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The analgesic activity of Paracetamol is prevented by the blockade of cannabinoid CB1 receptors
Abstract
The mechanism of the analgesic activity of paracetamol (acetaminophen), one of the most widely used drugs for the treatment of pain, is still not clear. Here we show that in rats, using the hot plate test, the analgesic effect of paracetamol is prevented by two antagonists at cannabinoid CB1 receptors (AM281 and SR141716A) at doses that prevent the analgesic activity of the cannabinoid CB1 agonist HU210. Our present results suggest that paracetamol-induced antinociception involves the cannabinoid system.
... As regard number of patient that need analgesia there is 15 patients (75% ) in group L need analgesia ,while in group D there was 6 patients (30%) that need analgesia, and in group P there was 7 patients (35%) that need analgesia ,but in group LDP there was only 2 patients (10%) that need analgesia as in table (6). As regard total amount of fentanyl consumption there is statistically significant difference between groups where group LDP had alittle amount of fentanyl consumption about (6.8 μg) while group L consume about (51.9 μg) as in table (7).As regard blood pressure and heart rate ther was no statically significant difference between groups as in table (8,9,10). ...
... As a week inhibitor of prostaglandin synthesis, paracetamol acts in a similar fashion to selective inhibitors of COX II, however, it lacks their anti-inflammatory effects (9) . Several mechanisms have been discussed for the analgesic effects of paracetamol; for example, Ottani et al. (10) hypothesized that it exerts its effects primarily by modification of cannabinoid receptors. The recent discovery of COX-3 suggested a central mechanism for paracetamol-induced analgesia, which has increasing popularity for the purpose of pain control (11) . ...
... Another probable mechanism, that 11 paracetamol modulates the endogenous cannabinoid system in brain a n d s p i n a l c o r d . P a r a c e t a m o l m e t a b o l i z e d i n t o N - 15,16 arachidonylphenolamine (AM404) which inhibits uptake of the endogenous cannabinoid/vanilloid anandamide by neurons. 16,17,18,19 Anandamide play major role in perception of pain. ...
... P a r a c e t a m o l m e t a b o l i z e d i n t o N - 15,16 arachidonylphenolamine (AM404) which inhibits uptake of the endogenous cannabinoid/vanilloid anandamide by neurons. 16,17,18,19 Anandamide play major role in perception of pain. ...
Spinal anaesthesia is safe and effective method of anaesthetic practice for infra umbilical surgeries. Commonly used drugs to alleviate postoperative pain after surgery include opioid, nonsteroidal anti-inammatory drugs (NSAIDS), and paracetamol. The purpose of this prospective randomized double-blind clinical study is to assess the effect of intravenous paracetamol on duration of post operative analgesia, when administered intra operatively after subarachnoid block, using hyperbaric bupivacaine. After obtaining approval of the institutional ethical committee and written informed consent from the patients, a prospective randomized double blind study was undertaken with 98 ASA I-II patients, aged between 18 to 60 years, scheduled for elective inguinal hernia surgeries under spinal anaesthesia. In our study the time to rst request for postoperative analgesic was signicantly prolonged in group P (163.98 ± 16.86 mins) as compared to group C (134.59 ± 16.45mins) (p<0.001). Total number of rescue analgesic doses in 24 hours was signicantly lower in group P (2.47±0.54) compared to group C (3.39±0.97) (p<0.001). Mean VAS score in rst 24 hours was signicantly lower in group P (1.42±0.145) compared to group C (1.82± 0.11) (p<0.001). We concluded that 1 gm intravenous paracetamol is safe and effective method of providing postoperative analgesia for rst 24 hours, in patients undergoing infra umbilical surgeries under spinal anaesthesia.
... 171 Drug Effect Significant increases in hind paw thermal escape latencies over baseline were observed over a range of dose 500-850 mg/kg in the rat or mouse. 68,73,76,77 Tail flick latencies were significantly elevated in mice after PO administration of acetaminophen (400 mg/kg). 66 Orally administered acetaminophen inhibited tail flick in a concentrationdependent manner (97-772 mg/kg). ...
... The effects of acetaminophen are reportedly blocked by Cannabinoid (CB) 1 receptor antagonism and by CB1 -/transgenic mice. 77,95 This effect is believed to reflect the fact that acetaminophen, by its metabolite AM404, also exerts a possible effect on the endocannabinoid system by acting as a ligand at cannabinoid CB1 receptors, or as an inhibitor of anandamide uptake, an endogenous agonist for CB1 receptors. 219,220 Anandamide (AEA) is an endocannabinoid that activates CB1. ...
Acetaminophen (APAP) in humans has robust effects with a high therapeutic index in altering postoperative and inflammatory pain states in clinical and experimental pain paradigms with no known abuse potential. This review considers the literature reflecting the preclinical actions of acetaminophen in a variety of pain models. Significant observations arising from this review are as follows: 1) acetaminophen has little effect upon acute nociceptive thresholds; 2) acetaminophen robustly reduces facilitated states as generated by mechanical and thermal hyperalgesic end points in mouse and rat models of carrageenan and complete Freund's adjuvant evoked inflammation; 3) an antihyperalgesic effect is observed in models of facilitated processing with minimal inflammation (eg, phase II intraplantar formalin); and 4) potent anti-hyperpathic effects on the thermal hyperalgesia, mechanical and cold allodynia, allodynic thresholds in rat and mouse models of polyneuropathy and mononeuropathies and bone cancer pain. These results reflect a surprisingly robust drug effect upon a variety of facilitated states that clearly translate into a wide range of efficacy in preclinical models and to important end points in human therapy. The specific systems upon which acetaminophen may act based on targeted delivery suggest both a spinal and a supraspinal action. Review of current targets for this molecule excludes a role of cyclooxygenase inhibitor but includes effects that may be mediated through metabolites acting on the TRPV1 channel, or by effect upon cannabinoid and serotonin signaling. These findings suggest that the mode of action of acetaminophen, a drug with a long therapeutic history of utilization, has surprisingly robust effects on a variety of pain states in clinical patients and in preclinical models with a good therapeutic index, but in spite of its extensive use, its mechanisms of action are yet poorly understood.
... The involvement of the endocannabinoid system is also related to nociceptive pathways, being involved in the analgesic activity of drugs used to treat pain, such as paracetamol [8], indomethacin and ibuprofen [9]. ...
... The present study demonstrates that the antinociceptive effect of LAL may have the participation of cannabinoid receptors, since previous treatment with the antagonists of AM251 (CB1) and AM630 (CB2) reversed the lectin antinociceptice effect. Some studies highlight the involvement of the endocannabinoid system in the analgesic activity of drugs widely used in the clinical practice to treat pain, like paracetamol [8], indomethacin and ibuprofen [9]. Also, it has already been demonstrated the role of endocannabinoids in the modulation of hypernociception by electrophysiological and behavioral aspects [12,17,18,19,20]. ...
The involvement of endocannabinoid receptors in the antinociceptive activity of Lonchocarpus araripensis lectin (LAL) was investigated in the model of carragenan-induced hypernociception. Swiss mice received LAL (10 mg/kg) by intravenous (i.v.) route 30 min before subcutaneous (s.c.) injection of carrageenan in the paws. Animals were treated with the antagonists of CB1 (AM251) or CB2 (AM630) cannabinoid receptors 30 min before the lectin. LAL inhibited the hypernociception induced by carrageenan (1 h: 11.87 ± 0.61 g; 3 h: 9.7 ± 0.70 g). AM251 (1 h: 4.75 ± 0.41 g; 3 h: 4.5 ± 0.53 g) and AM630 (1 h: 5.67 ± 0.56 g; 3 h: 5 ± 0.68 g) reversed the inhibitory effect of LAL. The antinociceptive effect of Lonchocarpus araripensis lectin is mediated by endocannabinoid receptors.
... The mechanisms of the analgesic activity of paracetamol are not fully understood and may involve Peripheral and Central Nervous System sites of action [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. It is widely accepted that paracetamol decreases the tissue concentrations of prostaglandins and proinflammatory mediators, whose synthesis is also inhibited by aspirin (acetylsalicylic acid). ...
... Paracetamol can affect the central neurotransmission of pain in different ways [18,[20][21][22][23][24][25][26][27][28][29][30]. In particular, the drug is metabolized to N-arachidonoylaminophenol (AM404), which is a compound with multiple potential analgesic activities, including the blockade of neuronal uptake of anandamide and of neuronal sodium channels [20,23,26]. ...
Musculoskeletal pain conditions are age-related, leading contributors to chronic pain and pain-related disability, which are expected to rise with the rapid global population aging. Current medical treatments provide only partial relief. Furthermore, non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are effective in young and otherwise healthy individuals but are often contraindicated in elderly and frail patients. As a result of its favorable safety and tolerability record, paracetamol has long been the most common drug for treating pain. Strikingly, recent reports questioned its therapeutic value and safety. This review aims to present guideline recommendations. Paracetamol has been assessed in different conditions and demonstrated therapeutic efficacy on both acute and chronic pain. It is active as a single agent and is additive or synergistic with NSAIDs and opioids, improving their efficacy and safety. However, a lack of significant efficacy and hepatic toxicity have also been reported. Fast dissolving formulations of paracetamol provide superior and more extended pain relief that is similar to intravenous paracetamol. A dose reduction is recommended in patients with liver disease or malnourished. Genotyping may improve efficacy and safety. Within the current trend toward the minimization of opioid analgesia, it is consistently included in multimodal, non-opioid, or opioid-sparing therapies. Paracetamol is being recommended by guidelines as a first or second-line drug for acute pain and chronic pain, especially for patients with limited therapeutic options and for the elderly.
... It was shown that when paracetamol-derived metabolite para-aminophenol, formed in the liver, enters the brain it conjugates with arachidonic acid through the action of fatty acid amidohydrolase (FAAH) to form N-(4-hydroxyphenyl)-arachidonamide (AM404). AM404 as a novel metabolite for paracetamol was shown to activate the endocannabinoid system and to also activate the transient receptor potential vanilloid-1 (TRPV-1) channel, both of which are involved in the modulation of pain signaling and proposed to mediate the analgesic action of paracetamol [86][87][88][89][90]. Prior to the work by Högestätt et al. (2005) AM404 was shown to have analgesic properties mediated through the inhibition of endocannabinoid reuptake, thereby by preventing the reuptake of anandamide from the synaptic cleft [91]. ...
... AM404 as a novel metabolite for paracetamol was shown to activate the endocannabinoid system and to also activate the transient receptor potential vanilloid-1 (TRPV-1) channel, both of which are involved in the modulation of pain signaling and proposed to mediate the analgesic action of paracetamol [86][87][88][89][90]. Prior to the work by Högestätt et al. (2005) AM404 was shown to have analgesic properties mediated through the inhibition of endocannabinoid reuptake, thereby by preventing the reuptake of anandamide from the synaptic cleft [91]. Experiments in which the conversion of p-aminophenol into AM404 has been interrupted using FAAH knockout mice or selective FAAH inhibitors, the analgesic actions of paracetamol were shown to be blocked [89,90,92,93]. The serotonergic system has also been shown to be targeted by the paracetamol-derived AM404 [94,95]. ...
Paracetamol (acetaminophen) undoubtedly is one of the most widely used drugs worldwide. As an over-the-counter medication, paracetamol is the standard and first-line treatment for fever and acute pain and is believed to remain so for many years to come. Despite being in clinical use for over a century, the precise mechanism of action of this familiar drug remains a mystery. The oldest and most prevailing theory on the mechanism of analgesic and antipyretic actions of paracetamol relates to the inhibition of CNS cyclooxygenase (COX) enzyme activities, with conflicting views on the COX isoenzyme/variant targeted by paracetamol and on the nature of the molecular interactions with these enzymes. Paracetamol has been proposed to selectively inhibit COX-2 by working as a reducing agent, despite the fact that in vitro screens demonstrating low potency on the inhibition of COX-1 and COX-2. In vivo data from COX-1 transgenic mice suggest that paracetamol works through inhibition of a COX-1 variant enzyme to mediate its analgesic and particularly thermoregulatory actions (antipyresis and hypothermia). A separate line of research provides evidence on potentiation of the descending inhibitory serotonergic pathway to mediate the analgesic action of paracetamol, but with no evidence of binding to serotonergic molecules. AM404 as a metabolite for paracetamol has been proposed to activate the endocannabinoid and the transient receptor potential vanilloid-1 (TRPV1) systems. The current review gives an update and in some cases challenges the different theories on the pharmacology of paracetamol and raises questions on some of the inadequately explored actions of paracetamol.
... 29 The non-steroidal anti-inflammatory drugs (NSAIDs), such as asprin, ibuprofen, diclofenac, ketorolac and mefenamic acid, have analgesic and anti-inflammatory properties, which are useful in the management of pain. 27 Ibuprofen is one of the most frequently used NSAIDs for mild and moderate pain. 34 The medicine has gained advantage in the market as is available as an over-the-counter medication for fever reduction, as well as pain relief. ...
... Despite this finding, however, the definite proof that the analgesic and antipyretic effects of paracetamol are dependent on COXinhibition is still unclear. Hence, it works effectively when is combined with codeine for more effective control of moderateto-severe pain and discomfort.27 ...
Muscle pain, also known as myalgia, is most commonly associated with sprains or strains. It frequently presents as redness at the site of injury, tenderness, swelling and fever. Muscle pain may occur as a result of excitation of the muscle nociceptor due to overuse of the muscle, viral infections or trauma. The most important endogenous substance released in response to the damaged tissues or nociceptor nerve endings in regards with muscle pain is adenosine triphosphate (ATP). Optimal pain management involves a combination of non-opioid, opioid analgesics, adjuvants, as well as non-pharmacologic strategies. Non-opiod analgesics include paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, which are indicated for mild to moderate pain. Whereas moderate to severe pain acquires opiod analgesics. This article provides an overview of muscle pain, the management and treatment thereof.
... It was initially believed to act similarly to nonsteroidal anti-inflammatory drugs (NSAIDs) and was studied for its potential impact on the prostanoid system [16][17][18]. Today, we know that it has a complex mechanism of action (MOA) and acts via cyclooxygenase 3 (COX-3) inhibition [19], serotonin receptor 3 (5-HT3) antagonism [20,21], nitric oxide synthase (NOS) inhibition [22], and CB1 agonism [23]. In 2006, Ottani et al. showed that the latter mechanism may be the most important one for paracetamol's properties. ...
... They blocked CB1 with two antagonists-SR141716A and AM281. In both cases, paracetamol's analgesic activity was prevented [23]. In 2017, Sharma et al. proved that paracetamol is metabolized in vivo to N-arachidonoylaminophenol (AM404) [24], which is the anandamide reuptake inhibitor [25], as well as weak CB1 [26] and TRPV1 agonist [27]. ...
The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.
... 45 In the setting of paracetamol injection, CB1 knockout models or mice pretreated with selective CB1 antagonists showed no analgesic response to paracetamol. 17,56 The expected synergism between paracetamol and opiates was also attenuated in mice pretreated with selective CB1 antagonist. 57 Notably, two previous reports showed that paracetamol injection did not alter the brain endocannabinoid content, suggesting that other studies are needed to know how CB1 receptors are involved. ...
Christophe Mallet,1 Jules Desmeules,2 Rassa Pegahi,3 Alain Eschalier1 1Université Clermont Auvergne, INSERM, NEURO-DOL Basics & Clinical Pharmacology of Pain, Clermont-Ferrand, France; 2Faculty of Medicine and The School of Pharmaceutical Sciences, Faculty of Sciences, Geneva University, Geneva, Switzerland; 3Medical Affairs Department, UPSA, Paris, FranceCorrespondence: Alain Eschalier, Faculté de Médecine, UMR Neuro-Dol, 49 Bd François Mitterrand, Clermont-Ferrand, 63000, France, Email alain.eschalier@uca.frAbstract: Paracetamol remains the recommended first-line option for mild-to-moderate acute pain in general population and particularly in vulnerable populations. Despite its wide use, debate exists regarding the analgesic mechanism of action (MoA) of paracetamol. A growing body of evidence challenged the notion that paracetamol exerts its analgesic effect through cyclooxygenase (COX)-dependent inhibitory effect. It is now more evident that paracetamol analgesia has multiple pathways and is mediated by the formation of the bioactive AM404 metabolite in the central nervous system (CNS). AM404 is a potent activator of TRPV1, a major contributor to neuronal response to pain in the brain and dorsal horn. In the periaqueductal grey, the bioactive metabolite AM404 activated the TRPV1 channel‐mGlu5 receptor‐PLC‐DAGL‐CB1 receptor signaling cascade. The present article provides a comprehensive literature review of the centrally located, COX-independent, analgesic MoA of paracetamol and relates how the current experimental evidence can be translated into clinical practice. The evidence discussed in this review established paracetamol as a central, COX-independent, antinociceptive medication that has a distinct MoA from non-steroidal anti-inflammatory drugs (NSAIDs) and a more tolerable safety profile. With the establishment of the central MoA of paracetamol, we believe that paracetamol remains the preferred first-line option for mild-to-moderate acute pain for healthy adults, children, and patients with health concerns. However, safety concerns remain with the high dose of paracetamol due to the NAPQI-mediated liver necrosis. Centrally acting paracetamol/p-aminophenol derivatives could potentiate the analgesic effect of paracetamol without increasing the risk of hepatoxicity. Moreover, the specific central MoA of paracetamol allows its combination with other analgesics, including NSAIDs, with a different MoA. Future experiments to better explain the central actions of paracetamol could pave the way for discovering new central analgesics with a better benefit-to-risk ratio.Keywords: paracetamol, acetaminophen, AM404, analgesia, molecular targets
... Also AM404inhibits sodium channels as like anesthetics, lidocaine and procaine [8]. Either of these actions by themselves has been shown to reduce pain and is suggested that its pain-relieving action is indeed mediated by the ECS [9]. ...
Aim: To study the use of paracetamol and ibuprofen for pediatrics pain and fever. Study selection: Data from original studies on pharmacogenomics, pharmacokinetics and pharmacology of par-acetamol were included in the analysis. Results: More published studies are required to comprehensively define the pharmacology and phamacokinetics of paracetamol and ibuprofen in paediatrics. Conclusion: An understanding of drug metabolic processes during ontogeny may enable predictions about the capacity of children to cope with medications. Pharmacogenomic screening may help elucidate the inter-individual variation in drug metabolism and pharmacokinetics.
... [11][12][13][14]24] Conversion of paracetamol to N-arachidonoylphenolamine (AM404), an endocannabinoid reuptake inhibitor, appears to be an important in pain control. [24,29] Lack of adverse effects associated with other antishivering drugs is the main advantage of paracetamol. [30,31] Many studies have reported adverse side effects for other antishivering medications. ...
... In a model of chronic pain, AEA and cannabinoid ligands were effective treatments [147,[149][150][151][152]. The combination of endocannabinoids and synthetic cannabinoids with nonsteroidal anti-inflammatory drugs promotes synergistic antinociceptive effects and may be useful in the pharmacotherapy of pain. In addition, studies of paracetamol (acetaminophen) activity, the most widely used painkiller, suggest that its analgesic efficacy is, in part, mediated by CB1R stimulation [144,[153][154][155][156][157]. Natural and synthetic cannabinoids, such as dronabinol and nabilone, have been studied in humans for chronic pain relief, and therapeutic efficacy for pain management and quality of life improvement in patients was observed. ...
The endocannabinoid system (eCB) has been studied to identify the molecular structures present in Cannabis sativa. eCB consists of cannabinoid receptors, endogenous ligands, and the associated enzymatic apparatus responsible for maintaining energy homeostasis and cognitive processes. Several physiological effects of cannabinoids are exerted through interactions with various receptors, such as CB1 and CB2 receptors, vanilloid receptors, and the recently discovered G-protein-coupled receptors (GPR55, GPR3, GPR6, GPR12, and GPR19). Anandamide (AEA) and 2-arachidoylglycerol (2-AG), two small lipids derived from arachidonic acid, showed high-affinity binding to both CB1 and CB2 receptors. eCB plays a critical role in chronic pain and mood disorders and has been extensively studied because of its wide therapeutic potential and because it is a promising target for the development of new drugs. Phytocannabinoids and synthetic cannabinoids have shown varied affinities for eCB and are relevant to the treatment of several neurological diseases. This review provides a description of eCB components and discusses how phytocannabinoids and other exogenous compounds may regulate the eCB balance. Furthermore, we show the hypo- or hyperfunctionality of eCB in the body and how eCB is related to chronic pain and mood disorders, even with integrative and complementary health practices (ICHP) harmonizing the eCB.
... A case study was performed for tablet manufacturing using paracetamol as an API. Paracetamol has been widely used as an analgesic (Ottani et al., 2006) and has high solubility (Kalantzi et al., 2006;Takagi et al., 2006). The tablet weight was taken as 300 mg, consisting of paracetamol (200 mg), lactose monohydrate (312 NF Lactose, Foremost Farms) (70 mg), and microcrystalline cellulose (Avicel DG, DuPont) (30 mg). ...
This paper presents surrogate models of dissolution behavior to identify the critical input parameters in tablet manufacturing processes. Dissolution behavior is a critical quality attribute, and is defined as the time profile of fraction of dissolved active pharmaceutical ingredients in a solvent from a tablet. Dissolution behavior was first calculated by mechanistic models using gPROMS® and fitted by the Weibull model. Random forest regression calculated the Weibull model parameters from the input model parameters. The developed models enabled to reduce computational cost without losing accuracy. Case studies were performed for both dry and wet granulation processes using paracetamol. The results identified key input and intermediate parameters to the dissolution behavior, e.g., granule bulk density and porosity. In addition, wet granulation had a tendency to make dissolution faster than dry granulation. The proposed approach can contribute to enhance simulation capabilities in the limited time of pharmaceutical process development.
... Paracetamol (acetaminophen), one of the most often used active substance all over the world, was proved to owe its analgesic activity in major part to anandamide reuptake inhibition and CB1 activation by its active metabolite�Narachidonoylphenolamine (AM404). 13,14 Other notable examples of pharmacologically relevant substances acting via CB1 or interacting with this receptor include metamizole (dipyrone), 15 fenofibrate 16 and raloxifene. 17 Is is possible that there may be other active drug ingredients with considerable affinity toward CB1. ...
Cannabinoid receptor type 1 (CB1) is an important modulator of many key physiological functions and thus a compelling molecular target. However, safe CB1 targeting is a non-trivial task. In recent years, there has been a surge of data indicating that drugs successfully used in the clinic for years (e.g. paracetamol) show CB1 activity. Moreover, there is a lot of promise in finding CB1 ligands in plants other than Cannabis sativa. In this study, we searched for possible CB1 activity among already existing drugs, their metabolites, phytochemicals, and natural-like molecules. We conducted two iterations of virtual screening, verifying the results with in vitro binding and functional assays. The in silico procedure consisted of a wide range of structure- and ligand-based methods, including docking, molecular dynamics, and quantitative structure-activity relationship (QSAR). As a result, we identified travoprost and ginkgetin as CB1 ligands, which provides a starting point for future research on the impact of their metabolites or preparations on the endocannabinoid system. Moreover, we found five natural-like compounds with submicromolar or low micromolar affinity to CB1, including one mixed partial agonist/antagonist viable for hit-to-lead phase. Finally, the computational procedure established in this work will be of use for future screening campaigns for novel CB1 ligands.
... Paracetamol is widely used for the relief of a number of acute pain conditions such as dysmenorrhea, muscle and joint pain, headache and toothache. Unlike non-steroidal anti-inflammatory drugs, paracetamol has no anti-inflammatory activity and is thought to exert antipyretic and analgesic effects through various mechanisms, including activation of selective and variable inhibition of prostaglandin synthesis and serotonergic pathways and cannabinoid receptors (7)(8)(9). Due to World of Health Organization's inclusion of this drug in the analgesic drug step (10) and also due to its decades of clinical experience, it is frequently prescribed in chronic pain conditions such as low back pain and osteoarthritis. Recently, meta-analyzes of randomized controlled trials covering these conditions have shown that effect sizes are moderate but still statistically significant compared to placebo (11)(12)(13)(14). ...
Aim: Paracetamol is a commonly used drug in acute and chronic pain. It is known that paracetamol, which is a pain reliever and antipyretic drug, is safe to use during pregnancy. The aim of this study was to investigate the effects of paracetamol on the uterine smooth muscle contraction- relaxation mechanism in female rats in diestrus.Material and Methods: Wistar-albino intact female rats were used in the study. Longitudinal strips of myometrium obtained from animals at the diestroeus stage. Stripes were suspended in an isolated organ bath containing crebs solution under 1 g passive tension. After the regulation period, paracetamol were added non-cumulatively at 1000μM and 2000μM concentrations. Before and after the application, the area under the curve (AUC) and peak to peak (p-p) values were normalized as % change.Results: Paracetamol caused a statistically significant decrease in p-p and area under the curve parameters of spontaneous uterine contractions at 1000 and 2000 μM doses (p <0.001).Conclusion: Paracetamol causes uterine relaxation by inhibiting uterine contraction. This effect should be taken into account in clinical use.
... Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) provide effective analgesia throughout the perioperative period. Dosing, analgesic mechanisms, and pharmacokinetics are summarized in Table 2. [46][47][48][49][50] Acetaminophen/Paracetamol Scheduled acetaminophen is associated with improved analgesia over per-request dosing. A retrospective review of geriatric patients with hip fractures found that scheduled acetaminophen (1000 mg intravenous [IV] every 8 hours) was associated with decreased length of stay (LOS), opioid consumption, pain scores, and missed therapy sessions versus those receiving per request acetaminophen (1000 mg orally). ...
Management of acute perioperative pain in the geriatric patient can be challenging as the physiologic and pharmacokinetic changes associated with aging may predispose older patients to opioid-related side effects. Furthermore, elderly adults are more susceptible to postoperative delirium and postoperative cognitive dysfunction, which may be exacerbated by both poorly controlled postoperative pain and commonly used pain medications. This narrative review summarizes the literature published in the past 10 years for several nonopioid analgesics commonly prescribed to the geriatric patient in the perioperative period. Nonopioid analgesics are broken down as follows: medications prescribed throughout the perioperative period (acetaminophen and nonsteroidal anti-inflammatory drugs), medications limited to the acute perioperative setting (N-methyl-D-aspartate receptor antagonists, dexmedetomidine, dexamethasone, and local anesthetics), and medications to be used with caution in the geriatric patient population (gabapentinoids and muscle relaxants). Our search identified 1757 citations, but only 33 specifically focused on geriatric analgesia. Of these, only 21 were randomized clinical trials' and 1 was a systematic review. While guidance in tailoring pain regimens that focus on the use of nonopioid medications in the geriatric patient is lacking, we summarize the current literature and highlight that some nonopioid medications may extend benefits to the geriatric patient beyond analgesia.
... It has been reported to cause renal insufficiency in about 1-2% of individuals. It is also found that paracetamol causes nephrotoxicity, hepatotoxicity and cardiovascular complications [5,6]. ...
Qurs Afsanteen Saghir is a polyherbal Unani formulation in the form of tablet. This formulation consists of multiple medicinal plants like Afsanteen (Artemisia absinthium L.), Badam Talkh (Prunus dulcis (Mill.) D.A.Webb), Asaroon (Asarum europaeum L.), Anisoon (Pimpinella anisum L.) and Tukhm-e-Karafs (Apium graveolens L.). The clinical adult dose of study drug is 3.5 –7 g per day as mentioned in Unani literature. The present study evaluated the antipyretic, analgesic and anti-inflammatory potential of Qurs Afsanteen Saghir using different animal models. Antipyretic activity was measured using yeast-induced pyrexia model in rats at 360 and 720 mg/kg bw dose of test drug and paracetamol (70 mg/kg bw p.o.) as standard control. Analgesic effect was evaluated using acetic acid-induced writhing test in mice using test drug at dose 720 and 1440 mg/kg bw and diclofenac sodium (15 mg/kg bw p.o.) as standard control. Eddy’s hot plate test was conducted in rats using test drug at the dose of 360 and 720 mg/kg bw and buprenorphine (0.10 mg/kg s.q.) as standard control. Anti-inflammatory activity was assessed by carrageenan-induced paw edema model in rats with the dose of 360 and 720 mg/kg of test drug and Indomethacin (10 mg/kg p.o.) as standard control. The study drug significantly reduced the temperature and pain at both dose levels in a time-dependent manner as compared to normal control. However, the reduction of inflammation was observed at low dose (360 mg/kg bw) only after 3 hours of carrageenan administration. These findings indicated that tested drug showed potential activity as antipyretic and analgesic; whereas the drug may not be considered quite effective as an anti-inflammatory agents.
... The antipruritic effect noted here is more robust than a previous study we conducted on the effect of topical 4% strontium on cowhage-induced itch (9). Studies have suggested that the analgesic relief afforded by acetaminophen involves activation of the cannabinoid system and, indeed, antagonism of the cannabinoid (CB)-1 receptor has been shown to block acetaminophen-induced analgesia (10,11). Given the similarities between pain and itch transmission, it is possible, through its action on CB1 receptors, that acetaminophen may have antipruritic properties. ...
There is a need for new topical antipruritics that are effective on many types of itch. This study examined the antipruritic efficacy of a new formulation of topical acetaminophen. In vitro skin permeability studies showed that 2.5% and 5% formulations are able to rapidly deliver an adequate amount of the drug into the skin. In a double-blind, vehicle-controlled, randomized study in 17 healthy volunteers, 1%, 2.5% and 5% acetaminophen gels and a vehicle gel were applied to the skin prior to histaminergic and non-histaminergic itch induction and assessment of thermal pain thresholds. The 2.5% and 5% gel formulations significantly reduced the itch intensity time course and the area under the curve for both histamine and cowhage itch. No effect was noted on heat pain thresholds and no adverse effects were observed. These results suggest that topical acetaminophen would be a safe and effective over-the-counter medication for itch.
... Results at Day 7 test-point showed: (G) MA animals which underwent the surgery model treated with Bup-0.1 mg/kg were significantly impaired compared to MA Controls. Par treatment (75 mg/kg or 150 mg/ kg) to surgery model animals prevented long lasting cognitive impairments; (H) MA + Surgery Model groups treated with Bup (0.05 mg/kg or 0.1 mg/kg) were impaired at delay time lengths[11][12][13][14][15] ...
Post-operative cognitive dysfunction (POCD) is a debilitating clinical phenomenon in elderly patients. Management of pain in elderly is complicated because analgesic opiates elicit major side effects. In contrast, paracetamol (acetaminophen) has shown analgesic efficacy, no impact on cognition, and its side effects are well tolerated. We investigated the efficacy of paracetamol, compared to the opioid analgesic buprenorphine, in a model of POCD by investigating cognitive decline, allodynia, peripheral and hippocampal cytokines levels, and hippocampal microtubule dynamics as a key modulator of synaptic plasticity. A POCD model was developed in middle-aged (MA) rats by inducing a tibia fracture via orthopaedic surgery. Control MA rats did not undergo any surgery and only received isoflurane anaesthesia. We demonstrated that cognitive decline and increased allodynia following surgery was prevented in paracetamol-treated animals, but not in animals which were exposed to anesthesia alone or underwent the surgery and received buprenorphine. Behavioral alterations were associated with different peripheral cytokine changes between buprenorphine and paracetamol treated animals. Buprenorphine showed no central effects, while paracetamol showed modulatory effects on hippocampal cytokines and markers of microtubule dynamics which were suggestive of neuroprotection. Our data provide the first experimental evidence corroborating the use of paracetamol as first-choice analgesic in POCD.
... One possible interaction with the serotonergic pathway maybe though altering CNS monoamine neuron types in the brain that contain a major receptor for PGE2 (EP3 receptor [139]). Further to the above, AM404 can inhibit anandamide [151], with stimulation of (canobinoide 1) CB1 receptor activity (without binding) via FAAH [133], suggesting a reliance of APAP antinociceptive activity on interaction with the endocannabinoid system [134,152]. Interestingly, AM404 is not identifiable in the blood after APAP administration [133] which might explain, to some degree, the absence of peripheral anti-inflammatory action [134]. ...
Chronic pain is a considerable health concern worldwide, effecting almost 30% of all European adults. Osteoarthritis (OA), a progressive pro-inflammatory condition, is one of the leading causes of chronic pain (effecting 13% of all those over 50 years, globally) and is the most common cause of joint pain. The prevalence of non-steroidal anti-inflammatory drug (NSAIDs) and analgesic use has been well studied and is abundant throughout the western world, with women being the greatest users and ibuprofen generally being the most reported NSAID. In the US, 65% of all OA patients are prescribed NSAIDs for pain management and form part of the current recommended strategy for OA clinical management. While some NSAIDs and analgesics are effective at improving pain and physical function, they come with significant and harmful side effects such as gastrointestinal complications, renal disturbances and severe cardiovascular events. Given these side-effects, any reduction in NSAID and analgesia use (and the resulting potentially harmful side effects) is of particular importance to OA public health. As such, a number of non-pharmaceutical alternatives (bioactive nutraceuticals) have been developed that may reduce NSAID and analgesia use while maintaining pain reduction and improvements in physical function. This chapter will discuss select nutraceuticals that are not currently in mainstream use but may have the potential to aid in the treatment of OA.
... In contrast, metamizole and paracetamol are the most widely used non-opioid analgesics. They have both central (inhibition of cyclooxygenase type 3 (COX-3)) and peripheral mechanisms of action [41][42][43][44][45][46], and they have proven their analgesic efficacy in the treatment of postoperative pain, even in a single dose administered as pre-emptive analgesia [47][48][49][50][51][52][53][54]. ...
Background and Objectives: Although vitreoretinal surgery (VRS) is most commonly performed under regional anaesthesia (RA), in patients who might be unable to cooperate during prolonged procedures, general anaesthesia (GA) with intraprocedural use of opioid analgesics (OA) might be worth considering. It seems that the surgical pleth index (SPI) can be used to optimise the intraprocedural titration of OA, which improves haemodynamic stability. Preventive analgesia (PA) is combined with GA to minimise intraprocedural OA administration. Materials and Methods: We evaluated the benefit of PA combined with GA using SPI-guided fentanyl (FNT) administration on the incidences of PIPP (postprocedural intolerable pain perception) and haemodynamic instability in patients undergoing VRS (p < 0.05). We randomly assigned 176 patients undergoing VRS to receive GA with SPI-guided FNT administration alone (GA group) or with preventive topical 2% proparacaine (topical anaesthesia (TA) group), a preprocedural peribulbar block (PBB) using 0.5% bupivacaine with 2% lidocaine (PBB group), or a preprocedural intravenous infusion of 1.0 g of metamizole (M group) or 1.0 g of paracetamol (P group). Results: Preventive PBB reduced the intraprocedural FNT requirement without influencing periprocedural outcomes (p < 0.05). Intraprocedural SPI-guided FNT administration during GA resulted in PIPP in 13.5% of patients undergoing VRS and blunted the periprocedural effects of preventive intravenous and regional analgesia with respect to PIPP and haemodynamic instability. Conclusions: SPI-guided FNT administration during GA eliminated the benefits of preventive analgesia in the PBB, TA, M, and P groups following VRS.
... However, the importance of treating other less deleterious ailments, or the treatment of the negative side effects that originate from the aggressive treatment strategies of major diseases such as cancer, chemotherapy for example, is not without utility. A suite of clinical trials have supported the ability of Cannabis-derived metabolite constituents to (1) act as effective antiemetics [184][185][186][187][188], (2) ease the spasticity symptoms associated with Motor Neuron Disease and Multiple Sclerosis [225], (3) stimulate appetite [173,174,[226][227][228][229], (4) help regulate sleep patterns [178,[230][231][232], (5) initiate analgesia [233][234][235][236], (6) act as an anxiolytic to alleviate the psychotic symptoms of schizophrenia [237][238][239][240][241], (7) treat anxiety and post-traumatic stress disorders [31, 171,242], (8) be utilised as palliative care agents [243,244], (9) aid in the acute inflammatory response and its protracted recovery [245], and (10) mitigate the effects of opioid addiction [246,247]. ...
Cannabis sativa (Cannabis) is one of the world’s most well-known, yet maligned plant species. However, significant recent research is starting to unveil the potential of Cannabis to produce secondary compounds that may offer a suite of medical benefits, elevating this unique plant species from its illicit narcotic status into a genuine biopharmaceutical. This review summarises the lengthy history of Cannabis and details the molecular pathways that underpin the production of key secondary metabolites that may confer medical efficacy. We also provide an up-to-date summary of the molecular targets and potential of the relatively unknown minor compounds offered by the Cannabis plant. Furthermore, we detail the recent advances in plant science, as well as synthetic biology, and the pharmacology surrounding Cannabis. Given the relative infancy of Cannabis research, we go on to highlight the parallels to previous research conducted in another medically relevant and versatile plant, Papaver somniferum (opium poppy), as an indicator of the possible future direction of Cannabis plant biology. Overall, this review highlights the future directions of cannabis research outside of the medical biology aspects of its well-characterised constituents and explores additional avenues for the potential improvement of the medical potential of the Cannabis plant.
... Par mechanism of action is still not fully understood, the drug lacks peripheral anti-in ammatory properties and it passes the blood-brain barrier to be homogenously distributed throughout the CNS even at low doses [11][12][13] . Experimental evidence suggest that the analgesic effects of Par might be due inhibition of Cyclooxygenase (COX) in the brain 14 ; and indirect activation of cannabinoid CB1 receptor 15,16 . Furthermore, growing evidence shows that Par have neuroprotective effects both in vitro 17 and in vivo 18 . ...
Post-operative cognitive dysfunction (POCD) is a debilitating clinical phenomenon in elderly patients. Management of pain in elderly is complicated because analgesic opiates elicit major side effects. In contrast, paracetamol (acetaminophen) has shown analgesic efficacy, no impact on cognition, and its side effects are well tolerated. We investigated the efficacy of paracetamol, compared to the opioid analgesic buprenorphine, in a model of POCD by investigating cognitive decline, allodynia, peripheral and hippocampal cytokines levels, and hippocampal microtubule dynamics as a key modulator of synaptic plasticity. A POCD model was developed in middle-aged (MA) rats by inducing a tibia fracture via orthopaedic surgery. Control MA rats did not undergo any surgery and only received isoflurane anaesthesia. We demonstrated that cognitive decline and increased allodynia following surgery was prevented in paracetamol-treated animals, but not in animals which were exposed to anesthesia alone or underwent the surgery and received buprenorphine. Behavioral alterations were associated with different peripheral cytokine changes between buprenorphine and paracetamol treated animals. Buprenorphine showed no central effects, while paracetamol showed modulatory effects on hippocampal cytokines and markers of microtubule dynamics which were suggestive of neuroprotection. Our data provide the first experimental evidence corroborating the use of paracetamol as first-choice analgesic in POCD.
... They showed that, formation of p-aminophenol was gift altogether tissues, however highest levels within the liver area unit according which AM404 was primarily found within the brain. AM404 may be a potent agonist of the TRPV1 receptor that is transient receptor potential vanilloid kind one, associate degree Anandamide Membrane Transporter (AMT) blocker, a low-affinity substance of the sort one Cannabinoid receptor (CB1) and what is more, it has been shown that AM404 induces physiological condition and physiological condition in animal models [9,[12][13][14][15][16]. ...
... Hence, it works effectively when combined with codeine for more effective control of moderate-to-severe pain and discomfort. 22 Paracetamol is available orally, in several tablet and liquid formulations, however the dosage should be guided by the age and general condition of the patient. ...
Back pain affects people across any socio-economic category and is a leading cause of absenteeism and decreased productivity in the workplace. This symptomatic condition is caused by multiple factors, making it difficult to manage. With a small proportion of people experiencing back pain due to pathological reasons, in the larger majority, back pain is due to a mechanical cause. Taking a complete history that includes identifying risk factors such as depression, poor posture, lack of exercise, older age and a physically demanding job is crucial to the effective management of the condition. Behavioural, psychological and social factors of the patient should form the backbone for treatment of back pain. Non-pharmacological management such as exercise, spinal manipulation and acupuncture should be the first-line treatment; however, if this provides poor results then pharmacological measures such as the use of non-steroidal anti-inflammatory drugs (NSAIDS) like ibuprofen or muscle relaxants such as cyclobenzaprine should be considered.
... But it is said to achieve this effect by inhibiting both isoforms of cyclooxygenase, COX-1 and COX-2 enzymes involved in prostaglandin (PG) synthesis. 18 Paracetamol is available in a number of dosage forms. However, the choice of dosage form and the strength of the dose is entirely dependent on patient factors like age and severity of pain. ...
Sport injuries and muscle pain can occur as a result of engagement in exercise and or organized sporting activities. These injuries affect all age groups and gender. The most common types of sporting activities known to cause these injuries include jogging, cycling, volleyball, swimming and heavy weight lifting. Lack of warm-ups before participating in sporting activity, overtraining and or excessive exposure to these physical activities may increase risk of causing injuries. These factors are categorized as extrinsic factors. Intrinsic factors that may lead to sport injuries or may precipitate these injuries are age, previous injuries and level of flexibility. The most common type of injuries seen are sprains and strains. These injuries are accompanied with pain, swelling and redness of injured area. Non-pharmacological and pharmacological management are available for the effective management of these injuries. Pain may vary from mild to severe depending on the severity of injury. These varying types of pain can be managed optimally using non-narcotics such as paracetamol and non-steroidal anti-inflammatory (NSAIDs) like ibuprofen. When pain is categorized as moderated to severe, narcotics may be prescribed and administered.
... Later on, studies on AM404 indicated an association of this active metabolite with the endocannabinoid system 247 In addition to AM404, NAPQI has also been shown to be involved in the analgesic effect of paracetamol by activating TRPA1 receptor on the spinal nociceptive sensory neurons 252 . ...
... There is some data to suggest that paracetamol may have analgesic activity on cannabinoid receptors in the CNS and that this activity is mediated through a metabolite (N-arachidonyphenolamine). 13 This metabolite may have an antianxiolytic activity through the same receptors but this has not yet been described. ...
Objective: To see the effect of oral paracetamol and clonidine on pediatric preoperative anxiety in adenotonsillectomy.
Methodology: The participants of this double blind clinical trial study consisted of 120 children.Their age range was between 3-12 years. They were in ASA class I of anesthesia and were chosen for elective adenotonsillectomy in Qods hospital in Qazvin, Iran.
The patients were randomly divided in three equal groups. One group received paracetamol 20mg/kg, another group received 4mcg/kg clonidine orally 60-90 minutes before operation and the third group received placebo. As the first step, in order to do the statistical analysis, intensity of preoperative anxiety had been evaluated by Modified-Yale Preoperative Anxiety Scale (m-Yale PAS) and data were transformed to the SPSS software. Then different statistical procedures like Chi-square, One way Annova and Tukey test were performed.
Results: There was no significant difference (statistical) of age, weight and sex among three groups. Mean score of anxiety was significantly lower in paracetamol and clonidine’s groups than placebo’s group, but there was no significant statistical difference between paracetamol and clonidine’s groups in decreasing preoperative anxiety score.
Conclusions: Oral paracetamol like oral clonidine decreases preoperative anxiety score. Thus one can use paracetamol instead of clonidine.
... In 2005, Högestatt et al. (61) reported that paracetamol, following deacetylation to p-aminophenol, is FAAH-dependently conjugated with arachidonic acid in the brain and spinal cord to form the bioactive AM-404. Then, CB1 receptors have been demonstrated to participate in both local and systemic antinociceptive effects of paracetamol (62,63). In their detailed research, Mallet et al. (28) suggested that AM-404 indirectly activates the supraspinal CB1 receptors, which in turn reinforces the activity of descending serotonergic inhibitory pathways. ...
Non-steroidal anti-inflammatory drugs (NSAIDs) are known to produce antinociceptive effects mainly through peripheral COX-inhibition. Paracetamol and dipyrone are different from classical NSAIDs, because they exert weak anti-inflammatory activity; mechanisms other than peripheral COX inhibition appear to play role in their antinociceptive actions. In this review, we specified classical NSAIDs, paracetamol and dipyrone as "non-opioid analgesics" and discussed the mechanisms mediating participation of the endocannabinoid system in the antinociceptive effects of these analgesics. Non-opioid analgesics and their metabolites may activate cannabinoid receptors. In addition, several mechanisms are implicated in the elevation of endocannabinoid levels following administration of non-opioid analgesics. Of these, reduction of endocannabinoid degradation via FAAH and/or COX-2 inhibition, accumulation of arachidonic acid to endocannabinoid biosynthesis following COX inhibition, inhibition of cellular uptake of endocannabinoids directly or following inhibition of nitric oxide synthase production, and induction of endocannabinoid release are among the proposed mechanisms.
... A potential mechanism of the antinociception activity of Paracetamol can block prostaglandin synthesis by inhibiting the cyclooxygenase (COX) enzymes. Furthermore, other mechanisms have been suggested that link Paracetamol with the opioid system, the serotonergic neurotransmitter system, and cannabinoid receptors 1 and 2 (CB1 and CB2) [4][5][6]. CB receptors are the target of a class of endogenous lipids known as endocannabinoids (ECS), such as 2-arachidonoylglycerol (2-AG) and anandamide (AEA). In addition to the classic ECS, the group extends to other endogenous lipids, which, despite showing low affinity for these two receptors, share the enzymes of biosynthesis and degradation with the canonical ECS, one of which is palmitoylethanolamide (PEA) [7]. ...
Inflammation is known to be an essential trigger of the pathological changes that have a critical impact on nerve repair and regeneration; moreover, damage to peripheral nerves can cause a loss of sensory function and produces persistent neuropathic pain. To date, various potential approaches for neuropathic pain have focused on controlling neuroinflammation. The aim of this study was to investigate the neuroprotective effects of a new association of ultramicronized Palmitoylethanolamide (PEAum), an Autacoid Local Injury Antagonist Amide (ALIAmide) with analgesic and anti-inflammatory properties, with Paracetamol, a common analgesic, in a rat model of sciatic nerve injury (SNI). The association of PEAum–Paracetamol, in a low dose (5 mg/kg + 30 mg/kg), was given by oral gavage daily for 14 days after SNI. PEAum–Paracetamol association was able to reduce hyperalgesia, mast cell activation, c-Fos and nerve growth factor (NGF) expression, neural histological damage, cytokine release, and apoptosis. Furthermore, the analgesic action of PEAum–Paracetamol could act in a synergistic manner through the inhibition of the NF-κB pathway, which leads to a decrease of cyclooxygenase 2-dependent prostaglandin E2 (COX-2/PGE2) release. In conclusion, we demonstrated that PEAum associated with Paracetamol was able to relieve pain and neuroinflammation after SNI in a synergistic manner, and this therapeutic approach could be relevant to decrease the demand of analgesic drugs.
... 6 Interference with serotonergic and cannabinoid pathways has been reported. 6,8 The potential mechanisms linking acetaminophen to psychiatric problems include excess toxic N-acetyl-p-benzoquinone imine formation, oxidative stress-and inflammation-induced immune dysregulation, altered brain-derived neurotropic factor levels, endocrine disruption, inhibition of prostaglandin synthesis, and cannabinoid receptor 9 and anti-androgenic effects. 10,11 Attention deficit/hyperactivity disorder and autism spectrum disorder are classified as neurodevelopmental disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 12 where it is stated that affected individuals may exhibit difficulties from birth onward and that the neurological cause arises during gestation or at birth, 13,14 which is supported by genomic findings. ...
Background
Several studies have reported that there is an association between developmental and emotional/behavioural problems in children exposed to acetaminophen during foetal development. However, few studies have focused on development and behavioural outcomes in early life.
Objectives
To test the association between prenatal exposure to acetaminophen and low neurodevelopmental performance at 24 months and behavioural/emotional problems at 48 months of life.
Methods
We used data from the 2004 Pelotas Birth Cohort, a population‐based longitudinal prospective study. Neurodevelopment was evaluated at 24 months using Battelle's Developmental Inventory (BDI) (n = 3737). We assessed global function as well as each domain (personal‐social, adaptative, motor, cognitive, and communication). Behavioural/emotional problems were assessed at 48 months using the Child Behaviour Checklist (CBCL) (n = 3624). We used the CBCL total, externalising, and internalising symptomatology and individual subscales (withdrawn, somatic complaints, anxious/depressed, social problems, cognitive problems, attention problems, aggressive behaviour, and rule‐breaking behaviour). Acetaminophen use during pregnancy was retrospectively assessed at the perinatal follow‐up. Poisson regression and multiple linear regression analyses were used to test the association, adjusting for several family and maternal sociodemographic and health factors, medication use during pregnancy, and the sex of the child.
Results
Acetaminophen exposure during prenatal development was not associated with low neurodevelopmental performance at 24 months assessed using the BDI or to emotional and behavioural problems assessed at 48 months using the CBCL in the adjusted models.
Conclusions
We cannot confirm the existence of an association between acetaminophen used during pregnancy and low neurodevelopmental performance at 24 months and emotional/behavioural problems at 48 months of life based on the present results.
... • Pharmacotherapies involving the 2-AG/CB 2 -related signalling system should be considered for treating paracetamol-induced liver injury. Clerc, Deveaux, & Lotersztajn, 2007;Ottani, Leone, Sandrini, Ferrari, & Bertolini, 2006 ...
Background and purpose:
Protective mechanisms of the endogenous cannabinoid (eCB) system against drug-induced liver injury (DILI) are actively being investigated regarding the differential regulatory role of the cannabinoid CB1 and CB2 receptors in liver fibrogenesis and inflammation.
Experimental approach:
The 2-arachidonoyl glycerol (2-AG)-related signaling receptors and enzymatic machinery, and inflammatory/fibrogenic factors were investigated in the liver of a mouse model of hepatotoxicity induced by acute and repeated overdoses (750 mg kg-1 day-1 ) of acetaminophen (APAP), previously treated with selective CB1 (ACEA) and CB2 (JWH015) agonists (10 mg/kg), or lacking CB1 and CB2 receptors.
Key results:
Acute APAP increased the expression of CB2, ABHD6 and COX-2, while repeated APAP increased that of CB1 and COX-2 and decreased that of DAGLβ. Both acute and repeated APAP decreased the liver content of acylglycerols (2-AG, 2-LG, 2-OG). Human liver samples from a patient suffering APAP hepatotoxicity confirmed CB1 and CB2 increments. Acute APAP-exposed CB2ko mice had higher expression of the fibrogenic αSMA and the cytokine IL6, and lower apoptotic cleaved Caspase3. CB1 deficiency enhanced the repeated APAP-induced increases in αSMA and cleaved Caspase3, and blocked those of Cyp2e1, TNFα, the chemokine MCP1, and the circulating transaminase γGT. Although JWH015 reduced the expression of αSMA and TNFα in acute APAP, ACEA increased the expression of cleaved Caspase3 and MCP1 in repeated APAP.
Conclusions and implications:
The differential role of CB1 versus CB2 receptors on inflammatory/fibrogenic factors related to APAP-induced hepatotoxicity should be considered for designing alternative therapies against DILI.
JNJ-10450232 (NTM-006) is a non-opioid, non-NSAID analgesic and antipyretic compound with structural similarity to acetaminophen. Preclinical models show comparable analgesia relative to acetaminophen and no evidence of hepatotoxicity associated with overdose. Moreover, it was safe and generally well tolerated in a First-in-Human Study. This single-dose, single-center, inpatient, randomized, double-blind study in moderate-to-severe acute pain following third molar extraction compared efficacy and safety of 250 mg and 1000 mg JNJ-10450232 (NTM-006), 1000 mg acetaminophen, and placebo during the 24 h following administration. While onset of action of 1000 mg JNJ-10450232 (NTM-006) was relatively slower compared with acetaminophen, its duration of action was sustained up to 24 h being superior beginning 7 h after administration. No clinically important differences among treatment groups in nature or severity of adverse events were observed and no serious adverse events were reported. Increased bilirubin, potentially due to UGT1A1 inhibition and ingestion of blood from oral surgery, was the most commonly reported adverse event and the only event reported by ≥ 5% of subjects across treatment groups. These data support further evaluation of JNJ-10450232 (NTM-006) for the treatment of moderate-to-severe pain. CLINICALTRIALS.GOV ID: NCT02209181.
Background: Intravenous Regional Anaesthesia (IVRA) also known as Biers block is a procedure used to provide regional block in both the upper and lower extremities. This study aims to determine the effects of adding paracetamol to lidocaine for intravenous regional anaesthesia (IVRA). Methods: Forty eligible patients undergoing short upper limb surgery received IVRA were assigned to two groups (n = 20 each): Group X: received lidocaine (3 mg/kg) diluted with normal saline and paracetamol 450 mg to a volume of 40 ml. Group Y: received lidocaine (3 mg/kg) diluted with normal saline a to a volume of 40 ml. Variables measured were: sensory onset and recovery time, visual analogue scale (VAS) scores; intraoperative and at 6 hours postoperatively, tourniquet pain and time to first analgesic requirement. Results: Sensory block onset time among group X was significantly shorter than group Y p= statistically significant. Durations of Sensory block in group X was also significantly longer than group Y p= statistically significant. Twenty minute intraoperatively till 60 minutes, VAS was significantly higher in group Y which required majority 68.4% to receive a single dose of intraoperative fentanyl analgesia compared to 27.6% among Group X. Postoperative VAS was lower among Group X from 2nd -5th hours compared to group Y, p= statistically significant. Similarly, time to first postoperative analgesic requirement was significantly longer in Group X p= statistically significant than group Y. Conclusion: Addition of paracetamol to Lidocaine for IVRA improves quality of analgesia and reduce intra and postoperative analgesic requirement.
Background
Aging is closely associated to several deleterious conditions and cognitive impairment. Administration of low-dose paracetamol (APAP) has previously been reported to improve cognitive performance in both human and animal studies. However, the altered cognitive effects of low-dose APAP treatment in the aging brain have not been elucidated.
Objectives
The purpose of this study was to determine whether low-dose APAP treatment improves cognitive dysfunction in a d-galactose (d-gal)-induced aging model.
Materials and methods
APAP (15 and 50 mg/kg p.o.) and vitamin E (Vit E 100 mg/kg p.o.) were administered once daily to d-gal-injected mice (200 mg/kg s.c.) for 6 weeks. The elevated plus maze (EPM), open field, novel object recognition (NOR), and Morris water maze (MWM) tests, respectively, were used to measure altered neurobehavioral functions, including anxiety-like behavior and exploratory locomotor activity, as well as learning and memory performance. The gene transcription of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling in brain tissues was evaluated by real-time polymerase chain reaction.
Results
Compared to the control, d-gal significantly decreased exploratory locomotor activity and NOR and MWM performance but did not significantly change the activity in the EPM test. However, APAP50 and Vit E significantly reversed the effects of d-gal injection on exploratory locomotor activity. In addition, low-dose APAP (15 and 50 mg/kg) and Vit E significantly improved the reduction in NOR and MWM performance induced by d-gal. Real-time polymerase chain reaction analysis revealed that the mRNA expression of BDNF, neurotrophic tyrosine receptor kinase (NTRK), which is the gene coding TrkB receptor, and cAMP response element-binding protein (CREB) was significantly decreased in the frontal cortex and hippocampus of the d-gal mice. However, APAP50 and Vit E significantly increased BDNF and NTRK mRNA expression in both the frontal cortex and the hippocampus. A lower dose of APAP (15 mg/kg) significantly elevated the mRNA expression of NTRK, but only in the hippocampus. Moreover, APAP50 significantly increased CREB mRNA expression in the frontal cortex and hippocampus.
Conclusion
Low-dose APAP treatment has a neuroprotective effect on cognitive dysfunction in the d-gal aging model, and the underlying molecular mechanisms depend on the activation of BDNF/TrkB signaling.
https://www.medrecordscongress.org/_files/ugd/628906_915c837c894e47f8b1b58df98913ed58.pdf
Purpose:
To determine whether intravenous administration of paracetamol can prevent postoperative ocular hypertension (POH) in dogs following routine phacoemulsification.
Methods:
Diabetic and non-diabetic patients (total 54 dogs) undergoing unilateral or bilateral phacoemulsification were recruited to this placebo-controlled, prospective study. The control group received 1 ml/kg saline via intravenous infusion while the treatment group received 10 mg/kg paracetamol via intravenous infusion. Infusions were administered 30 min prior to surgery and repeated 12 h following initial administration. All patients received topical latanoprost at the conclusion of surgery. Intraocular pressure (IOP) was measured before premedication (baseline), and at 1 h, 3 h, 5 h and 18 h following extubation. POH was defined as an IOP above 25 mmHg (POH25). In addition, the number of patients with an IOP exceeding 20 mmHg was analyzed (POH20).
Results:
POH20 occurred in 33 of 54 animals (61.1%), including 19 of 25 animals (76.0%) in the control group and 14 of 29 animals (55.2%) in the treatment group. POH25 occurred in 23 of 44 animals (52.3%), including 13 of 25 animals (52.0%) in the control group and 10 of 29 animals (34.5%) in the treatment group. Paracetamol administration showed a significant positive effect on reducing the incidence of POH20 (p = .048), but not POH25 (p = .221).
Conclusions:
When comparing groups, treatment with paracetamol showed a statistically significant reduction in the incidence of POH20, although no differences were observed in the incidence of POH25 between groups. Further studies are warranted to explore whether alternative drug regimes or routes of administration can provide enhanced efficacy in the prevention of POH25.
Paracetamol, or acetaminophen (AAP), is the most commonly used analgesic during pregnancy and early life. While therapeutic doses of AAP are considered harmless during these periods, recent findings in both humans and rodents suggest a link between developmental exposure to AAP and behavioral consequences later in life. The aim of this study is to evaluate the impact of neonatal exposure to clinically relevant doses of AAP on adult spontaneous behavior, habituation, memory, learning, and cognitive flexibility later in life using a mouse model. Markers of oxidative stress, axon outgrowth, and glutamatergic transmission were also investigated in the hippocampus during the first 24 h after exposure. In addition, potential long-term effects on synaptic density in the hippocampus have been investigated. In a home cage setting, mice neonatally exposed to AAP (30 + 30 mg/kg, 4 h apart) on postnatal day 10 displayed altered spontaneous behavior and changed habituation patterns later in life compared to controls. These mice also displayed reduced memory, learning and cognitive flexibility compared to control animals in the Morris water maze. An increase of markers for oxidative stress was observed in the hippocampus 6 h after AAP exposure. As AAP is the first choice treatment for pain and/or fever during pregnancy and early life, these results may be of great importance for risk assessment. Here we show that AAP can have persistent negative effects on brain development and suggest that AAP, despite the relatively low doses, is capable to induce acute oxidative stress in the hippocampus.
Aims:
This study investigated the relationship between the analgesic efficacy of acetaminophen and the descending noradrenergic systems using rodent models of inflammatory pain.
Main methods:
Inflammatory pain models were established by carrageenan injection into rats' paws. The models were defined as acute (4 h after carrageenan injection), subacute (24 h after carrageenan injection), and late (1 week after carrageenan injection) phase. To evaluate intravenous acetaminophen treatment, the withdrawal threshold to mechanical stimuli was assessed simultaneously with in vivo microdialysis assay of noradrenaline levels in the locus coeruleus (LC). Further analyses were performed to observe the effect of yohimbine on the treatment and the impact of AM404 treatment, a metabolite of acetaminophen, on noradrenaline levels in the LC.
Key findings:
In all phases, intravenous acetaminophen had a significant anti-hyperalgesic effect (p < 0.05). There was a significant time-dependent increase in the noradrenaline concentration within the LC (acetaminophen versus saline treatment; at 30 min, p < 0.001; 60 min, p < 0.01) in the subacute pain model, but not in the acute and late phase pain models. Intrathecal pre-injection of yohimbine attenuated the anti-hyperalgesic effect after acetaminophen injection only in the subacute model (p < 0.05). In the subacute pain model, intracerebroventricular administration of AM404 showed the same trend in noradrenaline levels as acetaminophen administration (AM404 versus vehicle group at 30 min, p < 0.001).
Significance:
We found the descending noradrenergic inhibitory system is involved in the antinociceptive action of acetaminophen in the subacute phase of inflammatory pain.
Otolaryngologic procedures in the pediatric population can present unique challenges to the anesthesiologist. Pediatric patients should not be considered “little adults” because they display differences in physical characteristics, physiology, pharmacology, coping strategies, emotional needs, and care coordination compared with the adult population. This chapter focuses on patient optimization, risk evaluation and mitigation, anesthetic concerns for specific pediatric conditions, and the perioperative management of children undergoing otolaryngologic procedures.
In present scenario the exploit of conventional medicine is enlarging to newer prospects in addition to plants still stay as the original source of the structurally significant compounds that guide to the expansion of the innovative drugs. Recently Bangladesh has concerning forty five thousands plant variety among which therapeutic assets has been treated to the several thousands. The conventional Bangladeshi system of the medicine, Ayurveda reveals the exercise of the plants in treatment of the various diseases. The ethnobotanical investigation done in the most recent few decades have revealed cognitive, anti-inflammatory as well as analgesic actions of the plants mentioned in the conventional literature. Numerous herbal groundings are being stipulated as the anti-inflammatory, cognitive as well as analgesic in traditional literature. The research for innovative anti-inflammatory, cognitive and analgesic agents from enormous array of the medicinal plant sources is escalating. This reviews such type of the plant species in addition to their products which have demonstrated experimental and clinical anti-inflammatory and also analgesic, cognitive actions, the possible method of the action in addition to their therapeutic value. Several of the significant taxa which are originated efficient as cognitive, anti-inflammatory and analgesic agents such as Callophyllum inophyllum L, Ananas comosus (L.) Merr., Calotropis gigantea (L.) R.Br., Camellia sinensis (L.) Kuntz., Calotropis procera (Ak.) R.Br., Cannabis sativa L., Curcuma longa L., Kalanchoe crenata Andr., Spillanthes acmella Murr, Mangifera indica L., Ricinus communis Linn., Sida cordifolia L., Zingiber officinale Roscoe, Ginkgo biloba , Zizyphus jujube, Emblica Officinalis, Cocos nucifera, Celastrus paniculatus. Here these plants species have shown contrasting degrees of cognitive, anti-inflammatory as well as analgesic activities. Peer Review History: Received: 4 September 2020; Revised: 6 October; Accepted: 27 October, Available online: 15 November 2020 UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file Average Peer review marks at initial stage: 6.0/10 Average Peer review marks at publication stage: 8.0/10 Reviewer(s) detail: Dr. Marwa A. A. Fayed, University of Sadat City, Egypt, maafayed@gmail.com Dr. Hatem Sameir Abbas, Al-Azhar University, Egypt, hsam8406@yahoo.com Comments of reviewer(s): Similar Articles: A REVIEW ON MEDICINAL USES OF DIFFERENT PLANTS OF EUPHORBIACEAE FAMILY EXPLORING THE ANTIPARASITIC ACTIVITY OF MEDICINAL PLANTS A STUDY ON DIFFERENT PLANTS OF APOCYNACEAE FAMILY AND THEIR MEDICINAL USES PHYTOCHEMISTRY STUDY OF PLANTS BELONGING TO CAPPARIS
The purpose of this book is not merely to be a source of information, but also to
present the background and context in which different classes of drugs have been
developed and are used. Pharmaceutical evaluation is concerned with the study of
industrial processes required to convert raw material into value added
pharmaceuticals such as drugs and excipients. It is subject of importance both to
the industrial pharmacist and the undergraduate students. Over the year student of
pharmacy have been feeling the need for a simple book yet in sufficient depth to
enable them to handle industrial operation with understanding of the principles
involved therein. This book deals with unit operations and processes utilized in the
production of bulk drugs, dosage forms and biological products. Along with the
development of new drug delivery systems and new drugs came new production
processes and machines for manufacture, new control methods for accurate
definition of drug delivery and new and improved quality control procedure. All of
these innovations and improvements contributed to superior quality drug dosage
forms, and in many cases, to enhanced concomitant production economics.
Although many anecdotal reports indicate that marijuana and its active constituent, delta-9-tetrahydrocannabinol (delta-9-THC), may reduce pain sensation, studies of humans have produced inconsistent results. In animal studies, the apparent pain-suppressing effects of delta-9-THC and other cannabinoid drugs are confounded by motor deficits. Here we show that a brainstem circuit that contributes to the pain-suppressing effects of morphine is also required for the analgesic effects of cannabinoids. Inactivation of the rostral ventromedial medulla (RVM) prevents the analgesia but not the motor deficits produced by systemically administered cannabinoids. Furthermore, cannabinoids produce analgesia by modulating RVM neuronal activity in a manner similar to, but pharmacologically dissociable from, that of morphine. We also show that endogenous cannabinoids tonically regulate pain thresholds in part through the modulation of RVM neuronal activity. These results show that analgesia produced by cannabinoids and opioids involves similar brainstem circuitry and that cannabinoids are indeed centrally acting analgesics with a new mechanism of action.
The purpose of this study was to find out whether the combination of inactive doses of paracetamol (PARA) and morphine was able to change dynorphin (DYN) A levels, evaluated by radioimmunoassay, and whether naloxone or [(−)-2-(3 furylmethyl)-normetazocine] (MR 2266), a κ-opioid antagonist, modifies or prevents the activity of this combination on nociception and on DYN levels. The work was suggested by our previous findings which demonstrated that inactive doses of PARA and morphine, when given in combination, share an antinociceptive effect, and that PARA, at antinociceptive doses, decreases DYN levels in the frontal cortex, thus indicating a selective action within the CNS. Our present results demonstrate that the combination of inactive doses of PARA (100 mg/kg) and morphine (3 mg/kg) is just as effective in decreasing the levels of DYN A as full antinociceptive doses of PARA or morphine alone in the frontal cortex of the rat. The values, expressed in pmol/g tissue, were: control = 2.83 ± 0.20; paracetamol (100) = 2.60 ± 0.23; morphine (3) = 2.73 ± 0.24; paracetamol + morphine = 1.34 + 0.16 (P < 0.05). The decrease was partially antagonised by MR 2266, but not by naloxone, suggesting that the activity of PARA and morphine in combination on DYN A levels could be mediated, at least in part, through κ-receptors, although other systems may be involved. On the other hand, both naloxone and MR 2266 prevented the antinociceptive effect of the combination in the hot plate test. All our experimental data suggest that PARA and morphine in combination exert their antinociceptive effect through the opioidergic system, which in turn may cause a decrease in DYN levels in the CNS of the rat.
The possible involvement of bulbo-spinal monoaminergic pathways in the antinociceptive effect of paracetamol was investigated in rats. Serotonergic pathways were lesioned with intrathecal 5,6-dihydroxytryptamine (5,6-DHT), and noradrenergic pathways with 6-hydroxydopamine (6-OHDA). Intact and lesioned rats were tested in the formalin test after i.p. paracetamol (400 mg/kg) or vehicle. Behaviour was scored for 1 h after the dorsal injection of 100 μ1 of 5% formalin into one hind paw. Behavioural variables were evaluated with a multivariate statistical procedure, as well as an analysis of variance. Paracetamol itself reduced pain-related behaviour and increased normal motor activity. This antinociceptive effect was reduced in rats lesioned with 5,6-DHT. In lesioned rats paracetamol caused a change in nociceptive behaviour from active, focused behaviour towards passive, protective and non-focused behaviour in the early phase of the formalin test. No significant effect of lesioning with 6-OHDA upon the paracetamol effect was found. These results show that activation of spinal serotonergic systems is involved in the antinociceptive effect of paracetamol. The relative importance of this mechanism in the central effect of paracetamol and the mechanisms that cause the activation remain to be determined.
In the present study we have characterized the hypothermic effect of the psychoactive cannabinoid HU-210, by investigating its interaction with the endogenous pyrogens, IL-1 and PGE2. We also studied the involvement of the adrenergic system in mediation of this hypothermic effect. Injection of HU-210 directly into the preoptic area caused a dose dependent reduction of rectal temperature from 37 to 32.1 degrees C. Injection of the non-psychoactive analog, HU-211 which does not bind to brain cannabinoid receptor, did not affect body temperature. Injection of the adrenergic agonists, CGP-12177 and clonidine (beta, and alpha adrenergic agonists, respectively) abrogated the hypothermia induced by HU-210. Injection of the adrenergic antagonists, prazosin (alpha 1) and propranolol (beta) enhanced the hypothermic effect of HU-210. Intracerebral administration of IL-1 or PGE2 to rats pretreated with HU-210 caused a transient inhibition of the hypothermia. The ex vivo rate of basal or bacterial endotoxin-induced synthesis of PGE2 by different brain regions, including the preoptic area was not affected by HU-210 administration. These results suggest that the synthetic cannabinoid HU-210 acts in the preoptic area, probably via the brain cannabinoid receptor to induce hypothermia. The hypothermic effect can be antagonized by adrenergic agonists and enhanced by adrenergic antagonists. HU-210 does not interfere with the pyrogenic effect of IL-1 or PGE2.
1. Possible interactions between non-steroidal anti-inflammatory drugs (NSAIDs) and endogenous opioids were examined in electrophysiological experiments in alpha-chloralose anaesthetized spinalized rats without or with carrageenan-induced acute inflammation of one hindpaw. Spinal reflex responses, monitored as single motor unit discharges, were elicited by noxious pinch and electrical stimuli. 2. The mu-opioid agonist, fentanyl, was an effective depressant of reflexes under all conditions (ED50 6-14 micrograms kg-1, i.v.). In rats without peripheral inflammation the NSAID, flunixin, a niflumic acid derivative, had only a small effect that was not dose-dependent. However, in animals with unilateral inflammation, flunixin reduced spinal reflexes evoked both by noxious pinch stimuli (that activate peripheral nociceptors; ID50 4 mg kg-1, i.v.) and by electrical stimuli (that bypass nociceptor endings; ID50 6.5- 11 mg kg-1, i.v.), indicating that it has a central site of action at doses comparable to those used clinically. 3. The opioid antagonist, naloxone (1 mg kg-1, i.v.), reversed all actions of fentanyl. It did not reverse the small effects that flunixin had in rats without inflammation, showing that the NSAID is not a direct opioid agonist. In rats with carrageenan-induced inflammation of the hindpaw, however, naloxone fully reversed or prevented the antinociception by flunixin, but not that by the alpha 2-adrenoceptor agonist, medetomidine. 4. We conclude that under conditions of peripheral inflammation and the resultant central changes, the NSAID, flunixin, has antinociceptive actions that are mediated by endogenous opioids acting within the spinal cord.
The antinociceptive activity of paracetamol in the hot plate and formalin tests was studied to establish the relationship between antinociceptive activity and the central serotonergic system. Significant antinociceptive activity of paracetamol was observed in the formalin test at the dose of 300 mg/kg, while, at the dose of 400 mg/kg, the drug was active both in the formalin and in the hot-plate test. Serum paracetamol levels remained sub-toxic and the behavioral profile remained unchanged. Depletion of brain serotonin with p-chlorophenylalanine prevented the antinociceptive effect of paracetamol in the hot-plate test and in the first phase of the formalin response. Paracetamol significantly increased the serotonin content in the pontine and cortical areas (by 75 and 70%, respectively). The pretreatment with p-chlorophenylalanine reduced the 5-hydroxytryptamine (5-HT) content in cortical and pontine areas to 12 and 19% of baseline values, respectively, and prevented the enhancement induced by paracetamol. The maximum number of cortical 5-HT2 receptors was reduced by paracetamol, while the number of 5-HT1A receptors in both cortical and pontine areas was unchanged. Pre-treatment with p-chlorophenylalanine prevented the reduction in the number of 5-HT2 receptors induced by paracetamol. These results provide evidence for the involvement of the central serotonergic system in the antinociceptive effect of paracetamol in the hot plate and formalin tests.
Mammalian tissues contain at least two types of cannabinoid receptor, CB(1) and CB(2), both coupled to G proteins. CB(1) receptors are expressed mainly by neurones of the central and peripheral nervous system whereas CB(2) receptors occur centrally and peripherally in certain non-neuronal tissues, particularly in immune cells. The existence of endogenous ligands for cannabinoid receptors has also been demonstrated. The discovery of this 'endocannabinoid system' has prompted the development of a range of novel cannabinoid receptor agonists and antagonists, including several that show marked selectivity for CB(1) or CB(2) receptors. It has also been paralleled by a renewed interest in cannabinoid-induced antinociception. This review summarizes current knowledge about the ability of cannabinoids to produce antinociception in animal models of acute pain as well as about the ability of these drugs to suppress signs of tonic pain induced in animals by nerve damage or by the injection of an inflammatory agent. Particular attention is paid to the types of pain against which cannabinoids may be effective, the distribution pattern of cannabinoid receptors in central and peripheral pain pathways and the part that these receptors play in cannabinoid-induced antinociception. The possibility that antinociception can be mediated by cannabinoid receptors other than CB(1) and CB(2) receptors, for example CB(2)-like receptors, is also discussed as is the evidence firstly that one endogenous cannabinoid, anandamide, produces antinociception through mechanisms that differ from those of other types of cannabinoid, for example by acting on vanilloid receptors, and secondly that the endocannabinoid system has physiological and/or pathophysiological roles in the modulation of pain.
During the last decade, rigorous scientific methods have been applied to determine the effects of cannabinoids on nociceptive neurotransmission. Cannabinoids have been observed to markedly decrease signalling in specific neural pathways that transmit messages about pain. These effects were found to be due to the suppression of spinal and thalamic nociceptive neurons, and independent of any actions on either the motor system or sensory neurons that transmit messages related to non-nociceptive stimulation. Spinal, supraspinal, and peripheral sites of cannabinoid analgesia have been identified. The discovery of endocannabinoids raised the question of their natural role in pain. Multiple lines of evidence indicate that endocannabinoids serve naturally to suppress pain. While it is now clear that cannabinoids suppress nociceptive neurotransmission, more work is needed to establish the clinical utility of these compounds. The few human studies conducted to date produced mixed results, with more promising findings coming from studies of clinical pain as compared with experimental pain. The therapeutic potential of cannabinoids remains an important topic for future investigations.
Cannabinoids and opioids both produce analgesia through a G-protein-coupled mechanism that blocks the release of pain-propagating neurotransmitters in the brain and spinal cord. However, high doses of these drugs, which may be required to treat chronic, severe pain, are accompanied by undesirable side effects. Thus, a search for a better analgesic strategy led to the discovery that delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, enhances the potency of opioids such as morphine in animal models. In addition, studies have determined that the analgesic effect of THC is, at least in part, mediated through delta and kappa opioid receptors, indicating an intimate connection between cannabinoid and opioid signaling pathways in the modulation of pain perception. A host of behavioral and molecular experiments have been performed to elucidate the role of opioid receptors in cannabinoid-induced analgesia, and some of these findings are presented below. The aim of such studies is to develop a novel analgesic regimen using low dose combinations of cannabinoids and opioids to effectively treat acute and chronic pain, especially pain that may be resistant to opioids alone.
Characterization of the hypothermic effect of the synthetic cannabinoid HU 210 in the rat. Relation to the adrenergic system and endogenous pyrogens
- Ovadia
Cannabinoid receptors and pain
- Pertwee