, but not HbAA mice. In the tail-flick assay, THC (1 and 3 mg-kg-1, i.p.) produced substantial antinociceptive effects in HbSS mice. By contrast, THC (1 mg-kg-1, i.p.) did not alter anxiety-like behavior (elevated plus maze) or long-term memory (24-h novel object recognition). Subchronic THC treatment (1 and 3 mg-kg-1, i.p.) provided sustained relief of mechanical hypersensitivity but led to tolerance in cold hypersensitivity in HbSS mice. Together, the findings identify THC as a possible therapeutic option for the management of chronic pain in SCD. Further research is warranted to elucidate its mechanism of action and possible interaction with other cannabis constituents. Significance Statement The study explores THC's efficacy in alleviating pain in sickle cell disease (SCD) using a humanized mouse model. Findings indicate that acute THC administration reduces mechanical and cold hypersensitivity in SCD mice without impacting emotional and cognitive dysfunction. Subchronic THC treatment offers sustained relief of mechanical hypersensitivity but leads to cold hypersensitivity tolerance. These results offer insights into THC's potential as an alternative pain management option in SCD, highlighting both its benefits and limitations.
... A number of therapeutic effects of cannabis and cannabinoids have been reported, such as neuroprotective and anti-inflammatory mechanisms, which are beneficial in the treatment of certain psychiatric illnesses [39]. The analgesic effects of cannabinoids are likely due to mechanisms of inhibiting the release of neurotransmitters and neuropeptides, reducing the signaling of neuroinflammation, triggering the descending inhibitory pathway, and modulating postsynaptic neuronal activity [40]. Concerning cannabinoids' anti-inflammatory properties, these effects are carried out by inducing apoptosis, decreasing the production of cytokines, inhibiting cell growth and division, and inducing Tregs [4]. ...
... A difference in the effects of CBD and THC on cytokines has also been discovered; it was observed that CBD elevated levels of IL-6, but reduced those of IL-1β and IL-10, and THC was antinociceptive, but did not have significant effects on cytokines; however, CBD demonstrated little antinociception, but affected cytokines significantly [131]. This difference suggests that, in the CFA model, the antinociceptive effects of THC were the result of the substance's neural actions instead of its actions on the immune system [40]. Essentially, cannabinoids in general have been demonstrated to have a variety of effects on body systems, one of them being modulating cytokine release [5]. ...
Background
The usage of nicotine and cannabinoids has rapidly grown in popularity, leading to increased research into how they can affect people’s health, both positively and negatively. Nicotine, Cannabidiol (CBD), and Tetrahydrocannabidiol (THC) have been shown to have significant effects on cytokine function and inflammatory response.
Objective
This study aimed to review and summarize the current literature on the effects of nicotine and cannabinoids on cytokines, including interleukins, TNF, IFN, and TGF-β.
Methods
Literature search was conducted on Medline/PubMed electronic databases utilizing the search terms “nicotine” OR “cannabis” OR “cannabinoids” AND “cytokine” AND “inflammation” AND “stress” AND “immune” from 11/1973 to 02/2024.
Results
THC and CBD usage have been associated with conflicting impacts on immune response, and observed to both exacerbate and inhibit inflammation. Nicotine has been shown to be generally proinflammatory with regards to cytokines. These responses have been reported to have significant effects on bodily response to inflammation-related diseases. Nicotine usage is associated with worsened outcomes for some conditions, like chronic pain, but improved outcomes for others, like arthritis. The impacts of cannabinoid usage tend to be more positive, exerting anti-inflammatory effects across a wide range of diseases. Given the widespread usage of these substances, it is important to understand the nature of their consequences on immune functions and the underlying mechanisms by which they act.
Conclusion
This review has covered how cannabinoids and nicotine affect inflammation directly and how these effects can be attributed to the treatment of inflammatory diseases. In summary, the existing research studying the effects of cannabinoids and nicotine supports the major relationship between nicotine and cannabis use and inflammatory diseases.
... and cannabinoid 2 receptor (CB 2 ) and their endogenous ligands (endocannabinoids), the two best characterised being anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The endocannabinoid system also encompasses the enzymes responsible for 1) endocannabinoid synthesis; N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and diacylglycerol lipase-α (DAGL-α) and 2) endocannabinoid degradation; fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) [67,86,87]. The endocannabinoids are lipid neuromodulators synthesised and released on demand from membrane phospholipid precursors in the post-synaptic neuron. ...
... The endocannabinoid system has emerged as a novel therapeutic target for managing several conditions and symptoms, including childhood epilepsy and spasticity associated with multiple sclerosis [173][174][175]. Modulation of this system has shown some promise in attenuating pain, and there is a growing body of preclinical and clinical literature investigating this application [78,86,88,115]. Given 1) the pressing need for novel therapeutics for the management of wound-related pain, 2) the role of the endocannabinoid system on a cutaneous and central level in skin homeostasis and wound healing and 3) the emerging anti-nociceptive efficacy of cannabinoid-based therapeutics, the future is promising for the investigation of endocannabinoid system modulators for the management of chronic wound-related pain. ...
... Thus, the following mechanistic discussion focuses on targets which have been linked to cannabinoid actions in neuropathic pain states, starting with the individual actions of THC and CBD in neuropathic pain states, followed by THC:CBD combinations. For more detailed general information on cannabinoid targets and mechanisms, the reader is referred to more detailed reviews (Castillo-Arellano et al., 2023;De Petrocellis et al., 2017;Howlett, 2005;Muller et al., 2018;Pertwee, 2008;Starowicz & Finn, 2017). ...
... In addition to GPCRs, nuclear receptors which regulate gene expression, such as peroxisome proliferator-activated receptors (PPARs), have also been implicated in neuropathic pain (Okine et al., 2019;Starowicz & Finn, 2017). Thus, PPARγ has been identified as a target of cannabinoids, such as CBD and THC, and has been shown to mediate their anti-allodynic effects in neuropathic pain models (Hind et al., 2016;Jhaveri et al., 2008;O'Sullivan, 2007O'Sullivan, , 2016Silva et al., 2022). ...
Chronic neuropathic pain is a debilitating pain syndrome caused by damage to the nervous system that is poorly served by current medications. Given these problems, clinical studies have pursued extracts of the plant Cannabis sativa as alternative treatments for this condition. The vast majority of these studies have examined cannabinoids which contain the psychoactive constituent delta‐9‐tetrahydrocannabinol (THC). While there have been some positive findings, meta‐analyses of this clinical work indicates that this effectiveness is limited and hampered by side‐effects. This review focuses on how recent preclinical studies have predicted the clinical limitations of THC‐containing cannabis extracts, and importantly, point to how they might be improved. This work highlights the importance of targeting channels and receptors other than cannabinoid CB1 receptors which mediate many of the side‐effects of cannabis.
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... The discovery of Cannabis sativa psychoactive principle (tetrahydrocannabinol -THC) in the second half of the 20th century inaugurated research that later came to identify dozens of other substances from this plant, including cannabinoids, terpenes, and flavonoids 1,2 . The subsequent description of interaction sites for these substances in animals (most vertebrates, such as dogs, XX cats, horses, rabbits, and others) and humans, as well as their endogenous ligands, transport proteins, and synthesis and degradation enzymes, revealed what has come to be known as the endocannabinoid system 1 . ...
... The discovery of Cannabis sativa psychoactive principle (tetrahydrocannabinol -THC) in the second half of the 20th century inaugurated research that later came to identify dozens of other substances from this plant, including cannabinoids, terpenes, and flavonoids 1,2 . The subsequent description of interaction sites for these substances in animals (most vertebrates, such as dogs, XX cats, horses, rabbits, and others) and humans, as well as their endogenous ligands, transport proteins, and synthesis and degradation enzymes, revealed what has come to be known as the endocannabinoid system 1 . Several receptors participate in this system. ...
BACKGROUND AND OBJECTIVES
The discovery of the psychoactive agent of Cannabis sativa (tetrahydrocannabinol - THC) in the second half of the 20th century originated the research that later came to identify dozens of other substances from this plant, including cannabinoids, terpenes and flavonoids. Ensuing description of their interaction sites in animals and humans, together with endogenous ligands, transport proteins as well as synthesis and degradation enzymes, revealed what came to be known as the endocannabinoid system. Several receptors participate in this system.
CONTENTS
The first receptors to be discovered were called CB1 and CB2, both are G protein-coupled (GPCR). It is noteworthy that CB1 receptors are among the most abundant and widely distributed GPCR in the mammalian brain, with marked expression in basal ganglia, cerebellum and hippocampus, for instance; on the other hand, they are scarce in areas of the brainstem related to breathing control. In light of the multiplicity of pharmacological effects of cannabinoids, concomitant with the lack of more clarifying studies on their mechanisms of action despite the great interest in research on their therapeutic application, it is necessary to deepen the knowledge in this area.
CONCLUSION
Considering the literature research conducted for the composition of this article, it is possible to conclude that cannabinoids have a broad spectrum of action mechanisms in the human body, and that more robust clinical studies are needed to better understand their broad therapeutic potential.
Keywords:
Cannabis; Cannabinoid receptor agonists; Cannabinoid receptor antagonists; Cannabinoids; Modulators; Neurobiology
... The discovery of Cannabis sativa psychoactive principle (tetrahydrocannabinol -THC) in the second half of the 20th century inaugurated research that later came to identify dozens of other substances from this plant, including cannabinoids, terpenes, and flavonoids 1,2 . The subsequent description of interaction sites for these substances in animals (most vertebrates, such as dogs, S110 cats, horses, rabbits, and others) and humans, as well as their endogenous ligands, transport proteins, and synthesis and degradation enzymes, revealed what has come to be known as the endocannabinoid system 1 . ...
... The discovery of Cannabis sativa psychoactive principle (tetrahydrocannabinol -THC) in the second half of the 20th century inaugurated research that later came to identify dozens of other substances from this plant, including cannabinoids, terpenes, and flavonoids 1,2 . The subsequent description of interaction sites for these substances in animals (most vertebrates, such as dogs, S110 cats, horses, rabbits, and others) and humans, as well as their endogenous ligands, transport proteins, and synthesis and degradation enzymes, revealed what has come to be known as the endocannabinoid system 1 . Several receptors participate in this system. ...
... CBs also target nuclear receptors such as PPAR-γ, which are involved in gene regulation and have been associated with NeP [7,95]. The activation of PPAR-γ by CBs contributes to their anti-allodynic effects in models of NeP. ...
The dysregulation of autophagy plays a significant role in the onset of various pathologies, with emerging evidence indicating its potential involvement in chronic pain conditions. The cellular and molecular mechanisms underlying this pathology have been thoroughly investigated, with the endocannabinoid system (ECS) identified as a crucial factor in the progression of chronic neuropathic pain. This chapter highlights several plant-derived cannabinoids, including cannabidiol, cannabinol, Δ-9-tetrahydrocannabinol, which exhibit unique modulatory effects on the ECS. We discuss the roles of cannabinoid receptors, cannabinoid enzymes, and PPARγ as modulators in decreased levels of inflammatory cytokines, as well as a reduction in microglial activation, and inhibit the assembly of NLRP3 inflammasome complex, which potentially provides substantial neuroprotective effects in neuropathic pain. Since the discovery of the endocannabinoid system and the implications of mitochondrial dysfunction and autophagy impairment in neuropathic pain, there has been an increasing interest in the therapeutic potential of this system.
... The implementation of IRT in the study and monitoring of pain in animals has led to the possibility of developing and applying this tool in the validation of the analgesic efficacy and clinical safety of some drugs commonly used during anesthetic surgical procedures [12,20]. In this regard, it is necessary to point out that compassionate care and pharmacological intervention for pain have had significant updates, as new drugs, such as phytocannabinoids, have been suggested and shown to reduce pain perception similarly to conventional analgesics [21][22][23][24][25][26]. However, the evidence regarding the use of these drugs for the control of acute postoperative pain is still limited. ...
Pain management requires the identification of certain indicators to recognize pain. Various tools have been suggested to achieve an objective evaluation, including infrared thermography (IRT). The objective of this study was to assess the facial thermal nociceptive response produced by the use of cannabidiol (CBD) alone and in combination with meloxicam in female dogs undergoing elective ovariohysterectomy anesthetized with isoflurane. Sixty-four female dogs of different breeds were randomly distributed into four study groups according to the treatment received. G1: Placebo group (n = 16); G2: Group receiving intravenous meloxicam as premedication (0.2 mg Kg−1) and every 24 h postoperatively 0.1 mg Kg−1 (n = 16); G3: Group treated with CBD (n = 16) at a dose of 2 mg kg−1 orally every 12 h; and G4: Group medicated with the combination of both treatments (n = 16). All treatments were administered for 48 h postoperatively. After the anesthetic surgical procedure, radiometric images were captured using IRT and physiological parameters during the events EBasal, E30min, E1h, E2h, E3h, E4h, E8h, E12h, E24h and E48h. Overall, it was found that the high, medium and low temperatures of the thermal windows of the eye, upper eyelid and lower eyelid, as well as the average temperature of the lacrimal gland in G1 between events, were significantly lower at E30min, E1h and E2h compared to EBasal (p = 0.01). Among treatments, a significantly higher temperature was observed in groups G2, G3 and G4 compared to G1 (p = 0.001) in the thermal windows of the upper eyelid, lower eyelid, lacrimal gland and ocular areas. Regarding physiological parameters, heart rate (HR) was higher in G1 compared to the animals in G2, G3 and G4 (p = 0.03). The respiratory rate (RR) was significantly lower in all four study groups during the postoperative events compared to their respective EBasal (p < 0.05), while among treatments, G2, G3 and G4 had a lower RR compared to G1 (p = 0.03). Mild hypothermia was observed in all study groups at E30min and E1h compared to EBasal (p = 0.001). No significant correlation was found between the temperatures of the assessed thermal regions and the physiological traits. In conclusion, CBD, whether administered alone or in combination with meloxicam, demonstrated comparable analgesic efficacy, which could control nociceptive cardiorespiratory and hemodynamic autonomic responses, as there were no significant changes in the facial thermal response between treatments G2, G3 and G4.
... ; https://doi.org/10.1101/2024.12.12.628159 doi: bioRxiv preprint 12/12/2024 (Jamali-Raeufy et al., 2011). However, cannabinoid compounds also affect the ascending and descending pathways that regulate pain perception (Starowicz & Finn, 2017). This is relevant, considering the aversive stimulus (a mild foot shock) inherent to this task (Bengoetxea de Tena et al., 2022). ...
The endocannabinoid system is involved in diverse processes, like learning and memory, governed by cholinergic neurotransmission. Recent research demonstrates that in a model of dementia derived from basal forebrain cholinergic degeneration, WIN55,212-2 improves cognition through increased cortical choline levels. However, the effect of cannabinoids on cholinergic deficits is still under investigation. In this work, we studied the effect of this treatment in a pharmacological model of transient cholinergic hypofunction by the acute administration of the muscarinic antagonist, scopolamine, in spatial, recognition and aversive memory tests. Scopolamine induced memory impairment was observed in the three tests and, importantly, the cannabinoid subchronic treatment with low doses of WIN55,212-2 prevented this deleterious effect in spatial memory when evaluated in spatial Barnes maze test. Autoradiographic studies indicate that, following the WIN55,212-2 treatment, cannabinoid receptor density increased in the motor and somatosensory cortices. In layers I-V of the motor cortex, the activity of cannabinoid and muscarinic receptors also increased. These results suggest that WIN55,212-2, through the activation of CB1 receptors, indirectly elevates the muscarinic tone in key cortical areas for learning and memory, preventing the memory deficits induced by scopolamine specifically in spatial memory. This highlights the importance of the crosstalk between the endocannabinoid and the cholinergic system for learning and memory processes and suggest that cannabinoid agonists might be an alternative for the treatment of cognitive deficits associated with cholinergic dysfunction.
... In the work of Mechoulam et al., CB1 and CB2 receptors have been shown to interact with anandamide and 2-arachidonyl-glycerol, affecting movement coordination and immune functions, expanding the understanding of their role in neurophysiology (9). Studies suggest that cannabinoids, when interacting with CB1 and CB2 receptors, exhibit analgesic and antiinflammatory effects, as highlighted by the work of Miranda-Cortés et al. and Starowicz et al. (10,11). These properties make cannabinoids promising for multimodal pain management as well as management of conditions such as seizures, epilepsy, dermatitis, degenerative myelopathies, asthma, diabetes, and glaucoma in humans and animals. ...
Background
Cannabis and its derivatives show encouraging therapeutic effects in the treatment of various diseases. However, further studies are needed to better assess their efficacy and safety. A promising base for research in the field of medicine and additional pharmacovigilance is social networks, in which experience and knowledge are exchanged between researchers, doctors, and patients, as well as information about the potential risks and benefits of using drugs for medical purposes is disseminated. The aim of this study was to investigate the reported efficiency and safety of medical use of cannabinoids in patients using posts on the social media Instagram and analyze the observed trends.
Methods
Social media listening platform Apify was used to collect data with hashtags as of June 4, 2024, including posts from 2023 and 2024, with some data extending into later periods, in compliance with a systematic approach to data collection. The analysis of the data obtained from the research was conducted using the RStudio platform.
Results
The analysis covered 1,466 posts containing hashtags related to cannabinoids. The posts studied were categorized as follows: 33.08% focused on advertising and commercialization, 25.58% on personal experience, 21.35% on other topics, and 19.99% contained educational content. An analysis of overall content relevance found that the majority of Instagram posts (81.79%) related to cannabis and cannabinoid hashtags are relevant. Most of the Instagram posts studied were posters, followed by personal photos and videos. The analysis shows that English dominates the studied category (70.74% of posts), while German, French, Spanish, and other languages also occupy a significant place, emphasizing the importance of a multilingual approach in content analysis. It has been revealed that organizations publish a larger percentage of posts under this study, with a higher percentage of relevance. Personal experience stories receive a significant number of “likes” indicating a strong emotional connection between audience and content. Instagram discussions about cannabinoid treatment support evidence from scientific studies about their effectiveness in treating a range of diseases, such as epilepsy with Lennox–Gastaut and Dravet syndromes, multiple sclerosis, cancer, and HIV-cachexia, nausea and vomiting caused by chemotherapy. At the same time, they emphasize the need for further clinical studies to better assess safety, side effects, and optimal dosages. Advertising and commercial posts can contribute to increased cannabis use, highlighting the need to raise awareness of risks and strengthen preventive measures.
Conclusion
Analysis of content on the social media Instagram can complement traditional scientific research by providing information on the real use of cannabis and its derivatives, contributing to the development of safe and effective recommendations for its use.
... A lower percentage improvement was assumed in part because it was an unblinded observational study, with a self-selecting sample in many regards. The placebo effect is always a consideration with any drug, the mechanism of action on pain by cannabinoids is, however, well documented [65][66][67], with studies on the analgesic effects on THC dating back as early as 1972 [68]. We acknowledge both the benefits and limitations of working with Real-World Evidence; the evidence on the efficacy of CBPMs on pain in the UK is still emerging, but the majority of studies suggest that a 5% increase is a conservative value to use in the model [10]. ...
Abstract
Background: Cannabis-based medicinal products (CBMPs) are increasingly demonstrating effectiveness in treating a wide range of conditions, with a relatively high safety profile in clinical usage compared to other prescription pain medications and few contraindications. Consultation and other prescription-related costs are, at present, higher for CBMPs than for some other treatment options, leading to some concern around wider prescribing.
Research design and methods: An early cost-effectiveness model was developed to estimate the impact of prescribing CBMPs alone and/or in addition to analgesics, physiotherapy, and cognitive behavioral therapy for chronic pain in the UK for 1 year.
Results: Due to their comparative effectiveness, CBMPs were found to be cost saving. Various scenarios were model tested; in all scenarios where CBMPs decrease pain-level states, less resource use is required. Increased efficacy of 5% was conservatively assumed based on current Real-World Evidence. In this scenario, CBMPs were significantly more cost-effective, and as costs relating to the prescribing of these continue to fall, relative savings are predicted to increase.
Conclusion: These findings highlight the substantial cost saving that CBMPs may represent for the treatment of chronic pain patients, and the benefits for healthcare providers as a treatment for this often hard-to-treat population.
Keywords: CBD; CBPMs; THC; cannabis; chronic pain; health economics; real world evidence.
... There is evidence that both CBD and THC may suppress nociceptive transmission, exerting an important role in pain modulation [3]. THC is recognized as a potent psychoactive molecule and when added to cannabis products may increase the risk of undesirable effects, such as ataxia and cognitive and behavioral changes [1,2]. ...
The aim of this study was to evaluate the perioperative analgesic and sedative effects of oral CBD in cats undergoing ovariohysterectomy. Twenty-two cats were assigned to receive either oral cannabidiol oil (2 mg/kg, CBD group, n = 12) or placebo oil (0.1 mL/kg, Placebo group, n = 10) 60 min before the premedication. The anesthetic protocol included dexmedetomidine/meperidine, propofol, and isoflurane. Intravenous fentanyl was given to control cardiovascular responses to surgical stimulation. Pain was assessed at 0.5, 1, 2, 4, 6 and 8 h post-extubation using the UNESP–Botucatu multidimensional composite pain scale and the Glasgow feline composite-measure pain scale. Sedation scores were assessed at the same timepoints and at 15 min after the premedication. Morphine was administered as rescue analgesia. Higher sedation scores were recorded in the CBD group at 15 min after premedication (p = 0.041). Intraoperatively, more cats required fentanyl in the Placebo group than in CBD group (p = 0.028). The pain scores did not differ between groups, except at 0.5 h post-extubation when lower scores were detected in the CBD group (p = 0.003–0.005). Morphine was required in 100% of the animals in both groups. CBD increased preoperative sedation and decreased intraoperative analgesic requirements, with minimal evidence of postoperative analgesic benefits over the placebo.
... The eCB are then released from the postsynaptic neuron to bind to and activate the CB 1 receptor on the presynaptic neuron, which in turn results in the inhibition of synaptic transmission [29,30,32]. The CB 1 receptor also binds the phytocannabinoid Δ9-THC and this mechanism of action, i.e. acting as "a brake" on neural transmission, may at least partially explain the analgesic [33,34] and psychotropic effects of Δ9-THC [35,36]. While the CB 1 receptors ...
Over forty years of evidence supports the integration of exercise therapy in cancer care. However, most cancer patients remain insufficiently active due in part to subjectively reported treatment-related side effects (and late effects) including fatigue, pain, appetite dysregulation, insomnia, cognitive impairment, depression, anxiety, low self-efficacy, and poor motivation. Many of these symptoms can be mitigated with exercise. However, the biological mechanisms by which exercise attenuates these cancer treatment-related side effects remain to be elucidated. This article presents a rationale for the investigation of endocannabinoid system (ECS) responses to exercise in cancer patients. We provide an overview of the ECS and preliminary evidence of ECS dysfunction induced by cancer, its risk factors (comorbidities) and cancer treatment. Further, we present a brief review of evidence from non-cancer cohorts demonstrating that acute (single bout) and chronic (>12 week) exercise can induce changes in circulating endo-cannabinoids (e.g. N-arachidonoylethanolamine (AEA or anandamide), 2-arachidonoylglycerol (2-AG) and related biogenic lipids). These changes are consistently accompanied by improvements in many subjectively reported, af-fective (mood) states (i.e. psychological outcomes) including sense of well-being, euphoria, vigour, anxiety, depression, fatigue, confusion, tension, mood disturbance, and pain. Given the substantial overlap between these subjective outcomes and the adverse effects that commonly arise as a consequence of cancer treatment, we clarify avenues for future research directed at improving our understanding of how cancer treatments negatively affect the ECS and patient symptomology, and how exercise may biologically mitigate these sequelae.
... Additionally, cannabinoids like THC and CBD act as positive allosteric modulators of specific subtypes of these ion channels, further contributing to pain relief [311,315]. Cannabinoids target nuclear receptors such as PPAR-γ, which regulate gene expression and have been implicated in neuropathic pain [316,317]. Activation of PPAR-γ by cannabinoids mediates their anti-allodynic effects in neuropathic pain models [318][319][320][321]. In addition to cannabinoid receptors, cannabinoids also interact with other G protein-coupled receptors such as 5-HT1A and GPR55 [318,319,321,322]. ...
Neurological disorders present a wide range of symptoms and challenges in diagnosis and treatment. Cannabis sativa, with its diverse chemical composition, offers potential therapeutic benefits due to its anticonvulsive, analgesic, anti-inflammatory, and neuroprotective properties. Beyond cannabinoids, cannabis contains terpenes and polyphenols, which synergistically enhance its pharmacological effects. Various administration routes, including vaporization, oral ingestion, sub-lingual, and rectal, provide flexibility in treatment delivery. This review shows the therapeutic efficacy of cannabis in managing neurological disorders such as epilepsy, neurodegenerative diseases, neurodevelopmental disorders, psychiatric disorders, and painful pathologies. Drawing from surveys , patient studies, and clinical trials, it highlights the potential of cannabis in alleviating symptoms , slowing disease progression, and improving overall quality of life for patients. Understanding the diverse therapeutic mechanisms of cannabis can open up possibilities for using this plant for individual patient needs.
... Anandamide is one of the best-known endogenous agonists recognized to play an important role in pain transmission. Surprisingly the role of AEA in the modulation of spinal cord nociceptive transmission was not studied in great detail [12,54,55] while the role of its target receptors CB 1 and TRPV1 was evaluated in numerous papers [56][57][58][59][60][61]. The dual role of AEA in the activation of these receptors could also be a complication and one of the reasons for the unsuccessful clinical trials with FAAH inhibitor [62]. ...
... Cannabinoids, endocannabinoids, and synthetic cannabimimetic agents have been extensively documented as powerful agents to control pain sensitization and transmission at both central and peripheral levels for their action on key cellular pathways [65]. In this regard, it was demonstrated that the endocannabinoid system is active in spinal and supraspinal structures regulating the pain sensation with the two major endocannabinoids AEA and 2-AG acting as antinociceptive agents through mechanisms depending on CB1 and CB2 receptors [65][66][67][68][69]. Overall, besides acting on CB1 and CB2 receptors, plant-derived cannabinoids and endocannabinoids are known to regulate the pain sensation and response through many other targets including G protein-coupled receptor (GPCR) 55, GPR18, opioid and serotonin receptors, PPARs, cys loop ligand-gated ion channels, and transient receptor potential (TRP) channels (TRPV1, TRPA, and TRPM subfamilies) [70][71][72]. Hence, the complex polyvalent pharmacological proprieties of cannabinoids, endocannabinoids, and derivates in pain mechanisms have been explored in a large number of preclinical studies [66,70,73,74]. ...
Neuromuscular disorders (NMDs) encompass a large heterogeneous group of hereditary and acquired diseases primarily affecting motor neurons, peripheral nerves, and the skeletal muscle system. The symptoms of NMDs may vary depending on the specific condition, but some of the most common ones include muscle weakness, pain, paresthesias, and hyporeflexia, as well as difficulties with swallowing and breathing. NMDs are currently untreatable. Therapeutic options include symptomatic and experimental medications aimed at delaying and alleviating symptoms, in some cases supplemented by surgical and physical interventions. To address this unmet medical need, ongoing research is being conducted on new treatments, including studies on medical cannabis, endocannabinoids, and related molecules with cannabimimetic properties. In this context, a significant amount of knowledge about the safety and effectiveness of cannabinoids in NMDs has been obtained from studies involving patients with multiple sclerosis experiencing pain and spasticity. In recent decades, numerous other preclinical and clinical studies have been conducted to determine the potential benefits of cannabinoids in NMDs. This review article aims to summarize and provide an unbiased point of view on the current knowledge about the use of cannabinoids, endocannabinoids, and synthetic analogs in NMDs, drawing from an array of compelling studies.
... The endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide, are endogenous ligands for cannabinoid receptors. 3 Modulation of the endocannabinoid system has emerged as a potential strategy to treat chronic pain, including pain resulting from OA. 4 Cannabinoid receptor agonists and inhibitors of the anandamide catabolizing enzyme fatty acid amide hydrolase (FAAH) have demonstrated efficacy in preclinical models of OA pain. 5,6 However, a clinical trial of a FAAH inhibitor unexpectedly failed to produce analgesia in OA patients. ...
Background: Osteoarthritis (OA) is a progressive degenerative joint disease that presents with significant pain and functional disability. The endocannabinoid 2-arachidonoylglycerol activates cannabinoid receptors to reduce pain while its hydrolysis by the enzyme monoacylglycerol lipase (MAGL) generates arachidonic acid, the direct precursor to proalgesic eicosanoids synthesized by cyclooxygenase-2 (COX-2), highlighting the potential for crosstalk between MAGL and COX-2. While COX-2 expression in human OA cartilage has been described, the distribution of MAGL in knee osteochondral tissue has not been reported and was the goal of the current study. Methods: MAGL and COX-2 expression in International Cartilage Repair Society grade II and grade IV knee osteochondral tissue obtained from male and female subjects with OA was investigated through immunohistochemistry. Immunolocalization of both proteins was investigated within articular cartilage and subchondral bone. Results: MAGL is expressed throughout the cartilage of grade II arthritic tissue, with prominent distribution in the superficial and deep zones. Elevated expression of MAGL was evident in grade IV samples, with additional distribution observed in subchondral bone. COX-2 expression followed a similar pattern, with uniform distribution in cartilage and increased expression in grade IV tissue. Conclusions: This study establishes MAGL expression in arthritic cartilage and subchondral bone of subjects with OA. The proximity between MAGL and COX-2 suggests the potential for crosstalk between endocannabinoid hydrolysis and eicosanoid signaling in the maintenance of OA pain.
... Há também evidências expressivas de receptor CB2 no corno dorsal da medula espinhal, atuando com a dor neuropática ou inflamatória. 19 Outro estudo aponta que, a maioria dos pacientes acredita que a Cannabis é um tratamento válido e que tem um papel na redução da dor pós-operatória e póslesão, pois sentiram que aliviou os sintomas de dor e reduziu a ingestão de opioides. ...
Há muitos anos os seres humanos desenvolvem tecnologias com o intuito de explorar o espaço através de viagens espaciais, submetendo os astronautas aos possíveis efeitos que essas viagens possam causar. Importantes alterações ocorrem no organismo humano, levando ao surgimento de algumas complicações, como: alterações no sistema imune; no sistema nervoso; no trato gastrointestinal; osteoporose; e processos de dor. Projetos buscam fornecer a melhor experiência para a espécie humana, fora do ambiente terrestre para as limitações encontradas durante e/ou depois de uma missão espacial. O presente artigo busca trazer o enfoque para o potencial uso da Cannabis medicinal, apresentando-a como uma alternativa altamente eficaz para essas questões. A planta Cannabis sativa L, cresce em ambiente controlado, com um ciclo médio de cultivo de três meses, podendo ser cultivada durante viagens espaciais de longa duração. Seu emprego no controle da dor; na regulação da atividade osteolítica, combatendo a osteoporose; no sistema imunológico, atuando também no microbioma intestinal; e na neuroproteção, a coloca em evidência para futuros avanços da fitofarmacologia aeroespacial. Restrições à pesquisa com a planta devem ser cada vez mais relaxadas para que se permita o avanço e emprego desta medicina milenar em um campo promissor, mais uma vez acompanhando o ser humano em suas explorações, como nas grandes navegações do século XV. Deve-se, assim, incentivar o fomento de pesquisas com a Cannabis para proporcionar aos astronautas uma viagem mais saudável, segura e com um maior potencial de sucesso.
... AEA and 2-AG, two dominant endocannabinoids, are present in key regions involved in the detection, relay and integration of nociceptive inputs, that include skin, DRG, spinal cord dorsal horn, periaqueductal gray (PAG) and rostral ventromedial medulla [33,37]. Previous studies have shown that following the induction of inflammatory and neuropathic pain, cannabinoid receptors and their endogenous ligands AEA and 2-AG are elevated in various regions of the pain pathway [38,39], suggesting that enhancement of endocannabinoid signaling might combat pain. ...
Chronic neuropathic pain resulting from peripheral nerve damage is a significant clinical problem, which makes it imperative to develop the mechanism-based therapeutic approaches. Enhancement of endogenous cannabinoids by blocking their hydrolysis has been shown to reduce inflammation and neuronal damage in a number of neurological disorders and neurodegenerative diseases. However, recent studies suggest that inhibition of their hydrolysis can shift endocannabinoids 2-arachidonoyl glycerol (2-AG) and anandamide (AEA) toward the oxygenation pathway mediated by cyclooxygenase-2 (COX-2) to produce proinflammatory prostaglandin glycerol esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs). Thus, blocking both endocannabinoid hydrolysis and oxygenation is likely to be more clinically beneficial. In this study, we used the chronic constriction injury (CCI) mouse model to explore the therapeutic effects of simultaneous inhibition of AEA hydrolysis and oxygenation in the treatment of neuropathic pain. We found that the fatty acid amide hydrolase (FAAH) inhibitor PF04457845 and the substrate-selective COX-2 inhibitor LM4131 dose-dependently reduced thermal hyperalgesia and mechanical allodynia in the CCI mice. In addition to ameliorating the pain behaviors, combined treatment with subeffective doses of these inhibitors greatly attenuated the accumulation of inflammatory cells in both sciatic nerve and spinal cord. Consistently, the increased proinflammatory cytokines IL-1β, IL-6, and chemokine MCP-1 in the CCI mouse spinal cord and sciatic nerve were also significantly reduced by combination of low doses of PF04457845 and LM4131 treatment. Therefore, our study suggests that simultaneous blockage of endocannabinoid hydrolysis and oxygenation by using the substrate-selective COX-2 inhibitor, which avoids the cardiovascular and gastrointestinal side effects associated with the use of general COX-2 inhibitors, might be a suitable strategy for the treatment of inflammatory and neuropathic pain.
Mobility disability (MD) manifests as walking dysfunction and postural instability in more than 90% of people with multiple sclerosis (MS) within 10 years of disease onset. Disease-modifying pharmacotherapies reduce rates of relapses and new lesions and slow disease progression, but ongoing decline in MD can persist or result from secondary, symptomatic pharmacotherapies. This systematic review focuses on symptomatic pharmacotherapies that potentially impact markers of MD in MS.
PubMed/Medline, Google Scholar, and Scopus were searched between January 1990 and December 2024. Eligible studies were included on the basis of the following criteria: (1) randomized, placebo-controlled trials (RCTs); (2) confirmed MS diagnosis; (3) one MD-related outcome; and (4) one symptomatic pharmacotherapy; OR (5) multiple doses of a symptomatic pharmacotherapy. Results were uploaded to Rayyan: Intelligent Systematic Review software and screened by two blinded reviewers for eligibility. Risk of bias was assessed using the PEDRo Scale for quality assessment.
This review included 23 RCTs (all RCTs scored good-to-excellent on PEDRo Scale); 13 RCTs examined fampridine (4-aminopyridine) for its direct effects on MD, and 10 RCTs assessed indirect effects of symptomatic pharmacotherapies, including cannabinoids (n = 9), and baclofen (n = 1) on MD. The MD outcomes included gait (25-foot walk [T25FW], kinetics, and kinematics), community mobility (12-item MS Walking Scale [MSWS-12]), endurance (6-min walk [6MW]), balance (Berg Balance Scale [BBS], Dynamic Gait Index [DGI], Six-Spot Step Test, posturography, and falls), and functional mobility (Timed Up and Go [TUG] and 5 Times Sit-to-Stand [5STS]). Fampridine significantly improved gait (T25FW, MSWS-12), endurance (6MW), and functional mobility (5STS, TUG), with the largest effect on gait speed; changes in balance were inconclusive. Indirect pharmacotherapies, specifically cannabinoids mainly reduced spasticity (Modified Ashworth Scale, nine out of nine studies), but rarely improved pain (Numerical Rating Scale, two out of nine studies) or MD outcomes (two out of nine studies). Both direct and indirect pharmacotherapies resulted in adverse effects, notably dizziness (n = 366), urinary tract infection (n = 216), and nausea (n = 150), potentially impacting MD in MS.
Fampridine may improve gait and functional mobility in MS, but its effect on balance requires further investigation in RCTs. Cannabinoids and baclofen may alleviate spasticity and pain, but seemingly have limited secondary effect on markers of MD, such as gait and postural stability. Clinicians should consider the impact of symptomatic pharmacotherapies on MD in MS, including potential side effects. Future research should explore integrating rehabilitation (e.g., balance training) with symptomatic pharmacotherapies, as this might enhance positive effects or combat deleterious effects on markers of MD.
We present a novel, multicomponent nanoparticulate carrier system based on superparamagnetic iron oxide nanoparticles with a designed hydrophilic/hydrophobic balance based on oleic acid and TWEEN 80 to incorporate hydrophobic cannabinoids—cannabigerol and cannabidiol—as well as the hydrophilic anthracycline drug epirubicin, forming a conjugate anticancer system. Additionally, the superparamagnetic iron oxide-based nanoparticles formed the core of the system, thus providing it with magnetic hyperthermia capabilities with a specific absorption rate comparable to the corresponding systems in the literature. The interaction of the conjugate with the cell membrane was studied using the Langmuir monolayers at the air/water interface formed of selected lipids modeling the healthy and cancerous cell membranes. Finally, cytotoxicity tests were carried out against the SKOV-3 cell line in vitro. A synergistic effect was observed when both the cannabinoid and epirubicin were present in the conjugate, as compared to the cannabinoid or epirubicin alone, making our system advantageous for further development for tentative therapeutic use.
Background
Chronic neuropathic pain (CNP) is a debilitating condition, often refractory to currently available drugs. Understanding biochemical alterations in peripheral tissues such as blood will be useful for understanding underlying pathophysiological processes relating to CNP.
Methods
We collected blood from two independent cohorts of CNP and pain‐free controls (CNP n = 129/Controls n = 127) in the UK and Ireland to investigate the relationship between CNP‐associated molecular/biochemical alterations and a range of clinical and pain metric parameters. Multiple statistical comparisons were conducted on the data, with selected variables included in one or more of the intended inferential analyses (six models).
Results
Gene expression analysis showed that choline phosphotransferase ( CHPT1 ) was increased ( p < .001) in the CNP group compared to controls. The levels of phosphatidylcholine, a metabolite of CHPT1 in the Kennedy Pathway, were significantly ( p = .008) decreased in the plasma of patients with CNP. Given the relationship between the Kennedy pathway and endocannabinoids, plasma endocannabinoids and related N‐ acylethanolamines were quantified in clinical samples by HPLC‐Tandem Mass Spectrometry. Plasma levels of the endocannabinoid 2‐arachidonoylglycerol were higher in CNP samples compared to controls, and in the statistical models applied, 2‐arachidonoylglycerol significantly increased the odds of CNP ( p < .001). The expression of genes related to the synthesis and catabolism of endocannabinoids also corroborated the increased plasma 2‐arachidonoylglycerol levels in patients with CNP.
Conclusions
Endocannabinoid levels, expression of genes related to endocannabinoid metabolism, age, sex, depression and anxiety state together were strong predictors of CNP. The observed molecular changes indicate that lipid metabolism is altered in CNP and thus may represent a viable target for novel analgesics or biomarker development.
Kashtartava (Dysmenorrhea) is a prevalent co-morbidity in women. The name "Kashtartava" might be inferred as the condition in which Artava sheds pain, which can be associated with Dysmenorrhea. Around the world, 50-90% of women in their reproductive years report having painful periods, a disorder known as Dysmenorrhea. In this review article, we delved into the traditional uses, pharmacological properties and challenges associated with using Bhanga (Cannabis sativa Linn) for managing Kashtartava and its related effects. Research expedition sheds light on the potential therapeutic benefits, mainly focusing on its active component, tetrahydrocannabinol (THC), which exhibits analgesic, anti-inflammatory, antiemetic, and neuroprotective properties. This review highlights the challenges in conducting rigorous research on using the herb during menstruation and pregnancy, owing to study design limitations and confounding variables. This legal ambiguity underscores the importance of understanding and addressing the cultural and legal context surrounding its use in contemporary healthcare prac-tices. Moreover, the psychoactive nature of THC raises concerns regarding its impact on mood and cognition, warranting cautious consideration in clinical applications.
Introduction:
This review highlights the critical role of the endocannabinoid system (ECS) in regulating neuropathic pain and explores the therapeutic potential of cannabinoids. Understanding the mechanisms of the ECS, including its receptors, endogenous ligands, and enzymatic routes, can lead to innovative treatments for chronic pain, offering more effective therapies for neuropathic conditions. This review bridges the gap between preclinical studies and clinical applications by emphasizing ECS modulation for better pain management outcomes.
Areas covered:
A review mapped the existing literature on neuropathic pain and the effects of modulating the ECS using natural and synthetic cannabinoids. This analysis examined ECS components and their alterations in neuropathic pain, highlighting the peripheral, spinal, and supraspinal mechanisms. This review aimed to provide a thorough understanding of the therapeutic potential of cannabinoids in the management of neuropathic pain.
Expert opinion:
Advances in cannabinoid research have shown significant potential for the management of chronic neuropathic pain. The study emphasizes the need for high-quality clinical trials and collaborative efforts among researchers, clinicians, and regulatory bodies to ensure safe and effective integration of cannabinoids into pain management protocols. Understanding the mechanisms and optimizing cannabinoid formulations and delivery methods are crucial for enhancing therapeutic outcomes.
O DSM-V-TR 2022 (Manual Diagnóstico e Estatístico de Transtornos Mentais), considera o TDAH um dos transtornos do neurodesenvolvimento, caracterizados por déficits de desenvolvimento ou diferenças nos processos cerebrais causadores de prejuízos no funcionamento pessoal, social, acadêmico e/ou ocupacional.
Para haver diagnóstico de TDAH, é necessário padrão persistente dos principais sintomas: desatenção e/ou hiperatividade-impulsividade, interferindo no funcionamento e no desenvolvimento da pessoa. Vários dos sintomas de desatenção ou hiperatividade-impulsividade devem estar presentes antes dos 12 anos, em dois ou mais ambientes (p. ex., em casa, na escola, no trabalho; com amigos ou parentes), precisam interferir ou reduzir a qualidade do funcionamento social, acadêmico ou profissional, além de não ocorrerem exclusivamente durante o curso de esquizofrenia ou outro transtorno psicótico e não serem melhor explicados por outro transtorno mental.
Este estudo aborda o TDAH de forma ampla e elucidativa, com enfoque na vida adulta e no comprometimento das funções executivas, ou seja, das habilidades relacionadas à capacidade de empenho em comportamentos orientados a objetivos e à realização de ações voluntárias, independentes, autônomas, auto-organizadas e direcionadas a metas específicas.
Abordou-se de forma pontual algumas das principais funções executivas, como: controle inibitório, memória de trabalho, flexibilidade cognitiva, atenção, resolução de problemas, tomada de decisões, processamento de informações, inteligência, regulação emocional, planejamento e organização.
O objetivo principal deste trabalho é nortear, através de informações científicas e atuais, os interessados na temática: profissionais da área da saúde, pais, educadores, cuidadores e pessoas com o transtorno, auxiliando na busca pelo esclarecimento de dúvidas e na reflexão sobre o TDAH, que impacta de forma significativa as dinâmicas sociais, familiares, emocionais e econômicas.
Objetiva-se promover a conscientização, demonstrar algumas das mais importantes formas de tratamento e estratégias para o adulto com o transtorno poder viver de modo funcional em sociedade, com bem-estar e enfrentando de forma positiva os desafios cotidianos.
A metodologia empregada consistiu em aprofundada análise bibliográfica, de artigos
científicos, revistas científicas (p. ex: Oxford University Press, Oxford American Psychiatry Press, Cambridge University Press, Humana Press), sites especializados (p. ex.: NIH - National Institute of Mental Health, Nature, ADDitude, Frontiers in Psychiatry), sobretudo em bancos de dados, como Springer, Researchgate, Google Acadêmico, Scopus-Elsevier, Scielo, PubMed, Cochrane, Routledge, MDPI.
Este e-book foi desenvolvido visando alcance amplo e elucidativo, a fim de levar à população conhecimento sobre o TDAH, demonstrando que o diagnóstico não
é uma sentença final, mas o caminho para encontrar tratamentos e estratégias eficazes, capazes de tornar melhor a vida da pessoa com o transtorno.
Cannabinoids and their receptors play a significant role in the regulation of gastrointestinal (GIT) peristalsis and intestinal barrier permeability. This review critically evaluates current knowledge about the mechanisms of action and biological effects of endocannabinoids and phytocannabinoids on GIT functions and the potential therapeutic applications of these compounds. The results of ex vivo and in vivo preclinical data indicate that cannabinoids can both inhibit and stimulate gut peristalsis, depending on various factors. Endocannabinoids affect peristalsis in a cannabinoid (CB) receptor-specific manner; however, there is also an important interaction between them and the transient receptor potential cation channel subfamily V member 1 (TRPV1) system. Phytocannabinoids such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) impact gut motility mainly through the CB1 receptor. They were also found to improve intestinal barrier integrity, mainly through CB1 receptor stimulation but also via protein kinase A (PKA), mitogen-associated protein kinase (MAPK), and adenylyl cyclase signaling pathways, as well as by influencing the expression of tight junction (TJ) proteins. The anti-inflammatory effects of cannabinoids in GIT disorders are postulated to occur by the lowering of inflammatory factors such as myeloperoxidase (MPO) activity and regulation of cytokine levels. In conclusion, there is a prospect of utilizing cannabinoids as components of therapy for GIT disorders.
Postoperative pain (POP) is a challenging clinical phenomenon that affects the majority of surgical patients and demands effective management to mitigate adverse outcomes such as persistent pain. The primary goal of POP management is to alleviate suffering and facilitate a seamless return to normal function for the patient. Despite compelling evidence of its drawbacks, opioid analgesia remains the basis of POP treatment. Novel therapeutic approaches rely on multimodal analgesia, integrating different pharmacological strategies to optimize efficacy while minimizing adverse effects. The recognition of the imperative role of the endocannabinoid system in pain regulation has prompted the investigation of cannabinoid compounds as a new therapeutic avenue. Cannabinoids may serve as adjuvants, enhancing the analgesic effects of other drugs and potentially replacing or at least reducing the dependence on other long-term analgesics in pain management. This narrative review succinctly summarizes pertinent information on the molecular mechanisms, clinical therapeutic benefits, and considerations associated with the plausible use of various cannabinoid compounds in treating POP. According to the available evidence, cannabinoid compounds modulate specific molecular mechanisms intimately involved in POP. However, only two of the eleven clinical trials that evaluated the efficacy of different cannabinoid interventions showed positive results.
In this chapter, we delve into a comprehensive exploration of both pharmacological and surgical interventions for pain relief. These approaches are firmly rooted in our understanding of nociception pathways, which we thoroughly explored previously.
The pharmacological section of this chapter takes us through a diverse landscape of pain relief strategies. It encompasses essential treatments such as Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), pivotal for addressing the inflammatory components of pain, and anticonvulsants acting on ion channels. Moreover, we navigate through the intriguing realm of psychotropic medications, opioids, cannabinoids, anti-NMDA agents, and even psychedelics. Each of these approaches is meticulously examined, shedding light on their mechanisms of action, potential adverse effects, and considerations regarding tolerance and dependence.
The effective utilization of these pharmacological tools relies on a nuanced understanding of factors such as medication selection and dosage. We emphasize the multifactorial considerations that underpin the art of effective pharmacotherapy for pain relief.
Complementing our exploration of pharmacology, we venture into the domain of surgical interventions aimed at modulating nociceptive pathways within the central nervous system. Neurostimulation has emerged as a frequently employed technique for managing pain perception. This involves precise stimulation at various trigger points along pain pathways, including the spinal cord’s posterior column, somatosensory thalamus, and motor cortex. Additionally, we delve into the intriguing field of psychosurgery, which targets both the sensory and affective components of pain perception.
This chapter serves as an in-depth examination of the fundamental techniques that drive pain alleviation in clinical practice. It offers a comprehensive overview of the latest therapeutic approaches used in the clinic, reflecting the ongoing evolution of pain management strategies. Our ultimate goal is to provide insights into the most current and effective methods for pain alleviation, equipping clinicians with the knowledge they need to optimize patient care.
Cannabis sativa is one of the oldest medicinal plants in human history. Even ancient physicians from hundreds of years ago used Cannabis sativa to treat several conditions like pain. In the modern era, the research community, including health-care providers, have witnessed wide-scale changes in cannabis policy, legislation, and marketing, with a parallel increase in patient interest. A simple search in PubMed using “cannabis and pain” as keywords provides more than 2,400 articles, about 80% of which were published in the last 8–10 years. Several advancements have been achieved in understanding the complex chemistry of cannabis along with its multiple pharmacological activities. Preclinical data have demonstrated evidence for the promising potential of cannabis for pain management, and the continuous rise in the prevalence of pain increases the urgency to translate this into clinical practice. Despite the large body of cannabis literature, researchers still need to find rigorous answers for the questions about the efficacy and safety of cannabis in treatment of certain disorders such as pain. In the current chapter, we seek to present a critical overview about the current knowledge on cannabis with special emphasis on pain-related disorders.
The Cannabis sativa plant, for its analgesic, anti-inflammatory, antiemetic, and anticonvulsant properties, has been used for thousands of years in Chinese, Indian, and Greek cultures and was introduced into Western medicine in the 19th century. There has been a rise in interest in cannabinoids since the main substances of cannabis were identified, as well as the recognition that the endocannabinoid system (ECS) controls multiple processes in pain treatment and neurologic and mental illnesses. However, the ECS has also been associated with negative effects, including harmful effects on emotional and cognitive functions, the development of tolerance and dependence, and withdrawal symptoms after drug cessation in humans. We recently found that repeated intraperitoneal administration of the two main components of cannabis, delta-9-tetrahydrocannabinol (THC) and cannabinolic acid (CBNA), led to the development of tolerance in male mice. In this review, we focus on the evidence demonstrating cannabinoid tolerance in animals. The common mechanisms and main signaling pathways for cannabinoid tolerance, including neuroadaptations primarily at cannabinoid 1 (CB1) receptors, such as desensitization and downregulation, which are mediated by several signaling pathways, are discussed.
Low back pain (LBP) is a major unmet clinical need. The
endocannabinoid system (ECS) has emerged as a promising
therapeutic target for pain, including LBP. This review examines the evidence for the ECS as a therapeutic target for LBP.
While preclinical studies demonstrate the potential of the ECS
as a viable therapeutic target, clinical trials have presented
conflicting findings. This review underscores the need for
innovative LBP treatments and biomarkers and proposes the
ECS as a promising avenue for their exploration. A deeper
mechanistic understanding of the ECS in LBP could inform the
development of new pain management strategies.
Approximately 60% of individuals with a spinal cord injury (SCI) experience neuropathic pain, which often persists despite the use of various pharmacological treatments. Increasingly, the potential analgesic effects of cannabis and cannabinoid products have been studied; however, little research has been conducted among those with SCI-related neuropathic pain. Therefore, the primary objective of the study was to investigate the perceived effects of cannabis and cannabinoid use on neuropathic pain among those who were currently or had previously used these approaches. Additionally, the study aimed to determine if common pain medications are being substituted by cannabis and cannabinoids. Participants (N = 342) were recruited from existing opt-in listserv sources within the United States. Of those, 227 met the inclusion criteria and were enrolled in the study. The participants took part in an anonymous online survey regarding past and current use of cannabis and their perceived effects on neuropathic pain, including the use of pain medication. Those in the sample reported average neuropathic pain intensity scores over the past week of 6.8 ± 2.1 (0 to 10 scale), reflecting a high moderate to severe level of pain. Additionally, 87.9% noted that cannabis reduced their neuropathic pain intensity by more than 30%, and 92.3% reported that cannabis helped them to better deal with their neuropathic pain symptoms. Most participants (83.3%) also reported substituting their pain medications with cannabis, with the most substituted medication categories being opioids (47.0%), gabapentinoids (42.8%) and over-the-counter pain medications (42.2%). These preliminary results suggest that cannabis and cannabinoids may be effective in reducing neuropathic pain among those with SCI and may help to limit the need for certain pain medications.
Pain is generated by a small number of peripheral targets. These can be made more sensitive by inflammatory mediators. The number of opioids prescribed to the patients can be reduced dramatically with better pain management. Any therapy that safely and reliably provides extended analgesia and is flexible enough to facilitate a diverse array of release profiles would be useful for improving patient comfort, quality of care, and compliance after surgical procedures. Comparisons are made between new and traditional methods, and the current state of development has been discussed; taking into account the availability of molecular and cellular level data, preclinical and clinical data, and early post-market data. There are a number of benefits associated with the use of nanotechnology in the delivery of analgesics to specific areas of the body. Nanoparticles are able to transport drugs to inaccessible bodily areas because of their small molecular size. This review focuses on targets that act specifically or primarily on sensory neurons, as well as inflammatory mediators that have been shown to have an analgesic effect as a side effect of their anti- inflammatory properties. New, regulated post-operative pain management devices that use existing polymeric systems were presented in this article, along with the areas for potential development. Analgesic treatments, both pharmacological and non-pharmacological, have also been discussed.
The practice of pain medicine has changed dramatically over the past few years. This practical and accessible evidence-based clinical handbook provides medical and nursing professionals with in-depth and up-to-date information on the various types of chronic pain, the underlying causes, and associated symptoms. Focused primarily on the management of chronic pain, the book covers the major chronic pain conditions in the head and neck, spine, and extremities. Also, it provides invaluable guidance on various pain management techniques, including medication, physical therapy, and psychological interventions. With this knowledge, healthcare professionals will be equipped to provide more effective and compassionate care, improve patients' quality of life, and reduce the risk of chronic pain and opioid dependence. An invaluable resource for pain medicine physicians, anesthesiologiests, primary care physicians, emergency medicine physicians, and nurse anaesthetists as well as those physicians preparing for US Board certification and recertification exams.
Pancreatic cancer presents with complicated symptoms that require management alongside cancer treatments to improve patient’s quality of life during treatment. Pain in pancreatic cancer is frequently present as the first sign of disease; its etiology is multifactorial, consisting of pancreatic enzyme insufficiency, neuropathic pain, inflammation, obstruction, and direct mass effect from the tumor. Proper pain management is crucial in the overall management of these patients. Non-steroidal anti-inflammatories and acetaminophen are typically used as first-line therapy, followed by opioids and other treatments reviewed here, including disease-specific treatment with chemotherapy and radiation to manage pain by reducing obstruction and decreasing inflammation. Nerve blocks, high-intensity focused ultrasound, and other integrative measures with supplements and acupuncture have also been studied to treat pain in pancreatic cancer. The implementation of these measures may improve the quality of life of these patients.
Introduction: Complex regional pain syndrome type I (CRPS-I) is a debilitating neuropathic painful condition associated with allodynia, hyperalgesia, sudomotor and/or vasomotor dysfunctions, turning investigation of its pathophysiology and new therapeutic strategies into an essential topic. We aim to investigate the impact of ischemia/reperfusion injury on the immunocontent of CB1 and CB2 cannabinoid receptor isoforms in the paws of mice submitted to a chronic postischemia pain (CPIP) model and the effects of local administration of cannabidiol (CBD) on mechanical hyperalgesia. Methods: Female Swiss mice, 30-35 g, were submitted to the CPIP model on the right hind paw. Skin and muscle samples were removed at different periods for western blot analysis. Results: No changes in the immunocontent of CB1 and CB2 receptors in paw muscle tissues after ischemia-reperfusion were observed. CBD promoted an antihyperalgesic effect in both phases. AM281 reversed the effect of CBD, whereas ruthenium red abolished the late phase. Conclusion: Our results point to the possible beneficial effects of local administration of CBD in modulating CRPS-I in humans. As possible targets for CBD antihyperalgesia in this model, the contribution of cannabinoid receptor CB1, in addition to TRPM8 is suggested.
Cannabis sativa is widely used as a folk medicine in many parts of the globe and has been reported to be a treasure trove of phytoconstituents, including cannabinoids, terpenoids, and flavonoids. Accumulating evidence from various pre-clinical and clinical studies revealed the therapeutic potential of these constituents in various pathological conditions, including chronic pain, inflammation, neurological disorders, and cancer. However, the psychoactive effect and addiction potential associated with cannabis use limited its clinical application. In the past two decades, extensive research on cannabis has led to a resurgence of interest in the clinical application of its constituents, particularly cannabinoids. This review summarizes the therapeutic effect and molecular mechanism of various phytoconstituents of cannabis. Furthermore, recently developed nanoformulations of cannabis constituents have also been reviewed. Since cannabis is often associated with illicit use, regulatory aspects are of vital importance and this review therefore also documented the regulatory aspects of cannabis use along with clinical data and commercial products of cannabis.
A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide-mounted sections of rat brain and pituitary. Assay conditions for 3H-CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.
The G-protein coupled receptor GPR55 has been postulated to serve as a novel cannabinoid receptor. A previous report indicated that GPR55 knockout mice fail to develop mechanical hyperalgesia, suggesting a pro-nociceptive role for GPR55 in the control of nociceptive responding. However, GPR55 knockout mice remain incompletely characterized in models of pathological pain. Here we provide a comprehensive assessment of responses of GPR55 knockout and wild-type mice to mechanical and thermal (heat, cold) stimulation in multiple, mechanistically distinct models of inflammatory and neuropathic pain. Inflammatory sensitization was produced by intraplantar administration of capsaicin, formalin or complete Freund's adjuvant. No differences in responding were detected between GPR55 knockout and wild-type mice in any model of inflammatory nociception assessed. Neuropathic pain was induced by partial sciatic nerve ligation (which induces hypersensitivity to mechanical, cold and heat stimulation) or by treatment with the chemotherapeutic agent paclitaxel (which induces hypersensitivity to mechanical and cold stimulation only). No differences were observed between GPR55 knockout and wild type mice in either development or maintenance of neuropathic nociception in either neuropathic pain model. In conclusion, genetic deletion of GPR55 did not alter the development of pathological pain in adult mice in any chronic pain model evaluated.
The G-protein coupled receptor 55 (GPR55) is activated by cannabinoids and non-cannabinoid molecules and has been speculated to play a modulatory role in a large variety of physiological and pathological processes, including in metabolically perturbed states. We therefore generated male mice deficient in the gene coding for the cannabinoid/lysophosphatidylinositol (LPI) receptor Gpr55 and characterized them under normal dietary conditions as well as during high energy dense diet feeding followed by challenge with the CB1 receptor antagonist/GPR55 agonist rimonabant. Gpr55 deficient male mice (Gpr55 KO) were phenotypically indistinguishable from their wild type (WT) siblings for the most part. However, Gpr55 KO animals displayed an intriguing nocturnal pattern of motor activity and energy expenditure (EE). During the initial 6 hours of the night, motor activity was significantly elevated without any significant effect observed in EE. Interestingly, during the last 6 hours of the night motor activity was similar but EE was significantly decreased in the Gpr55 KO mice. No significant difference in motor activity was detected during daytime, but EE was lower in the Gpr55 KO compared to WT mice. The aforementioned patterns were not associated with alterations in energy intake, daytime core body temperature, body weight (BW) or composition, although a non-significant tendency to increased adiposity was seen in Gpr55 KO compared to WT mice. Detailed analyses of daytime activity in the Open Field paradigm unveiled lower horizontal activity and rearing time for the Gpr55 KO mice. Moreover, the Gpr55 KO mice displayed significantly faster reaction time in the tail flick test, indicative of thermal hyperalgesia. The BW-decreasing effect of rimonabant in mice on long-term cafeteria diet did not differ between Gpr55 KO and WT mice. In conclusion, Gpr55 deficiency is associated with subtle effects on diurnal/nocturnal EE and motor activity behaviours but does not appear per se critically required for overall metabolism or behaviours.
Significance statement:
These studies demonstrate that endocannabinoid signaling to CB1- and CB2-receptors in adult RVM is altered in persistent inflammation. The emergence of CB2 receptor function in the RVM provides additional rationale for the development of CB2 receptor-selective agonists as useful therapeutics for chronic inflammatory pain.
This overview covers a wide range of cannabis topics, initially examining issues in dispensaries and self-administration, plus regulatory requirements for production of cannabis-based medicines, particularly the Food and Drug Administration “Botanical Guidance.” The remainder pertains to various cannabis controversies that certainly require closer examination if the scientific, consumer, and governmental stakeholders are ever to reach consensus on safety issues, specifically: whether botanical cannabis displays herbal synergy of its components, pharmacokinetics of cannabis and dose titration, whether cannabis medicines produce cyclo-oxygenase inhibition, cannabis-drug interactions, and cytochrome P450 issues, whether cannabis randomized clinical trials are properly blinded, combatting the placebo effect in those trials via new approaches, the drug abuse liability (DAL) of cannabis-based medicines and their regulatory scheduling, their effects on cognitive function and psychiatric sequelae, immunological effects, cannabis and driving safety, youth usage, issues related to cannabis smoking and vaporization, cannabis concentrates and vape-pens, and laboratory analysis for contamination with bacteria and heavy metals. Finally, the issue of pesticide usage on cannabis crops is addressed. New and disturbing data on pesticide residues in legal cannabis products in Washington State are presented with the observation of an 84.6% contamination rate including potentially neurotoxic and carcinogenic agents. With ongoing developments in legalization of cannabis in medical and recreational settings, numerous scientific, safety, and public health issues remain.
Compared with acute pain that arises suddenly in response to a specific injury and is usually treatable, chronic pain persists over time, and is often resistant to medical treatment. Because of the heterogeneity of chronic pain origins, satisfactory therapies for its treatment are lacking, leading to an urgent need for the development of new treatments. The leading approach in drug design is selective compounds, though they are often less effective and require chronic dosing with many side effects. Herein, we review novel approaches to drug design for the treatment of chronic pain represented by dual-acting compounds, which operate at more than one biological target. A number of studies suggest the involvement of the cannabinoid and vanilloid receptors in pain. Interestingly cannabinoid system is in interrelation with other systems that comprise lipid mediators: prostaglandins, produced by COX enzyme. Therefore, in the present review, we summarize the role of dual-acting molecules (FAAH/TRPV1 and FAAH/COX-2 inhibitors) that interact with endocannabinoid and endovanillinoid systems and act as analgesics by elevating the endogenously produced endocannabinoids and dampening the production of pro-inflammatory prostaglandins. The plasticity of the endocannabinoid system (ECS) and the ability of a single chemical entity to exert an activity on two receptor systems has been developed and extensively investigated. Here, we review up-to-date pharmacological studies on compounds interacting with FAAH enzyme together with TRPV1 receptor or COX-2 enzyme respectively. Multi-target pharmacological intervention for treating pain may lead to the development of original and efficient treatments.
Background:
The function of the Cannabinoid 1 receptor (CB1R) in the development of neuropathic pain is not clear. Mounting evidence suggest that CB1R expression and activation may contribute to pain. Cannabinoid 1 receptor knockout mice (CB1R-/-) generated on a C57Bl/6 background exhibit hypoalgesia in the hotplate assay and formalin test. These findings suggest that Cannabinoid 1 receptor expression mediates the responses to at least some types of painful stimuli. By using this mouse line, we sought to determine if the lack of Cannabinoid 1 receptor unveils a general hypoalgesic phenotype, including protection against the development of neuropathic pain. The acetone test was used to measure cold sensitivity, the electronic von Frey was used to measure mechanical thresholds before and after spared-nerve injury, and analysis of footprint patterns was conducted to determine if motor function is differentially affected after nerve-injury in mice with varying levels of Cannabinoid 1 receptor.
Results:
At baseline, CB1R-/- mice were hypersensitive in the acetone test, and this phenotype was maintained after spared-nerve injury. Using calcium imaging of lumbar dorsal root ganglion (DRG) cultures, a higher percentage of neurons isolated from CB1R-/- mice were menthol sensitive relative to DRG isolated from wild-type (CB1R+/+) mice. Baseline mechanical thresholds did not differ among genotypes, and mechanical hypersensitivity developed similarly in the first two weeks following spared-nerve injury (SNI). At two weeks post-SNI, CB1R-/- mice recovered significantly from mechanical hypersensitivity, while the CB1R+/+ mice did not. Heterozygous knockouts (CB1R+/-) transiently developed cold allodynia only after injury, but recovered mechanical thresholds to a similar extent as the CB1R-/- mice. Sciatic functional indices, which reflect overall nerve health, and alternation coefficients, which indicate uniformity of strides, were not significantly different among genotypes.
Conclusion:
Cold allodynia and significant recovery from spared-nerve injury-induced mechanical hypersensitivity are two novel phenotypes which characterize the global CB1R-/- mice. An increase in transient receptor potential channel of melastatin 8 channel function in DRG neurons may underlie the cold phenotype. Recovery of mechanical thresholds in the CB1R knockouts was independent of motor function. These results indicate that CB1R expression contributes to the development of persistent mechanical hypersensitivity, protects against the development of robust cold allodynia but is not involved in motor impairment following spared-nerve injury in mice.
Fatty-acid amide hydrolase (FAAH) is the major enzyme responsible for degradation of anandamide, an endocannabinoid. Pharmacological inhibition or genetic deletion of FAAH (FAAH KO) produces antinociception in preclinical pain models that is largely attributed to anandamide-induced activation of cannabinoid receptors. However, FAAH metabolizes a wide range of structurally related, biologically active lipid signaling molecules whose functions remain largely unknown. Some of these endogenous lipids, including anandamide itself, may exert pro-nociceptive effects under certain conditions. In our study, FAAH KO mice exhibited a characteristic analgesic phenotype in the tail flick test and in both formalin and carrageenan models of inflammatory nociception. Nonetheless, intradermal injection of the transient receptor potential channel V1 (TRPV1) agonist capsaicin increased nocifensive behavior as well as mechanical and heat hypersensitivity in FAAH KO relative to wild-type mice. This pro-nociceptive phenotype was accompanied by increases in capsaicin-evoked Fos-like immunoreactive (FLI) cells in spinal dorsal horn regions implicated in nociceptive processing and was attenuated by CB1 (AM251) and TRPV1 (AMG9810) antagonists. When central sensitization was established, FAAH KO mice displayed elevated levels of anandamide, other fatty-acid amides, and endogenous TRPV1 agonists in both paw skin and lumbar spinal cord relative to wild-type mice. Capsaicin decreased spinal cord 2-AG levels and increased arachidonic acid and prostaglandin E2 levels in both spinal cord and paw skin irrespective of genotype. Our studies identify a previously unrecognized pro-nociceptive phenotype in FAAH KO mice that was unmasked by capsaicin challenge. The heightened nociceptive response was mediated by CB1 and TRPV1 receptors and accompanied by enhanced spinal neuronal activation. Moreover, genetic deletion of FAAH has a profound impact on the peripheral and central lipidome. Thus, genetic deletion of FAAH may predispose animals to increased sensitivity to certain types of pain. More work is necessary to determine whether such changes could explain the lack of efficacy of FAAH inhibitors in clinical trials.
Stress has a complex, bidirectional modulatory influence on pain. Stress may either reduce (stress-induced analgesia) or exacerbate (stress-induced hyperalgesia) pain depending on the nature, duration, and intensity of the stressor. The endogenous cannabinoid (endocannabinoid) system is present throughout the neuroanatomical pathways that mediate and modulate responses to painful stimuli. The specific role of the endocannabinoid system in the brain in pain and the modulation of pain by stress is reviewed herein. We first provide a brief overview of the endocannabinoid system, followed by a review of the evidence that the brain's endocannabinoid system modulates pain. We provide a comprehensive evaluation of the role of the endocannabinoid system supraspinally, and particularly in the rostral ventromedial medulla, periaqueductal gray, amygdala, and prefrontal cortex, in pain, stress-induced analgesia, and stress-induced hyperalgesia. Increased understanding of endocannabinoid-mediated regulation of pain and its modulation by stress will inform the development of novel therapeutic approaches for pain and its comorbidity with stress-related disorders.
Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids--arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series--and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB(1) cannabinoid receptor (K(i) = 21.2 +/- 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB(2) receptor (K(i) > 3 microM).
Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear.
To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids.
Twenty-eight databases from inception to April 2015.
Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome.
Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis.
Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs.
A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], -0.46 [95% CI, -0.80 to -0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, -0.36 [95% CI, -0.69 to -0.05]; 7 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.
There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.
The levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol In this study, we investigated the role of the endocannabinoid system (ECS) in the emotional and cognitive alterations associated with osteoarthritis pain. The monosodium iodoacetate model was used to evaluate the affective and cognitive manifestations of osteoarthritis pain in type 1 (CB1R) and type 2 (CB2R) cannabinoid receptor knockout and wild-type mice, and the ability of CB1R (ACEA) and CB2R (JWH133) selective agonists to improve these manifestations during a three week time period.(2-AG) were measured in plasma and brain areas involved in the control of these manifestations. Knee osteoarthritis patients and healthy controls were recruited to evaluate pain, affective and cognitive symptoms, as well as plasma endocannabinoid levels and cannabinoid receptor gene expression in peripheral blood lymphocytes. The affective manifestations of osteoarthritis were enhanced in CB1R knockout mice and absent in CB2R knockouts. Interestingly, both ACEA and JWH133 ameliorated the nociceptive and affective alterations, whereas ACEA also improved the associated memory impairment. An increase of 2-AG levels in prefrontal cortex and plasma was observed in this mouse model of osteoarthritis. In agreement, an increase of 2-AG plasmatic levels and an up-regulation of CB1R and CB2R gene expression in peripheral blood lymphocytes were observed in osteoarthritis patients compared to healthy subjects. Changes found in these biomarkers of the ECS correlated with pain, affective and cognitive symptoms in these patients. The ECS plays a crucial role in osteoarthritis and represents an interesting pharmacological target and biomarker of this disease.
Emerging evidence indicates the involvement of GPR55 and its proposed endogenous ligand, lysophosphatidylinositol (LPI), in nociception, yet their role at central pain processing has not been explored. Using Ca(2+) imaging, we show here that LPI elicits concentration-dependent and GPR55-mediated increases in intracellular Ca(2+) levels in dissociated rat periaqueductal gray (PAG) neurons, which express GPR55 mRNA. This effect is mediated by Ca(2+) release from the endoplasmic reticulum via inositol 1,4,5-trisphosphate receptors and by Ca(2+) entry via P/Q-type of voltage-gated Ca(2+) channels. Moreover, LPI depolarizes PAG neurons and upon intra-PAG microinjection, reduces nociceptive threshold in the hot plate test. Both these effects are dependent on GPR55 activation, since they are abolished by pretreatment with ML-193, a selective GPR55 antagonist. Thus, we provide the first pharmacological evidence that GPR55 activation at central levels is pronociceptive, suggesting that interfering with GPR55 signaling in the PAG may promote analgesia.
The American Society for Pharmacology and Experimental Therapeutics.
There is evidence to suggest that a dysregulation of endocannabinoid signaling may contribute to the etiology and pathophysiology of migraine. Thus, patients suffering from chronic migraine or medication overuse headache showed alterations in the activity of the arachidonoylethanolamide (AEA) degrading enzyme fatty acid amide hydrolase (FAAH) and a specific AEA membrane transporter, alongside with changes in AEA levels. The precise role of different endocannabinoid system components is, however, not clear. We have therefore investigated mice with a genetic deletion of the two main cannabinoid receptors CB1 and CB2, or the main endocannabinoid degrading enzymes, FAAH and monoacylglycerol lipase (MAGL), which degrades 2-arachidonoylglycerol (2-AG), in a nitroglycerine-induced animal model of migraine. We found that nitroglycerin-induced mechanical allodynia and neuronal activation of the trigeminal nucleus were completely abolished in FAAH-deficient mice. To validate these results, we used two structurally different FAAH inhibitors, URB597 and PF3945. Both inhibitors also dose-dependently blocked nitroglycerin-induced hyperalgesia and the activation of trigeminal neurons. The effects of the genetic deletion of pharmacological blockade of FAAH are mediated by CB1 receptors, because they were completely disrupted with the CB1 antagonist rimonabant. These results identify FAAH as a target for migraine pharmacotherapy.
Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
An updated systematic review of randomized controlled trials examining cannabinoids in the treatment of chronic non-cancer pain was conducted according to PRISMA guidelines for systematic reviews reporting on health care outcomes. Eleven trials published since our last review met inclusion criteria. The quality of the trials was excellent. Seven of the trials demonstrated a significant analgesic effect. Several trials also demonstrated improvement in secondary outcomes (e.g., sleep, muscle stiffness and spasticity). Adverse effects most frequently reported such as fatigue and dizziness were mild to moderate in severity and generally well tolerated. This review adds further support that currently available cannabinoids are safe, modestly effective analgesics that provide a reasonable therapeutic option in the management of chronic non-cancer pain.
Aims:
To carry out a systematic review to assess the effectiveness of cannabis extracts and cannabinoids in the management of chronic nonmalignant neuropathic pain.
Methods:
Electronic database searches were performed using Medline, PubMed, Embase, all evidence-based medicine reviews, and Web of Science, through communication with the Canadian Consortium for the Investigation of Cannabinoids (CCIC), and by searching printed indices from 1950. Terms used were marijuana, marihuana, cannabis, cannabinoids, nabilone, delta- 9-tetrahydrocannabinol, cannabidiol, ajulemic acid, dronabinol, pain, chronic, disease, and neuropathic. Randomized placebo-controlled trials (RCTs) involving cannabis and cannabinoids for the treatment of chronic nonmalignant pain were selected. Outcomes considered were reduction in pain intensity and adverse events.
Results:
Of the 24 studies that examined chronic neuropathic pain, 11 studies were excluded. The 13 included studies were rated using the Jadad Scale to measure bias in pain research. Evaluation of these studies suggested that cannabinoids may provide effective analgesia in chronic neuropathic pain conditions that are refractory to other treatments.
Conclusion:
Cannabis-based medicinal extracts used in different populations of chronic nonmalignant neuropathic pain patients may provide effective analgesia in conditions that are refractory to other treatments. Further high-quality studies are needed to assess the impact of the duration of the treatment as well as the best form of drug delivery.
Significance
Although early studies suggested that cannabinoid CB 2 receptors (CB 2 Rs) are absent in the brain, this view has been challenged by recent findings of significant brain CB 2 R involvement in several dopamine (DA)-related CNS disorders. The cellular mechanisms underlying these actions are unclear, however. Using multiple approaches, we found that CB 2 R genes and receptors are expressed in midbrain DA neurons, and that activation of CB 2 Rs inhibits DA neuronal firing and i.v. cocaine self-administration. These findings not only challenge the long-held view that brain CB 2 Rs are not expressed in neurons, but also suggest that neuronal CB 2 Rs modulate DA neuronal activity and DA-regulated behavior. Thus, brain CB 2 Rs may constitute a new therapeutic target in medication development for treatment of a number of CNS disorders.
The past decades have seen an exponential rise in our understanding of the endocannabinoid system, comprised of CB1 and CB2 cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes that synthesize and degrade endocannabinoids. The primary focus of this review is the CB2 receptor. CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential towards treating various pathologies while avoiding the adverse psychotropic effects, which can accompany CB1 receptor-based therapies. With the appreciation that CB2 selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research both from a mechanistic as well as therapeutic perspective. In this review we will summarize our present knowledge of CB2 receptor signaling, localization and regulation. We will discuss the availability of genetic tools (and their limitations) to study CB2 receptors and also provide an update on preclinical data using CB2 agonists in pain models. Finally, we suggest possible reasons for the failure of CB2 ligands in clinical pain trials and offer possible ways to move the field forward in a way that can help reconcile the inconsistencies between preclinical and clinical data.
Direct-acting cannabinoid receptor ligands are well known to reduce hyperalgesic responses after nerve injury, although their psychoactive side effects have damped enthusiasm for their therapeutic development. Hemopressin (Hp) is a nonapeptide that selectively binds CB1 cannabinoid receptors (CB1 receptors) and exerts antinociceptive action in inflammatory pain models. We investigated the effect of Hp on neuropathic pain in rats subjected to chronic constriction injury (CCI) of the sciatic nerve, and explored the mechanisms involved. Oral administration of Hp inhibits mechanical hyperalgesia of CCI-rats up to 6hours. Hp treatment also decreases Egr-1 immunoreactivity (Egr-1Ir) in the superficial layer of the dorsal horn of the spinal cord of CCI rats. The antinociceptive effect of Hp seems to be independent of inhibitory descending pain pathway since methisergide (5HT1A receptor antagonist) and yohimbine (α-2 adrenergic receptor antagonist) were unable to prevent Hp antinociceptive effect. Hp decreased calcium flux on DRG neurons from CCI rats, similarly to that observed for AM251, a CB1 receptor antagonist. We also investigated the effect of Hp on potassium channels of CCI rats using UCL 1684 (a blocker of Ca(2+) -activated K(+) channels) which reversed Hp-induced antinociception. Furthermore, concomitant administration of URB-584 (FAAH inhibitor) but not JZL-184 (MAGL inhibitor) potentiates antinociceptive effect of Hp in CCI rats indicating an involvement of anadamide on HP-induced antinociception. Together, these data demonstrate that Hp displays antinociception in pain from neuropathic etiology through local effects. The release of anandamide and the opening of peripheral K(+) channels are involved in the antinociceptive effect.
Cannabinoid receptor type 2 (CB2R) plays a critical role in nociception. In contrast to cannabinoid receptor type 1 ligands, CB2R agonists do not produce undesirable central nervous system effects and thus promise to treat neuropathic pain that is often resistant to medical therapy. In the study presented here, we evaluated the bilateral distribution of the CB2R protein and messenger RNA (mRNA) in rat dorsal root ganglia (DRG) after unilateral peripheral nerve injury using immunohistochemistry, western blot, and in situ hybridization analysis. Unilateral chronic constriction injury (CCI) of the sciatic nerve induced neuropathic pain behavior and bilateral elevation of both CB2R protein and mRNA in lumbar L4-L5 as well as cervical C7-C8 DRG when compared with naive animals. CB2R protein and mRNA were increased not only in DRG neurons but also in satellite glial cells. The fact that changes appear bilaterally and (albeit at a lower level) even in the remote cervical DRG can be related to propagation of neuroinflammation alongside the neuraxis and to the neuroprotective effects of CB2R.
Neuropathic pain elevates spinal anandamide (AEA) levels in a way further increased when URB597, an inhibitor of AEA hydrolysis by fatty acid amide hydrolase (FAAH), is injected intrathecally. Spinal AEA reduces neuropathic pain by acting at both cannabinoid CB1 receptors and transient receptor potential vanilloid-1 (TRPV1) channels. Yet, intrathecal URB597 is only partially effective at counteracting neuropathic pain. We investigated the effect of high doses of intrathecal URB597 on allodynia and hyperalgesia in rats with chronic constriction injury (CCI) of the sciatic nerve. Among those tested, the 200 µg/rat dose of URB597 was the only one that elevated the levels of the FAAH non-endocannabinoid and anti-inflammatory substrates, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), and of the endocannabinoid FAAH substrate, 2-arachidonoylglycerol, and fully inhibited thermal and tactile nociception, although in a manner blocked almost uniquely by TRPV1 antagonism. Surprisingly, this dose of URB597 decreased spinal AEA levels. RT-qPCR and western blot analyses demonstrated altered spinal expression of lipoxygenases (LOX), and baicalein, an inhibitor of 12/15-LOX, significantly reduced URB597 analgesic effects, suggesting the occurrence of alternative pathways of AEA metabolism. Using immunofluorescence techniques, FAAH, 15-LOX and TRPV1 were found to co-localize in dorsal spinal horn neurons of CCI rats. Finally, 15-hydroxy-AEA, a 15-LOX derivative of AEA, potently and efficaciously activated the rat recombinant TRPV1 channel. We suggest that intrathecally injected URB597 at full analgesic efficacy unmasks a secondary route of AEA metabolism via 15-LOX with possible formation of 15-hydroxy-AEA, which, together with OEA and PEA, may contribute at producing TRPV1-mediated analgesia in CCI rats.
The function of the central cannabinoid receptor (CB1) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive
role of the CB1 receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates
were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced.
These observations suggest that the CB1 receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the
concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior.
Cannabis is reported to be remarkably effective for the relief of otherwise intractable pain. However, the bases for pain relief afforded by this psychotropic agent are debatable. Nonetheless, the frontal-limbic distribution of cannabinoid receptors in the brain suggests that cannabis may target preferentially the affective qualities of pain. This central mechanism of action may be relevant to cannabinoid analgesia in humans, but has yet to be demonstrated. Here, we employed functional magnetic resonance imaging to investigate the effects of delta-9-tetrahydrocannabinol (THC), a naturally occurring cannabinoid, on brain activity related to cutaneous ongoing pain and hyperalgesia that were temporarily induced by capsaicin in healthy volunteers. On average, THC reduced the reported unpleasantness, but not the intensity of ongoing pain and hyperalgesia: the specific analgesic effect on hyperalgesia was substantiated by diminished activity in the anterior mid cingulate cortex. In individuals, the drug-induced reduction in the unpleasantness of hyperalgesia was positively correlated with right amygdala activity. THC also reduced functional connectivity between the amygdala and primary sensorimotor areas during the ongoing-pain state. Critically, the reduction in sensory-limbic functional connectivity was positively correlated with the difference in drug effects on the unpleasantness and the intensity of ongoing pain. Peripheral mechanisms alone cannot account for the dissociative effects of THC on the pain that was observed. Instead, the data reveal that amygdala activity contributes to interindividual response to cannabinoid analgesia, and suggest that dissociative effects of THC in the brain are relevant to pain relief in humans.
The rostral ventromedial medulla (RVM) is a relay in the descending pain modulatory system and an important site of endocannabinoid modulation of pain. Endocannabinoids inhibit GABA release in the RVM, but it is not known whether this effect persists in chronic pain states. In the present studies, persistent inflammation induced by complete Freund’s adjuvant (CFA) increased GABAergic miniature IPSCs (mIPSCs). Endocannabinoid activation of cannabinoid (CB1) receptors known to inhibit presynaptic GABA release was significantly reduced in the RVM of CFA-treated rats compared with naive rats. The reduction in CFA-treated rats correlated with decreased CB1 receptor protein expression and function in the RVM. Paradoxically, the nonselective CB1/CB2 receptor agonist WIN55212 inhibited GABAergic mIPSCs in both naive and CFA-treated rats. However, WIN55212 inhibition was reversed by the CB1 receptor antagonist rimonabant in naive rats but not in CFA-treated rats. WIN55212-mediated inhibition in CFA-treated rats was blocked by the CB2 receptor-selective antagonist SR144528, indicating that CB2 receptor function in the RVM is increased during persistent inflammation. Consistent with these results, CB2 receptor agonists AM1241 and GW405833 inhibited GABAergic mIPSC frequency only in CFA-treated rats, and the inhibition was reversed with SR144528. When administered alone, SR144528 and another CB2 receptor-selective antagonist AM630 increased mIPSC frequency in the RVM of CFA-treated rats, indicating that CB2 receptors are tonically activated by endocannabinoids. Our data provide evidence that CB2 receptor function emerges in the RVM in persistent inflammation and that selective CB2 receptor agonists may be useful for treatment of persistent inflammatory pain.
Hemopressin and related peptides have shown to function as the endogenous ligands or the regulator of cannabinoid receptors. Moreover, hemopressin and its truncated peptides were also reported to produce a slight modulatory effect on opioid system. In the present work, based on the amino acid sequence analyses of hemoglobin subunit α, rat VD-hemopressin(α) [(r)VD-Hpα] was predicted as a cannabinoid peptide derived from rat α-hemoglobin. Furthermore, (r)VD-Hpα was synthesized and characterized in a series of in vitro and in vivo assays. Our results demonstrated that (r)VD-Hpα induced neurite outgrowth in Neuro 2A cells via CB1 receptor. In the tail-flick assay, (r)VD-Hpα dose-dependently exerted central antinociception through CB1 receptor, but not CB2 and opioid receptors. In mice, supraspinal administration of (r)VD-Hpα produced dose-dependent hypothermia, which was partially reduced by the CB1 receptor antagonist AM251, but not by the antagonists of CB2 and opioid receptors. In addition, (r)VD-Hpα caused hypoactivity after intracerebroventricular injection, and this effect was insensitive to the antagonists of cannabinoid and opioid receptors. Further assessment of the side-effects demonstrated that (r)VD-Hpα evoked the limited effects on gastrointestinal transit at antinociceptive doses, but repeated i.c.v. injection of (r)VD-Hpα induced development of antinociceptive tolerance. Taken together, these data suggest that the predicted peptide (r)VD-Hpα produces antinociception, hypothermia and hypoactivity via different pharmacological mechanisms, at least partially, which may offer an attractive strategy for separating cannabinoid analgesia from hypoactivity. Moreover, it implies that (r)VD-Hpα has therapeutic potential in pain management with limited side-effects.
The neural substrates and mechanisms mediating the antinociceptive effects of the endogenous bioactive lipid, N-palmitoylethanolamide (PEA), require further investigation. We investigated the effects of exogenous PEA administration into the anterior cingulate cortex (ACC), an important brain region linked with cognitive and affective modulation of pain, on formalin-evoked nociceptive behaviour in rats. Potential involvement of peroxisome proliferator-activated receptor isoforms (PPAR) ? and ? or endocannabinoid-mediated entourage effects at cannabinoid1 (CB1) receptors or transient receptor potential subfamily V member 1 (TRPV1) in mediating the effects of PEA was also investigated. Intra-ACC administration of PEA significantly attenuated the first and early second phases of formalin-evoked nociceptive behaviour. This effect was attenuated by the CB1 receptor antagonist AM251, but not by the PPAR? antagonist GW6471, the PPAR? antagonist GW9662, or the TRPV1 antagonist 5'-iodo resiniferatoxin. All antagonists, administered alone, significantly reduced formalin-evoked nociceptive behaviour, suggesting facilitatory/permissive roles for these receptors in the ACC in inflammatory pain. Post-mortem tissue analysis revealed a strong trend for increased levels of the endocannabinoid anandamide in the ACC of rats that received intra-ACC PEA. Expression of c-Fos, a marker of neuronal activity, was significantly reduced in the basolateral nucleus of the amygdala, but not in the central nucleus of the amygdala, the rostral ventromedial medulla or the dorsal horn of the spinal cord. In conclusion, these data indicate that PEA in the ACC can reduce inflammatory pain-related behaviour, possibly via AEA-induced activation of CB1 receptors and associated modulation of neuronal activity in the basolateral amygdala.
Pain is a complex sensation involving the perception and transduction of diverse environmental pain stimuli with cognitive and emotional processing by the central nervous system. It can manifest as acute or chronic pain. Pain is controlled by a series of enzymes and receptors, implicated in a variety of interconnected mechanisms and pathways. In fact, several studies have shown the cannabinoid receptor 1 and the transient receptor potential vanilloid channel 1 to be new players in modulating the sophisticated pain transduction system at the central level. At the peripheral level, the perception of pain involves cyclooxygenases and fatty acid amide hydrolase, as recent studies demonstrate. This Minireview describes the physiological aspects of the receptors and enzymes mentioned above and focuses on the consideration of dual mechanisms as a new therapeutic approach in the treatment of pain.
The transient receptor potential subfamily V member 1 (TRPV1) belongs to the diverse transient receptor potential (TRP) family of cation channels. It was first characterized in primary afferent fibres as a receptor for capsaicin. Peripheral TRPV1 has a very well-described role in nociception. However, TRPV1 is now recognized to have a broader distribution and function, with supraspinal/brain TRPV1 known to modulate pain processing. Recently, studies employing histological, genetic and pharmacological approaches have provided evidence that supraspinal TRPV1 also modulates brain neurobiology and behaviours related to anxiety, depression and schizophrenia. Key brain regions involved in TRPV1-mediated modulation of pain and affect include the periaqueductal grey, hippocampus and medial prefrontal cortex. Thus, TRPV1 in the brain is emerging as an important molecular substrate which is dually implicated in both pain and psychiatric disorders, and represents a novel therapeutic target for these conditions and their comorbidity.
The cannabinoid CB2 receptor has recently emerged as a potential anti-inflammatory target to break the self-sustaining cycle of neuroinflammation and neurodegeneration that is associated with neurodegenerative diseases. However, in order to facilitate the development of cannabinoid drugs for neurodegenerative disease, the changes that occur in the endocannabinoid system in response to different neurodegenerative triggers needs to be elucidated. Therefore, the aim of this study was to investigate and compare the changes that occur in the endocannabinoid system in neurotoxic and inflammation-driven models of Parkinson's disease. To do so, male Sprague Dawley rats were given unilateral, intra-striatal injections of the dopaminergic neurotoxin, 6-hydroxydopamine, or the bacterial inflammagen, lipopolysaccharide (LPS). Animals underwent behavioural testing for motor dysfunction on Days 7, 14 and 28 post-surgery, and were sacrificed on Days 1, 4, 14 and 28. Changes in the endocannabinoid system were investigated by qRT-PCR, liquid chromatography-mass spectrometry and immunohistochemistry. After injection of 6-hydroxydopamine or LPS into the rat striatum, we found that expression of the CB2 receptor was significantly elevated in both models, and that this increase correlated significantly with an increase in microglial activation. Interestingly, the increase in CB2 receptor expression in the inflammation-driven model was significantly more pronounced than that in the neurotoxic model. Moreover, endocannabinoid levels were also elevated in the LPS model but not the 6-hydroxydopamine model. Thus, this study has shown that the endocannabinoid system is dysregulated in animal models of Parkinson's disease, and has also revealed significant differences in the level of dysregulation between the models themselves. This study indicates that targeting the CB2 receptor may represent a viable target for anti-inflammatory disease modification in Parkinson's disease.
Patients suffering from chronic pain are often also diagnosed with a psychiatric condition, in particular generalized anxiety and major depression. The underlying pathomechanisms contributing to this comorbidity, however, are not entirely clear. In this manuscript we have focussed on the potential role of the cannabinoid receptor CB1, because it is known to modulate neuronal circuits contributing to chronic pain states and affective behaviours. For this purpose we analysed the consequences of a partial sciatic nerve ligation on anxiety- and depression related behaviours in mice lacking CB1 receptors. Our results show that the development of mechanical hypersensitivity was similar in CB1 deficient mice and wild type controls. However, CB1 knockouts showed much more pronounced behavioural manifestations of anxiety-related behaviors in the light-dark and zero-maze tests, sucrose anhedonia, and disturbed home-cage activity. These results indicate that the endocannabinoid system affects chronic pain-induced mood changes through CB1 receptors.
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Background:
Burn injury causes nociceptive behaviors, and inflammation-related pathologic pain can lead to glial cell activation. This study tested the hypothesis that burn injury activates glial cells, and cannabinoid receptor 1 (CB1R) antagonist, AM251, will decrease burn pain.
Methods:
Anesthetized rats received 0.75-cm third-degree burn on dorsal hind paw. Vehicle or AM251 30 μg intrathecally (older rats, n=6 per group) or, either vehicle, 0.1 or 1.0 mg/kg intraperitoneally (younger rats, n=6 per group), started immediate postburn, was administered for 7 days. Mechanical allodynia and thermal hyperalgesia were tested on ventral paw for 14 days. Microglial and astroglial activity was assessed by immunocytochemistry.
Results:
Allodynia, observed on burn side from day 1 to 14, was significantly (P<0.05) attenuated by intrathecal and intraperitoneal AM251 (1 mg/kg) starting from 3 to 14 days. Hyperalgesia, observed from day 3 to 12, was completely (P<0.05) reversed by intrathecal and intraperitoneal AM251 (1 mg/kg). AM251 0.1 mg/kg had no effect. Microglial activity (n=3 per time point) increased (P<0.05) 18.5±7.5 and 12.3±1.6 (mean±SD) fold at 7 and 14 days, respectively. Astroglial activity (n=4 per time point) increased 2.9±0.3 fold at day 7 only. Glial activities were unaltered by AM251.
Conclusions:
AM251 inhibited nociceptive behaviors after burn even beyond 7-day period of administration. Although many studies have documented the utility of CB1R agonists, this study indicates that endogenous cannabinoids may have an unexpected pronociceptive effect during development of burn pain, explaining why CB1R antagonist, AM251, improves nociceptive behaviors. The decreased nociception with AM251 without altering glial activity indicates that AM251 acts further downstream of activated glial cells.
The nonapeptide hemopressin and its N-terminal extension VD-hemopressin(α) were reported as an antagonist/inverse agonist and an agonist of CB1 receptor, respectively. These novel cannabinoid peptides have been demonstrated to modulate the acute pain. In the present study, hemopressin (11, 22 and 45 nmol, i.c.v.) dose-dependently produced antinociception after supraspinal administration in the radiant heat tail-flick test. Furthermore, the development of antinociceptive tolerance to hemopressin, VD-hemopressin(α) and WIN55,212-2, and cross-tolerance among these cannabinoids were investigated in mice. The tolerance developed on day 4 after supraspinal injection of hemopressin (45 nmol), VD-hemopressin(α) (20 nmol) and WIN55,212-2 (7.5 nmol). Our results indicated symmetrical cross-tolerance between hemopressin, VD-hemopressin(α) and WIN55,212-2 at the supraspinal level in mice. These results demonstrate that both hemopressin and VD-hemopressin(α) have a time-course and extent of tolerance similar to the synthetic cannabinoid WIN55,212-2. In addition, our data imply that a common mechanism is involved in the antinociception of the three cannabinoid ligands.
Monoacylglycerol lipase (MGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Selective inhibitors of MGL have antinociceptive effects upon acute administration and, therefore, hold promise as analgesics. To gain insight into the possible consequences of their prolonged administration, genetically modified mice with the knocked-out MGL gene were tested in several models of acute (phasic, tonic) and chronic (inflammatory, neuropathic) pain. MGL knockout mice showed normal acute phasic pain perception (pain thresholds) and no alleviation of pain perception in models of inflammatory and neuropathic pain. However, compared with wild-type controls, they showed significantly augmented nociceptive behavior in models of acute somatic and visceral tonic pain (formalin and acetic acid tests). The observed proalgesic changes in perception of tonic pain in MGL knockouts could have resulted from desensitization of cannabinoid receptors (known to occur after genetic inactivation of MGL). Supporting this notion, chronic pretreatment with the selective CB1 receptor antagonist AM 251 (employed to re-sensitize cannabinoid receptors in MGL knockouts) resulted in normalization of their tonic pain-related behaviors. Similar augmentation of tonic pain-related behaviors was replicated in C57BL/6N mice pretreated chronically with the selective MGL inhibitor JZL 184 (employed to pharmacologically desensitize CB1 receptors). These findings imply that prolonged use of MGL inhibitors, at doses causing close to complete inhibition of MGL enzymatic activity, not only have no beneficial analgesic effects, they may lead to exacerbation of some types of pain (particularly those with a tonic component).
Background:
Mixed cannabinoid receptor 1 and 2 (CB1 and CB2) agonists such as Δ(9)-tetrahydrocannabinol (Δ(9)-THC) can produce tolerance, physical withdrawal, and unwanted CB1-mediated central nervous system side effects. Whether repeated systemic administration of a CB2-preferring agonist engages CB1 receptors or produces CB1-mediated side effects is unknown.
Methods:
We evaluated antiallodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB2-preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB1 knockout (CB1KO), CB2 knockout (CB2KO), and wild-type (WT) mice. Comparisons were made with the prototypic classic cannabinoid Δ(9)-THC. We also explored the site and possible mechanism of action of AM1710.
Results:
Paclitaxel-induced mechanical and cold allodynia developed to an equivalent degree in CB1KO, CB2KO, and WT mice. Both AM1710 and Δ(9)-THC suppressed established paclitaxel-induced allodynia in WT mice. In contrast to Δ(9)-THC, chronic administration of AM1710 did not engage CB1 activity or produce antinociceptive tolerance, CB1-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Antiallodynic efficacy of systemic administration of AM1710 was absent in CB2KO mice and WT mice receiving the CB2 antagonist AM630, administered either systemically or intrathecally. Intrathecal administration of AM1710 also attenuated paclitaxel-induced allodynia in WT mice, but not CB2KO mice, implicating a possible role for spinal CB2 receptors in AM1710 antiallodynic efficacy. Finally, both acute and chronic administration of AM1710 decreased messenger RNA levels of tumor necrosis factor-α and monocyte chemoattractant protein 1 in lumbar spinal cord of paclitaxel-treated WT mice.
Conclusions:
Our results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects.
Chronic pain is an important public health problem that negatively impacts quality of life of affected individuals and exacts an enormous socio-economic cost. Currently available therapeutics provide inadequate management of pain in many patients. Acute pain states generally resolve in most patients. However, for reasons that are poorly understood, in some individuals, acute pain can transform to a chronic state. Our understanding of the risk factors that underlie the development of chronic pain is limited. Recent studies have suggested an important contribution of dysfunction in descending pain modulatory circuits to pain 'chronification'. Human studies provide insights into possible endogenous and exogenous factors that may promote the conversion of pain into a chronic condition.
Descending pain modulatory systems have been studied and characterized in animal models. Human brain imaging techniques, deep brain stimulation and the mechanisms of action of drugs that are effective in the treatment of pain confirm the clinical relevance of top-down pain modulatory circuits. Growing evidence supports the concept that chronic pain is associated with a dysregulation in descending pain modulation. Disruption of the balance of descending modulatory circuits to favour facilitation may promote and maintain chronic pain. Recent findings suggest that diminished descending inhibition is likely to be an important element in determining whether pain may become chronic. This view is consistent with the clinical success of drugs that enhance spinal noradrenergic activity, such as serotonin/norepinephrine reuptake inhibitors (SNRIs), in the treatment of chronic pain states. Consistent with this concept, a robust descending inhibitory system may be normally engaged to protect against the development of chronic pain. Imaging studies show that higher cortical and subcortical centres that govern emotional, motivational and cognitive processes communicate directly with descending pain modulatory circuits providing a mechanistic basis to explain how exogenous factors can influence the expression of chronic pain in a susceptible individual.
Preclinical studies coupled with clinical pharmacologic and neuroimaging investigations have advanced our understanding of brain circuits that modulate pain. Descending pain facilitatory and inhibitory circuits arising ultimately in the brainstem provide mechanisms that can be engaged to promote or protect against pain 'chronification'. These systems interact with higher centres, thus providing a means through which exogenous factors can influence the risk of pain chronification. A greater understanding of the role of descending pain modulation can lead to novel therapeutic directions aimed at normalizing aberrant processes that can lead to chronic pain.
The medial prefrontal cortex (mPFC) serves executive control functions and forms direct connections with subcortical areas such as the amygdala. Our previous work showed abnormal inhibition of mPFC pyramidal cells and hyperactivity of amygdala output neurons in an arthritis pain model. To restore mPFC activity and hence control pain-related amygdala hyperactivity this study focused on CB1 and mGluR5 receptors, which are important modulators of cortical functions. Extracellular single-unit recordings of infralimbic mPFC pyramidal cells and of amygdala output neurons in the laterocapsular division of the central nucleus (CeLC) were made in anesthetised adult male rats. mPFC neurons were classified as 'excited' or 'inhibited' based on their response to brief innocuous and noxious test stimuli. After arthritis pain induction, background activity and evoked responses of excited neurons and background activity and inhibition of inhibited neurons decreased. Stereotaxic application of an mGluR5-positive allosteric modulator (N-cyclobutyl-6-((3-fluorophenyl)ethynyl) nicotinamide hydrochloride, VU0360172) into the mPFC increased background and evoked activity of excited, but not inhibited, mPFC neurons under normal conditions but not in arthritis. A selective CB1 receptor agonist (arachidonyl-2-chloroethylamide) alone had no effect but restored the facilitatory effects of VU0360172 in the pain model. Coactivation of CB1 and mGluR5 in the mPFC inhibited the pain-related activity increase of CeLC neurons but had no effect under normal conditions. The data suggest that excited mPFC neurons are inversely linked to amygdala output (CeLC) and that CB1 can increase mGluR5 function in this subset of mPFC neurons to engage cortical control of abnormally enhanced amygdala output in pain.
The nuclear hormone receptor, peroxisome proliferator activated receptor (PPAR)-α, and its endogenous ligands, are involved in pain modulation. PPAR-α is expressed in the medial prefrontal cortex (mPFC), a key brain region involved in both the cognitive-affective component of pain and in descending modulation of pain. However the role of PPAR-α in the mPFC in pain responding has not been investigated. Here, we investigated the effects of pharmacological modulation of PPAR-α in the rat mPFC on formalin-evoked nociceptive behaviour and the impact of formalin-induced nociception on components of PPAR-α signalling in the mPFC.
The effects of intra-mPFC microinjection of a PPAR-α agonist (GW7647) or a PPAR-α antagonist (GW6471) on formalin-evoked nociceptive behaviour in rats were studied. qRT-PCR and LC-MS/MS were used to study the effects of intra-plantar injection of formalin on PPAR-α mRNA expression and levels of endogenous ligands, respectively, in the mPFC.
Intra-mPFC administration of GW6471, but not GW7647, resulted in delayed onset of the early second phase of formalin-evoked nociceptive behaviour. Furthermore, formalin-evoked nociceptive behaviour was associated with significant reductions in mPFC levels of endogenous PPAR-α ligands (N-palmitoylethanolamide [PEA] and N-oleoylethanolamide [OEA]) and a 70% reduction in PPAR-α mRNA but not protein expression.
These data suggest that endogenous ligands may act at PPAR-α in the mPFC to play a facilitatory/permissive role in second phase formalin-evoked nociceptive behaviour in rats.
Prostamides are emerging lipid mediators formed from cycloxygenase-2 (COX-2)-catalysed oxidation of the endocannabinoid anandamide. They produce effects that are often opposite to those caused by cannabinoid receptor activation by anandamide. COX-2-mediated oxygenation of anandamide may occur when hydrolysis of this compound by fatty acid amide hydrolase (FAAH) is physiologically, pathologically or pharmacologically reduced. Thus, the therapeutic properties of FAAH inhibitors might be attenuated by the concomitant production of prostamide F2α , which acts at specific receptors.
We investigated whether a series of synthetic compounds designed to selectively antagonize prostamide versus prostanoid receptors, could also inhibit FAAH. Among these compounds were the previously described selective prostamide antagonists AGN 204396, AGN 211335 and AGN 211336.
The prostamide F2α receptor antagonists were active against mouse and rat FAAH in the low μM range of concentrations They appeared to behave as non-competitive and plasma membrane-permeant inhibitors of the enzyme. AGN 211335, the most potent against rat FAAH of these compounds (IC50 = 1.2 μM), elevated exogenous anandamide levels in intact cells, and also exhibited affinity for cannabinoid CB1 receptors. Both AGN 211335 and AGN 211336 (0.25-1 mg kg(-1) , i.p.) inhibited the formalin-induced nociceptive response in mice.
These findings suggest that synthetic compounds with indirect agonist activity at cannabinoid receptors and antagonistic activity at prostamide receptors can be developed. Such compounds could be used in the future as an alternative to selective FAAH inhibitors to prevent a potential consequence of FAAH inhibition, namely prostamide F2α -induced inflammation and pain.
Pain is both a sensory and an emotional experience and is subject to modulation by a number of factors including genetic background modulating stress/affect. The Wistar-Kyoto (WKY) rat exhibits a stress-hyperresponsive and depressive-like phenotype and increased sensitivity to noxious stimuli, compared with other rat strains. Here, we show that this genotype-dependent hyperalgesia is associated with impaired pain-related mobilisation of endocannabinoids and transcription of their synthesising enzymes in the rostroventromedial medulla (RVM). Pharmacological blockade of the CB1 receptor potentiates the hyperalgesia in WKY rats, while inhibition of the endocannabinoid catabolising enzyme, fatty acid amide hydrolase, attenuates the hyperalgesia. The latter effect is mediated by CB1 receptors in the RVM. Together, these behavioural, neurochemical and molecular data indicate that impaired endocannabinoid signalling in the RVM underpins hyper-responsivity to noxious stimuli in a genetic background prone to heightened stress/affect.
The effects of morphine and Δ9-tetrahydrocannabinol (THC) on the tail-flick reflex, body temperature, and catecholamine synthesis were examined in the mouse in order to compare their effects in a single species and strain under uniform conditions. Naloxone antagonism of THC and cross-tolerance between morphine and THC were also studied. Both morphine and THC produced antinociception, hypothermia, and increased catecholamine synthesis at 30 min after s.c. injection. Morphine produced greater increases in dopamine synthesis and was a more potent antinociceptive agent, while THC produced greater increases in norepinephrine synthesis and was a more potent hypothermic agent. Naloxone pretreatment (1 mg/kg) partially antagonized the hypothermia and increase in catecholamine synthesis produced by THC. There was also crosstolerance between morphine and THC, but it was asymmetric in that THC-tolerant animals were crosstolerant to only the hypothermic action of morphine and morphine-tolerant animals cross-tolerant to only the antinociceptive action of THC.
The cannabinoid receptor type 2 (CB2), is a class A GPCR that was cloned in 1993 while looking for an alternate receptor that could explain the pharmacological properties of 9- tetrahydrocannabinol. CB2 was identified among cDNAs based on its similarity in amino-acid sequence to the CB1 receptor and helped provide an explanation for the established effects of cannabinoids on the immune system. In addition to the immune system, CB2 has widespread tissue expression and has been found in brain, PNS and GI tract. Several "mixed" cannabinoid agonists are currently in clinical use primarily for controlling pain and it is believed that selective CB2 agonism may afford a superior analgesic agent devoid of the centrally mediated CB1 effects. Thus, selective CB2 receptor agonists represent high value putative therapeutics for treating pain and other disease states. In this perspective, we seek to provide a concise update of progress in the field.
We have examined the effects of cannabinoid agonists on hyperalgesia in a model of neuropathic pain in the rat and investigated the possible sites of action. The antihyperalgesic activity of the cannabinoids was compared with their ability to elicit behavioural effects characteristic of central cannabinoid activity. WIN55,212-2 (0.3–10 mg kg−1), CP-55,940 (0.03–1 mg kg−1) and HU-210 (0.001–0.03 mg kg−1) were all active in a ‘tetrad’ of tests consisting of tail-flick, catalepsy, rotarod and hypothermia following subcutaneous administration, with a rank order of potency in each of HU-210>CP-55,940>WIN55,212-2. The effects of WIN55,212-2 in each assay were blocked by the Cannabinoid1 (CB1) antagonist SR141716A. In the partial sciatic ligation model of neuropathic pain WIN55,212-2, CP-55,940 and HU-210 produced complete reversal of mechanical hyperalgesia within 3 h of subcutaneous administration with D50 values of 0.52, 0.08 and 0.005 mg kg−1, respectively. In this model WIN55,212-2 was also effective against thermal hyperalgesia and mechanical allodynia. WIN55,212-2 produced pronounced reversal of mechanical hyperalgesia following intrathecal administration that was blocked by the CB1 antagonist SR141716A. Following intraplantar administration into the ipsilateral hindpaw, WIN55,212-2 produced up to 70% reversal of mechanical hyperalgesia, although activity was also observed at high doses following injection into the contralateral paw. The antihyperalgesic effect of WIN55,212-2 injected into the ipsilateral paw was blocked by subcutaneously administered SR141716A, but was not affected by intrathecally administered SR141716A. These data show that cannabinoids are highly potent and efficacious antihyperalgesic agents in a model of neuropathic pain. This activity is likely to be mediated via an action in both the CNS and in the periphery.
Immunohistochemical distribution of cannabinoid receptors in the adult rat brain was studied using specific purified antibodies against the amino-terminus of the CB1 receptor. Our results generally agree well with the previous studies using CB1 receptor autoradiography and messenger RNA in situ hybridization. However, because of its greater resolution, immunohistochemistry allowed identification of particular neuronal cells and fibers that possess cannabinoid receptors. CB1-like immunoreactivity was found in axons, cell bodies and dendrites, where it appeared as puncta in somata and processes. Both intensely and moderately or lightly stained neurons were observed. The intensely stained neurons were dispersed and only occur in cortical structures including hippocampal formation and olfactory bulb. Moderately or lightly stained neurons were found in caudate-putamen and amygdala. In the hippocampal formation only intensely stained neurons were observed. The cell bodies of pyramidal neurons in CA1 and CA3 fields appeared to be unstained but surrounded by a dense plexus of immunoreactive fibers. The granule cells in the dentate area were also immunonegative. Many intensely stained neurons were located at the base of the granule cell layer. CB1-like immunoreactive neurons and fibers were also found in the somatosensory, cingulate, perirhinal, entorhinal and piriform cortices, in claustrum, amygdaloid nuclei, nucleus accumbens and septum. Beaded immunoreactive fibers were detected in periaqueductal gray, nucleus tractus solitarius, spinal trigeminal tract and nucleus, dorsal horn and lamina X of the spinal cord. A triangular cap-like mass of immunoreactivity was found to surround the basal part of the Purkinje cell body in the cerebellum. Only small, lightly stained cells were found in the molecular layer in the cerebellum close to the Purkinje cell layer. The CB1 receptor is widely distributed in the forebrain and has a more restricted distribution in the hindbrain and the spinal cord. It appears to be expressed on cell bodies, dendrites and axons. According to the location and morphology, many, but not all, CB1-like immunoreactive neurons appear to be GABAergic. Therefore, cannabinoids and cannabinoid receptors may play a role in modulating GABAergic neurons.
Historically, the evidence for cannabinoids acting as analgesics has been mostly anecdotal. Recently, studies utilizing animal models have indicated that cannabinoids produce antinociception and antihyperalgesia by acting at peripheral, spinal, and supraspinal sites to inhibit mast cell degranulation, primary afferent activity, and responses of nociceptive neurons. Additionally, a number of studies indicate that the cannabinoid system tonically regulates nociceptive thresholds, raising the possibility that hypoactivity of the cannabinoid system produces or prolongs hyperalgesia and chronic pain. Other studies have indicated that inactive doses of cannabinoids potentiate the antinociceptive effects of opioids. Collectively, these studies suggest that administration of peripherally selective cannabinoids, enhancement of endogenous cannabinoid activity, and coadministration of inactive doses of cannabinoids with other analgesics, such as morphine, may prove therapeutically beneficial and may also provide ways to separate the analgesic effects of cannabinoids from their side effects.
Central antinociceptive effects of cannabinoids have been well documented. However, relatively little is known about the peripheral effects of the cannabinoids on inflammation. In the present study, we evaluated the effects of peripherally administered cannabinoids on three indices of inflammation: carrageenan-induced thermal hyperalgesia, carrageenan-induced edema, and capsaicin-induced plasma extravasation. In addition, we determined the effect of cannabinoids on capsaicin-evoked neuropeptide release from isolated rat hindpaw skin. Our results indicate that cannabinoids produce antihyperalgesia via interaction with a peripheral CB1 receptor. Peripheral, but not systemic, administration of 0.01 ng anandamide inhibited the induction of hyperalgesia. Peripheral administration of anandamide also attenuated hyperalgesia after its development via interaction with the CB1 cannabinoid receptor subtype as indicated by its reversal with the CB1 receptor antagonist SR 141716A. Additionally, peripheral, but not systemic, administration of 0.01 ng anandamide inhibited edema. Peripherally administered cannabinoids also interacted with CB1 receptors to inhibit capsaicin-evoked plasma extravasation into the hindpaw. One potential mechanism for the anti-inflammatory actions of the cannabinoids is the inhibition of neurosecretion from the peripheral terminals of nociceptive primary afferent fibers. This hypothesis is supported by the finding that anandamide inhibited capsaicin-evoked release of calcitonin gene-related peptide from isolated hindpaw skin. Collectively, these results indicate that cannabinoids reduce inflammation via interaction with a peripheral CB1 receptor. A potential mechanism for this effect is the inhibition of neurosecretion from capsaicin-sensitive primary afferent fibers.
It has been shown that GABAA receptor blockade in the dorsomedial and ventromedial hypothalamic nuclei (DMH and VMH, respectively) induces elaborated defensive behavioural responses accompanied by antinociception, which has been utilized as an experimental model of panic attack. Furthermore, the prelimbic (PL) division of the medial prefrontal cortex (MPFC) has been related to emotional reactions and the processing of nociceptive information. The aim of the present study was to investigate the possible involvement of the PL cortex and the participation of local cannabinoid CB1 receptors in the elaboration of panic-like reactions and in innate fear-induced antinociception. Elaborated fear-induced responses were analysed during a 10-min period in an open-field test arena. Microinjection of the GABAA receptor antagonist bicuculline into the DMH/VMH evoked panic-like behaviour and fear-induced antinociception, which was decreased by microinjection of the non-selective synaptic contact blocker cobalt chloride in the PL cortex. Moreover, microinjection of AM251 (25, 100 or 400 pmol), an endocannabinoid CB1 receptor antagonist, into the PL cortex also attenuated the defensive behavioural responses and the antinociception that follows innate fear behaviour elaborated by DMH/VMH. These data suggest that the PL cortex plays an important role in the organization of elaborated forward escape behaviour and that this cortical area is also involved in the elaboration of innate fear-induced antinociception. Additionally, CB1 receptors in the PL cortex modulate both panic-like behaviours and fear-induced antinociception elicited by disinhibition of the DMH/VMH through microinjection of bicuculline.
The basolateral amygdala (BLA) is a key substrate facilitating the expression of fear-conditioned analgesia (FCA). However, the neurochemical mechanisms in the BLA which mediate this potent suppression of pain responding during fear remain unknown. The present study investigated the role of cannabinoid(1) (CB(1)) receptors and interactions with GABAergic (GABA(A) receptor) and glutamatergic (metabotropic glutamate receptor type 5; mGluR5) signalling in the BLA in formalin-evoked nociceptive behaviour and FCA in rats. Reexposure to a context previously paired with foot shock significantly reduced formalin-evoked nociceptive behaviour. Systemic or intra-BLA microinjection of the CB(1) receptor antagonist/inverse agonist AM251 prevented this expression of FCA, while injection of AM251 into the central nucleus of the amygdala did not. The suppression of FCA by systemic AM251 administration was partially attenuated by intra-BLA administration of either the GABA(A) receptor antagonist bicuculline or the mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine, (MPEP). Bilateral microinjection of MPEP, but not bicuculline, alone into the BLA enhanced formalin-evoked nociceptive behaviour. Postmortem analyses revealed that FCA was associated with a significant increase in tissue levels of anandamide in the BLA side contralateral to intraplantar formalin injection. In addition, fear-conditioned rats exhibited a robust formalin-induced increase in levels of 2-arachidonyl glycerol and N-palmitoylethanolamide in the ipsilateral and contralateral BLA, respectively. These data suggest that CB(1) receptors in the BLA facilitate the expression of FCA, through a mechanism which is likely to involve the modulation of GABAergic and glutamatergic signalling.
Joint pain is a common clinical problem for which both inflammatory and degenerative joint diseases are major causes. The purpose of this study was to investigate the role of CB1 and CB2 cannabinoid receptors in the behavioral, histological, and neurochemical alterations associated with joint pain. The murine model of monosodium iodoacetate (MIA) was used to induce joint pain in knockout mice for CB1 (CB1KO) and CB2 cannabinoid receptors (CB2KO) and transgenic mice overexpressing CB2 receptors (CB2xP). In addition, we evaluated the changes induced by MIA in gene expression of CB1 and CB2 cannabinoid receptors and μ-, δ- and κ-opioid receptors in the lumbar spinal cord of these mice. Wild-type mice, as well as CB1KO, CB2KO, and CB2xP mice, developed mechanical allodynia in the ipsilateral paw after MIA intra-articular injection. CB1KO and CB2KO demonstrated similar levels of mechanical allodynia of that observed in wild-type mice in the ipsilateral paw, whereas allodynia was significantly attenuated in CB2xP. Interestingly, CB2KO displayed a contralateral mirror image of pain developing mechanical allodynia also in the contralateral paw. All mouse lines developed similar histological changes after MIA intra-articular injection. Nevertheless, MIA intra-articular injection produced specific changes in the expression of cannabinoid and opioid receptor genes in lumbar spinal cord sections that were further modulated by the genetic alteration of the cannabinoid receptor system. These results revealed that CB2 receptor plays a predominant role in the control of joint pain manifestations and is involved in the adaptive changes induced in the opioid system under this pain state.