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Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system
Abstract
Nausea and vomiting (emesis) are important elements in defensive or protective responses that animals use to avoid ingestion or digestion of potentially harmful substances. However, these neurally-mediated responses are at times manifested as symptoms of disease and they are frequently observed as side-effects of a variety of medications, notably those used to treat cancer. Cannabis has long been known to limit or prevent nausea and vomiting from a variety of causes. This has led to extensive investigations that have revealed an important role for cannabinoids and their receptors in the regulation of nausea and emesis. With the discovery of the endocannabinoid system, novel ways to regulate both nausea and vomiting have been discovered that involve the production of endogenous cannabinoids acting centrally. Here we review recent progress in understanding the regulation of nausea and vomiting by cannabinoids and the endocannabinoid system, and we discuss the potential to utilize the endocannabinoid system in the treatment of these frequently debilitating conditions.
... C. sativa has long been recognised for its ability to reduce or prevent nausea and vomiting caused by a range of factors. This has resulted in substantial research revealing a vital function for cannabis derivatives in nausea and vomiting treatments (Sharkey et. al., 2014). Several C. sativa compounds are available for the treatment of nausea and vomiting due to the dispersion of the endocannabinoid system in the gut. The FDA (Food and Drug Administration) authorised nabilone, a synthetic analogue of D9-THC, in 1985 for the treatment of chemotherapy-induced nausea and vomiting that had not responded to st ...
... Several C. sativa compounds are available for the treatment of nausea and vomiting due to the dispersion of the endocannabinoid system in the gut. The FDA (Food and Drug Administration) authorised nabilone, a synthetic analogue of D9-THC, in 1985 for the treatment of chemotherapy-induced nausea and vomiting that had not responded to standard antiemetic medicines (dopamine receptor 2 (D2) antagonists) (Sharkey et al., 2014;Whiting et al., 2015). Indeed, nabilone medication reduces nausea and vomiting episodes in chemotherapy patients as compared to metoclopramide (D2 antagonist) (Sharkey et al., 2014, Badowsky, 2017. ...
... The FDA (Food and Drug Administration) authorised nabilone, a synthetic analogue of D9-THC, in 1985 for the treatment of chemotherapy-induced nausea and vomiting that had not responded to standard antiemetic medicines (dopamine receptor 2 (D2) antagonists) (Sharkey et al., 2014;Whiting et al., 2015). Indeed, nabilone medication reduces nausea and vomiting episodes in chemotherapy patients as compared to metoclopramide (D2 antagonist) (Sharkey et al., 2014, Badowsky, 2017. Furthermore, cancer patients treated with dronabinol, a synthetic analogue of D9-THC, had less acute nausea and a much shorter duration than those treated with prochlorperazine (D2 antagonist) (Badowski, 2017). ...
Cannabis sativa is a widely dispersed plant that may be found in a broad range of habitats, elevations, and climatic conditions all over the globe. It is a member of the Cannabis genus. Historically, it has been used by humans for more than 5000 years, making it one of the oldest plant sources of food and textile fibres. Originating in Western Asia and Egypt, the cultivation of Cannabis sativa for textile fibre later spread to Europe, and in 1606, the cultivation of hemp was brought to North America, where it has remained since. For the majority of the 18th and 19th centuries, hemp had an important economic role in Europe, primarily in the manufacturing of ropes and textiles. Cannabis sativa L. (marijuana; Cannabaceae) is a popular plant with extensive distribution that produces fibre and food, as well as a psychoactive drug. Hemp seed has traditionally been harvested for the oil that can be derived from it and used in a variety of applications, including culinary and the production of soaps, paints, lubricants, and cosmetics. Furthermore, hemp has long been used as a medical plant.
... Lennox-Gastaut, Dravet syndrome, Tuberous sclerosis complex) [76]. Their action is mediated through agonism of CB1 receptors that are found both centrally and peripherally in a multifaceted endocannabinoid system with potential 5HT-1/3, D2, and transient receptor potential vallinoid-1 (TRPV1) modulation [6,[77][78][79]. ...
... Prolonged and high dose activation of this system may result in dysregulation and development of paradoxical hyperemetic syndrome (i.e. cannabinoid hyperemesis syndrome) [6,7,77]. ...
Purpose of Review
We aim to provide a mechanistic review of available anti-emetic medications along with practical strategies of use and future areas of study in patients with cirrhosis.
Recent Findings
There is a dearth of liver-specific data for most, if not all, antiemetic medications in patients with cirrhosis. Of medications available, 5HT3 antagonists, prokinetics, and atypical antipsychotics carry targeted roles and favorable risk profiles when appropriately dosed. Other pharmacologic therapies (e.g. prucalopride) carry promising potential but require further study. Some nonpharmacologic therapies (e.g. aromatherapy, acupuncture) may carry practical benefit with minimal risk and cost.
Summary
Nausea and vomiting is a common symptom in the illness trajectory of cirrhosis with minimal to no liver-specific outcomes data on many of our anti-emetic medications. At this time, safe and educated treatment of nausea and vomiting requires familiarity with basic pharmacologic mechanisms, acknowledgement of gaps in data, and intentional discussions with patients regarding risks and goals of therapy.
... As reviewed previously, CB1 receptors are widely distributed in the nervous system and can be found in central and peripheral structures involved in nausea and vomiting. 121 In animal models, cannabinoids inhibit acute and delayed emesis, primarily through a CB1 receptor mechanism in the dorsal vagal complex of the brain stem. 121 CB2 receptors have also been identified in the brainstem structures and contribute to antiemetic effects of the eCB 2-AG in the ferret, but the mechanisms are not clear and clinical studies are needed to further elucidate therapeutic potential. ...
... 123 Nabilone was compared to D2-receptor antagonists for their antiemetic/antinausea effects in patients receiving chemotherapy; nabilone treatment resulted in fewer vomiting episodes and nausea severity when patients received moderately toxic chemotherapeutic agents, but the drug was equally effective as a D2 receptor antagonist in reducing vomiting when given cisplatin, a more toxic agent, was administered. 121 There is a paucity of literature regarding cannabinoid efficacy for managing clinical postoperative nausea and vomiting, either as a prophylactic or rescue treatment. In a study examining prophylactic IV THC or placebo in 40 high-risk patients, the relative risk reduction of PONV in the treatment group was 12% (compared to 25% demonstrated by other medications); the study was terminated after 40 patients because the antiemetic effects were unclear, and the side effects of sedation and confusion were clinically unacceptable. ...
The cannabis plant has been used for centuries to manage the symptoms of various ailments including pain. Hundreds of chemical compounds have been identified and isolated from the plant and elicit a variety of physiological responses by binding to specific receptors and interacting with numerous other proteins. In addition, the body makes its own cannabinoid-like compounds that are integrally involved in modulating normal and pathophysiological processes. As the legal cannabis landscape continues to evolve within the United States and throughout the world, it is important to understand the rich science behind the effects of the plant and the implications for providers and patients. This narrative review aims to provide an overview of the basic science of the cannabinoids by describing the discovery and function of the endocannabinoid system, pharmacology of cannabinoids, and areas for future research and therapeutic development as they relate to perioperative and chronic pain medicine.
... In humans, the ECS is involved in the regulation of a wide range of functions from digestion to pain management and memory formation; it influences mood and emotional responses and is implicated in the regulation of stress, anxiety, and depression [10,11]. The ECS plays a role in digestive processes including the control of nausea, vomiting, appetite, and food intake [12][13][14] and has an impact on the regulation of sleep patterns [15,16], and immune function, where it plays a role in modulating immune system responses and inflammatory processes [16,17]. The effects of the ECS extend deep into human physiology, including involvement in reproductive processes, fertility, embryo development and implantation [18], the modulation of pain perception, and the processing of pain signals [19]. ...
A unifying mechanistic cause for amyotrophic lateral sclerosis (ALS) remains uncertain. Multiple pathophysiological processes appear to occur simultaneously. Cannabinoids, including delta‐9‐tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), and others found in cannabis, and cannabis extracts (CEs), appear to have activity in these pathogenic pathways, which have led to increasing interest in cannabinoids as therapeutic agents for ALS. The use of cannabinoids as a treatment strategy is substantiated by preclinical evidence suggesting a role for the endocannabinoid system (ECS) in ALS and other neurodegenerative disorders. Preclinical data indicate that cannabis and CEs have powerful antioxidative, anti‐inflammatory, and neuroprotective effects in the SOD1 G93A mouse model of ALS. The use of CEs in SOD1 G93A murine models has been shown to prolong neuronal cell survival, which leads to delayed onset of the disease state, and slows progression of the disease. Although research in humans remains limited, a few studies suggest that cannabis and CBD, in humans, provide benefits for both motor symptoms, including rigidity, cramps, and fasciculations, and non‐motor symptoms including sleep quality, pain, emotional state, quality of life, and depression. There remains a need for further, well‐designed clinical trials to validate further the use of an individual cannabinoid, or a combination of cannabinoids, as a disease‐modifying therapy for ALS.
... In addition, cannabis has been used for millennia to treat many ailments [17], including attenuation of gastrointestinal tract inflammation, as well as providing relief of functional problems, such as cramps and stomach pain, nausea, vomiting and diarrhoea [18,19]. The most frequent physical health reasons for use of medical cannabis are to alleviate and manage pain (53 %), treat sleep disorders (46 %), relieve headaches/migraines (35 %), control of appetite (22 %) and to reduce nausea/vomiting (21 %); whilst the most prevalent mental health reasons to use cannabis are to combat anxiety (52 %), depression (40 %) and for post-traumatic stress disorder (PTSD) and other traumatic events (17 %) [20]. ...
... Dysfunction in these pathways leads to recurrent nausea and vomiting in CHS. Potential causes of CHS include influence on the activity of cannabinoid receptors, conversion of cannabis into emetic substances, or contamination with other toxins [36]. Cannabis leads to upregulation of CB1 receptor activity in the hypothalamus, which enhances the hypothermic effects of THC. ...
Cannabis, derived from Cannabis sativa plants, is a prevalent illicit substance in the United States, containing over 400 chemicals, including 100 cannabinoids, each affecting the body’s organs differently upon ingestion. Cannabis hyperemesis syndrome (CHS) is a gut–brain axis disorder characterized by recurring nausea and vomiting intensified by excessive cannabis consumption. CHS often goes undiagnosed due to inconsistent criteria, subjective symptoms, and similarity to cyclical vomiting syndrome (CVS). Understanding the endocannabinoid system (ECS) and its dual response (pro-emetic at higher doses and anti-emetic at lower doses) is crucial in the pathophysiology of CHS. Recent research noted that type 1 cannabinoid receptors in the intestinal nerve plexus exhibit an inhibitory effect on gastrointestinal motility. At the same time, the thermoregulatory function of endocannabinoids might explain compulsive hot bathing in CHS patients. The prevalence of cannabis CHS is expected to rise as legal restrictions on its recreational use decrease in several states. Education and awareness are vital in diagnosing and treating CHS as its prevalence increases. This comprehensive review explores the ECS’s involvement, CHS management approaches, and knowledge gaps to enhance understanding of this syndrome.
... Recent studies investigating ∆9-THC and cannabidiol oil-based capsules have shown promising results in terms of appetite stimulation and improvements in mood, quality of life, and symptom management, although adverse effects have been reported. The combination of ∆9-THC and cannabidiol in cannabis preparations may influence appetite stimulation differently, with higher cannabidiol strains reported to produce less appetite stimulation and anxiety (Table 2) [59,[62][63][64][65][66][67][68]. ...
Simple Summary
Cancer is a major disease and a leading cause of death worldwide. Improving treatment and management strategies for cancer is critical. This article explores cannabis and its pharmacological properties as a promising tool in cancer care, especially in easing symptoms like appetite loss, pain, nausea, vomiting, and insomnia. Moreover, it examines the anti-tumor properties of cannabis, highlighting that, although some evidence suggests benefits, more research is necessary to confirm these effects. The article addresses the evidence concerning the clinical challenges of using cannabis, such as its psychoactive effects, and potential side effects. The article aims to clarify the current understanding of cannabis use in cancer care, helping healthcare professionals and patients make better-informed decisions and improve treatment outcomes.
Abstract
As the legalization of medical cannabis expands across several countries, interest in its potential advantages among cancer patients and caregivers is burgeoning. However, patients seeking to integrate cannabis into their treatment often encounter frustration when their oncologists lack adequate information to offer guidance. This knowledge gap is exacerbated by the scarcity of published literature on the benefits of medical cannabis, leaving oncologists reliant on evidence-based data disheartened. This comprehensive narrative article, tailored for both clinicians and patients, endeavors to bridge these informational voids. It synthesizes cannabis history, pharmacology, and physiology and focuses on addressing various symptoms prevalent in cancer care, including insomnia, nausea and vomiting, appetite issues, pain management, and potential anti-cancer effects. Furthermore, by delving into the potential mechanisms of action and exploring their relevance in cancer treatment, this article aims to shed light on the potential benefits and effects of cannabis in oncology.
... Notably, in A. acris, the anandamide degradation pathway was repressed (Figure 4). Anandamide is a bioactive fatty acid amide widely studied in mammals that functions as a messenger molecule regulating feeding behavior (e.g., hunger, and satiety perception), among other functions (Sharkey et al., 2014). However, in insects, there are few studies on the metabolism of anandamide and its functions (Ban et al., 2003;Farrell and Merkler, 2008;Tortoriello et al., 2013;Jeffries et al., 2014). ...
The Manchineel, Hippomane mancinella (“Death Apple Tree”) is one of the most toxic fruits worldwide and nevertheless is the host plant of the monophagous fruit fly species Anastrepha acris (Diptera: Tephritidae). Here we aimed at elucidating the detoxification mechanisms in larvae of A. acris reared on a diet enriched with the toxic fruit (6% lyophilizate) through comparative transcriptomics. We compared the performance of A. acris larvae with that of the sister species A. ludens, a highly polyphagous pest species that is unable to infest H. mancinella in nature. The transcriptional alterations in A. ludens were significantly greater than in A. acris . We mainly found two resistance mechanisms in both species: structural, activating cuticle protein biosynthesis (chitin-binding proteins likely reducing permeability to toxic compounds in the intestine), and metabolic, triggering biosynthesis of serine proteases and xenobiotic metabolism activation by glutathione-S-transferases and cytochrome P450 oxidoreductase. Some cuticle proteins and serine proteases were not orthologous between both species, suggesting that in A. acris , a structural resistance mechanism has been selected allowing specialization to the highly toxic host plant. Our results represent a nice example of how two phylogenetically close species diverged over recent evolutionary time related to resistance mechanisms to plant secondary metabolites.
... -It may be difficult to apply to a species when intake is small, and it can be produced by factors other than nausea such as stress or pain (Sharkey et al., 2014). -The reliability of pica as a screening model for predicting nausea or vomiting in human has been questioned (Goineau and Castagné 2016) Gastric dysmotility Mouse → cisplatin Rat → cisplatin, vincristine -X-Ray is a non-invasive method that allows for transit and morphological studies (stomach size). ...
... The potential shared indications for CB1 and CB2 agonists include pain, 24 anxiety, 25 neurodegenerative disorders, 26 cancer, 27 emesis, and nausea. 28 Of note, there are some conditions such as addiction, 29 systemic sclerosis, 30 atherosclerosis, 31 obesity, 32 or diabetes, 33 where CB1 antagonists can be successfully replaced with CB2 agonists without seriously compromising the therapeutic outcome. What is more, in some diseases that are characterized by a prominent inflammatory component (e.g., rheumatoid arthritis or osteoarthritis), CB2 activation may seem the preferred mechanism of action. ...
Cannabinoid receptor type 2 (CB2) is a very promising therapeutic target for a variety of potential indications. However, despite the existence of multiple high affinity CB2 ligands, none have yet been approved as a drug. Therefore, it would be beneficial to explore new chemotypes of CB2 ligands. The recent elucidation of CB2 tertiary structure allows for rational hit identification with structure-based (SB) methods. In this study, we established a virtual screening workflow based on SB techniques augmented with ligand-based ones, including molecular docking, MM-GBSA binding energy calculations, pharmacophore screening, and QSAR. We screened nearly 7 million drug-like, commercially available compounds. We selected 16 molecules for in vitro evaluation and identified two novel, selective CB2 antagonists with Ki values of 65 and 210 nM. Both compounds are structurally diverse from CB2 ligands known to date. The established virtual screening protocol may prove useful for hit identification for CB2 and similar molecular targets. The two novel CB2 ligands provide a desired starting point for future optimization and development of potential drugs.
... In turn, these afferent nerves transmit the stimuli to the brain, which processes the emetic reflex and signals organs and tissues to induce vomiting. Activation of CB1 in enterochromaffin cells by a CB1 receptor agonist may thus reduce serotonin release from these cells, blocking the emetic signaling (Sharkey et al., 2014). ...
Los cannabinoides se dirigen principalmente al sistema endocannabinoide (ECS), que surge como un objetivo terapéutico potencialmente interesante debido a su importante papel en la modulación de procesos biológicos clave en todo el organismo. Como tal, los cannabinoides ya se han propuesto como, por ejemplo, antieméticos, agentes antiespásticos, estimulantes del apetito, antiepilépticos, analgésicos, depresores de la presión intraocular o como agentes para controlar los trastornos del movimiento en el síndrome de Tourette. Aquí revisamos las pruebas de investigación disponibles sobre el uso del cannabis y los cannabinoides para un conjunto de aplicaciones terapéuticas sugeridas, y abordamos algunos de los riesgos a corto y largo plazo que se han correlacionado con el uso de estas sustancias. Encontramos escasas pruebas científicas que apoyen el uso de productos basados en el cannabis para la mayoría de las aplicaciones sugeridas, así como ninguna necesidad médica no satisfecha que no esté ya abordada por los medicamentos existentes (algunos basados en cannabinoides) en el mercado. En este escenario, los riesgos potenciales asociados al uso crónico de estas sustancias pueden disuadir su uso médico.
... In turn, these afferent nerves transmit the stimuli to the brain, which processes the emetic reflex and signals organs and tissues to induce vomiting. Activation of CB1 in enterochromaffin cells by a CB1 receptor agonist may thus reduce serotonin release from these cells, blocking the emetic signaling (Sharkey et al., 2014). ...
Cannabinoids mainly target the endocannabinoid system, which emerges as a potentially interesting therapeutical target due to its major role in modulating key biological processes throughout the body. As such, cannabinoids have already been proposed as, for example, anti-emetics, antispasticity agents, appetite stimulants, anti-epileptic, analgesic, depressants of intraocular pressure or as agents to control movement disorders in Tourette syndrome. Here, we reviewed the research evidence available regarding the use of cannabis and cannabinoids for a set of suggested therapeutical applications, and addressed some of the short- and long-term risks that have been correlated with the use of these substances. We found scarce scientific evidence supporting the use of cannabis-based products for most of the suggested applications, as well as no unmet medical need that is not already tackled by existing medicines (some cannabinoid-based) in the market. In such a scenario, the potential risks associated with the chronic use of these substances may deter their medical use.
... Anandamide reuptake is inhibited by AM404, a byproduct of paracetamol metabolism in the brain (20). In humans, it was discovered that decreased anandamide levels were linked to a high prevalence of nausea and vomiting (21). This may be yet additional explanation for paracetamol's antiemetic properties. ...
... changes in CB 1 R-positive cells across the lifespan are highlighted in red. nausea and vomiting against detrimental substances (Sharkey et al., 2014), and reducing neuropathic nociception (Coffeen et al., 2018). ...
Many brain functions that underlie behavior, cognition, and emotions vary with age, as does susceptibility to neuropsychological disorders. The expression of specific genes that are involved in these functions, such as the genes encoding for oxytocin, its receptors, and apolipoprotein D, varies with age across different brain regions. The cannabinoid 1 receptor (CB1 R) is one of the most widely spread G-protein coupled receptors in the central nervous system and is increasingly recognized for its important contribution to various brain functions. Although changes in CB1 R expression with age have been reported in the male mouse brain, they have not been well investigated in the female brain. Here, we used fluorescence in situ hybridization to target CB1 R mRNA in the whole brains of female C57BL/6J mice aged 4, 6, 12, 52 (12 months) and 86 weeks (20 months), and quantified CB1 R-positive cells in 36 brain regions across the whole brain. The results showed that CB1 R-positive cells number changed with age. Specifically, CB1 R expression increased with age in some subregions of the cortex, decreased with age in the lateral septal area, and reached its lowest level at 52 weeks in the thalamus, hypothalamus, and hindbrain subregions. Cluster analysis revealed that some brain regions shared similar temporal characteristics in CB1 R-positive cell number across the lifespan. Our results provide evidence that investigation of the neural basis of age-related characteristics of female brain functions is not only warranted but required.
... CB1 agonists or partial agonists are useful among others as analgetics 3 and anti-emetic agents. 4 CB1 antagonists/inverse agonists may act as anorectics 5 or antifibrotic agents. 6 However, effective and safe CB1 targeting is a non-trivial task, as the ECS is a multi-purpose system. 2 Although CB1 agonists, including phytocannabinoids, are generally well tolerated, 7 their pharmacotherapeutic profile is not perfect. ...
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.
... Cannabis has medicinal benefit other than reported use for pain relief [1,2]. However, the psychoactive component, tetrahydrocannabinol (THC), listed as a schedule-1 illicit drug in the United Nations' Single Page 2 of 13 Nwonuma et al. ...
Background
Data available support that ninety percent of male infertility cases are due to low sperm counts. There is a scarcity of data on the medicinal effects of cannabis on fertility. This study evaluated testicular function and sperm quality modulation with cannabis in rats.
Methodology
Twenty-five male Wistar rats were randomly grouped into five: A, B, C, and D, each group have 5 rats. A (control): 0.2 ml 2% DMSO, B (vitamin C): 90 mg/kg body weight, C, D, and E were administered: 5 mg/kg, 10 mg/kg and 20 mg/kg body weight of ethanolic leaf extract of cannabis (ELEC) respectively. The rats were sacrificed 24 h after the last day of the 60 day oral administrations. Flavonoids were the predominant phytochemical present in the extract while quercetin, kemferol, silyman and gallic acid were identified.
Results
The results showed a significant improvement ( p < 0.05) in sperm quality and a significant increase in the concentrations of follicle-stimulating hormone, luteinizing hormone, triglycerides, cholesterol, and total protein determination compared to the normal control. Similarly, there was a significant increase ( p < 0.05) in the activities of acid phosphatase, alkaline phosphatase, and superoxide dismutase compared to the normal control. RAC-alpha serine/threonine-protein kinase (AKT1)-silymarin complexes (-8.30 kcal/mol) and androgen receptor (AR)-quercetin complexes (9.20 kcal/mol) had the highest affinity.
Conclusion
The antioxidant effects of the flavonoids in the ethanolic extract of cannabis may have protected testicular and sperm cells from oxidative damage. Biochemical processes and histopathological morphology were preserved by cannabis. The docking prediction suggests that the bioactive principle of cannabis may activate the androgenic receptors. The androgenic receptor modulation may be attributed to silymarin and quercetin.
This study explores the trajectory of interest in and use of Extractum Cannabis (hemp extract, i.e., extract of Cannabis sativa L.) for the symptomatic treatment of minor gastrointestinal distress and dyspepsia in nineteenth- and early twentieth-century Barcelona (Catalonia, Spain) prior to 1939, through a review of primary sources. The objective of this paper is to present a historical pharmaceutical and applied review of the medical use of the hemp genus (Cannabis L.) prior to its prohibition, thereby contributing to its recognition as a medicinal product. The information provided demonstrates evidence of the medicinal use of cannabis within the historical context studied. The interactions between this legacy medical use and the contemporary body of pharmacological and toxicological knowledge (on hemp, its constituents, and the endocannabinoid system in gastrointestinal and stomach disorders) are discussed, providing new possible clinical perspectives. Within its limitations—including the scope, limited accessibility to, and varying quality of archives—this research contributes to a more granular understanding of the historical embeddedness of psychoactive hemp medicines in northeastern Spain, suggesting that medical and pharmaceutical traditions could play a role in informing contemporary approaches to “medical marijuana”.
Background
Classical antiemetics that target the serotonin system may not be effective in treating certain nausea and vomiting conditions like cyclic vomiting syndrome (CVS) and cannabinoid hyperemesis syndrome (CHS). As a result, there is a need for better therapies to manage the symptoms of these disorders, including nausea, vomiting, and anxiety. Cannabis is often used for its purported antiemetic and anxiolytic effects, given regulation of these processes by the endocannabinoid system (ECS). However, there is considerable evidence that cannabinoids can also produce nausea and vomiting and increase anxiety in certain instances, especially at higher doses. This paradoxical effect of cannabinoids on nausea, vomiting, and anxiety may be due to the dysregulation of the ECS, altering how it maintains these processes and contributing to the pathophysiology of CVS or CHS.
Purpose
The purpose of this review is to highlight the involvement of the ECS in the regulation of stress, nausea, and vomiting. We discuss how prolonged cannabis use, such as in the case of CHS or heightened stress, can dysregulate the ECS and affect its modulation of these functions. The review also examines the evidence for the roles of ECS and stress systems' dysfunction in CVS and CHS to better understand the underlying mechanisms of these conditions.
Overview
Dramatic progress has been made in the prevention and treatment of chemotherapy‐induced emesis, especially since the introduction of the 5‐HT3 receptor antagonists in the early 1990s and the 2003 introduction of the NK‐1 receptor antagonist, aprepitant. Recent surveys indicate the need for heightened awareness of the frequency and severity of acute and, especially, delayed nausea and vomiting from chemotherapy. Fortunately, new agents have been added to the antiemetic arsenal to further enhance the efficacy of antiemetic prophylaxis. Complementary therapies such as acupuncture and mind–body interventions appear promising in controlling nausea, and are being explored further. Appropriate implementation of guidelines for prophylaxis based on the specific chemotherapy agents used will ensure that fewer patients experience these most distressing of side effects.
Cyclic vomiting syndrome (CVS) is an underdiagnosed disorder of the gut-brain interaction. Our understanding of the pathophysiology of CVS is evolving. Here, we tested the hypotheses that: (1) the levels of endocannabinoids and related lipids are altered in CVS, and (2) cephalic-vagal stimulation drive changes in endolipid levels. Ten adult patients with CVS and 8 healthy controls were included. Indirect measurements of parasympathetic (RFa) functions were performed with spectral analysis of heart rate variability and respiratory activity. Plasma levels of endocannabinoids and related lipids were measured at baseline and during a sham feeding. Values are reported as mean ± SEM and compared using t-test or ANONA. CVS patients had a lower parasympathetic tone and response to Valsalva maneuver and deep breathing than the controls. The baseline 2-Arachidonoylglycerol (2-AG) had a significantly higher concentration in CVS (5.9e-008 ± 3.7e-008 mole/L) than control (3.7e-008 ± 1.3e-008 mole/; p<0.05). Sham feeding did not change the concentration of 2-AG. 2-linoleoylglycerol and 2-oleoylglycerol were significantly higher in CVS than control and did not change with sham feeding. Levels of N-acyl ethanolamines, including Anandamide (AEA), were not different in CVS vs. control. After sham feeding, AEA showed a trend toward increasing (P=0.08) in CVS, but not in control. With sham feeding, palmitoyl ethanolamine significantly increased in both CVS and control groups; oleoyl ethanolamine in CVS only, and stearoyl ethanolamine in the control group. Levels of endocannabinoids and related lipids are altered in CVS patients. Sham feeding affects endogenous signaling lipids in a disease and time-dependent manner.
Cannabis, commonly known as marijuana, is a drug extracted from the Cannabis plant known for its psychotropic and medicinal properties. It has been used for healing purposes during ancient times, although its psychoactive components led to its restricted use in medicine. Nonetheless, cannabis is found to have modulatory effects on the endocannabinoid system exhibiting its medicinal role in the gastrointestinal (GI) system. Emerging animal and human studies demonstrate the influential effects of cannabis on a variety of GI diseases including inflammatory bowel disease, motility disorders and GI malignancies. It also has a regulatory role in GI symptoms including nausea and vomiting, anorexia, weight gain, abdominal pain, among others. However, both its acute and chronic use can lead to undesirable side effects such as dependency and addiction, cognitive impairment and cannabinoid hyperemesis syndrome. We will discuss the role of cannabis in the GI system as well as dosing strategies to help guide gastroenterologists to assess its efficacy and provide patient counseling before prescription of medical marijuana.
Nabilone, a synthetic analogue of delta-9-Tetrahydrocannabinol, is an agonist of cannabinoid receptors (CB-1 and CB-2) approved to treat chemotherapy-induced vomiting refractory to antiemetics. Its use in patients with refractory vomiting due to gastrointestinal dysmotility (GID) has not been reported. Our study aims are to assess nabilone usefulness and side-effects in patients with refractory vomiting due to GID. Patients prescribed nabilone at St. Mark's intestinal rehabilitation unit (January 2017 to September 2022) due to GID vomiting have been retrospectively reviewed. Descriptive analysis has been done. Variables measured: age, sex, comorbidities, antiemetics/prokinetics, enteral or parenteral nutrition, nabilone prescription, subjective symptom improvement and side-effects. Seven patients received nabilone. 5/7 (72%) were females. Median age:25 years (23-37). 3/7 (43%) had gastroparesis (1/3 related to postural orthostatic tachycardia syndrome -POTS- , 1/3 to Ehlers-Danlos' Syndrome, POTS, Crohn's Disease and adrenal insufficiency -AI- and 1/3 to sinus node ablation and AI), 2/7 (29%) had gastroparesis and intestinal dysmotility (1/2 related to POTS and 1/2 related to EDS and other connective tissue diseases) and 2/7 (29%) had intestinal dysmotility (1/2 because of polyglucosan body visceral myopathy and 1/2 to intestinal surgery). All patients had received antiemetics or prokinetics before (median of 5 drugs; 2-11). 1/7 (14%) received enteral supplements, 5/7 (72%) enteral nutrition through enteral tubes and 4/7 (57%) parenteral nutrition. 5/7 (72%) patients received 1mg of nabilone bd orally, 1/7 (14%) 2 mg bd through jejunostomy and 1/7 (14%) started nabilone at 2 mg bd orally, but had to be switched to 1 mg bd because of side-effects. The median treatment's duration was 9 days (7-35). Regarding the efficacy of nabilone, 3/7 (43%) had symptomatic improvement. In terms of side-effects 4/7 (57%) patients reported some incidence under the treatment such as headache, light-headedness, drowsiness, dizziness or hallucinations. Patients with refractory GID vomiting despite multiple anti-sickness are difficult to treat. Nabilone improved symptoms in almost half of the patients although adverse effects appeared in more than 50%. Doses higher than 1 mg bd po did not show benefit. Although our study has important limitations, nabilone might be a temporary measure in these patients. Side-effects should be taken into consideration.
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.
Background. The cannabinoid hyperemesis syndrome (CHS) was first described in 2004. It is considered as a functional gastrointestinal syndrome characterized by the presence of nausea, severe and cyclic morning vomiting, epigastric abdominal pain, hot water bathing for symptom relief, in patients that use cannabis regularly and has a resolution of the syndrome after cessation of cannabis consumption. Clinical Case. Report of a 29 year old male, with daily consumption of cannabis, with history of intense epigastric abdominal pain and recurrent vomiting that partially responded to the use of antispasmodics. After 4 visits to the emergency department he was hospitalized for study and treatment. Laboratory and image exploration are carried out without positive results for organic disease. Therefore, a functional gastrointestinal syndrome is thought, and a cannabinoid hyperemesis syndrome was suspected. A psychiatric evaluation is carried out, diagnosing a cannabis use disorder. Discussion and conclusion. CHS is a syndrome that has been described recently and is not usually considered as a differential diagnosis for patients with hyperemesis. However, the current high prevalence of cannabis consumption, will probably lead to a more frequent presentation of the syndrome at different health providers. Therefore, it is important to diffuse and update the knowledge about this syndrome to recognize it and develop a timely treatment, avoiding medical complications from invasive exploratory methods and the use of unnecessary resources.
Introduction:
The antiemetic properties of cannabis have motivated its use in the management of chemotherapy-induced nausea and vomiting. Conversely, case reports of intractable vomiting among heavy cannabis users have increasingly appeared in the literature. Studies on cannabis and gastrointestinal tract (GIT) health are scare. Here, we use data for the National Health and Nutrition Examination Surveys (NHANES, 2005-2018) to estimate the association between cannabis use and GIT illness.
Methods:
The study sample included non-pregnant adult NHANES participants (20-59 years) without history of cancer or HIV (n = 18,753). Cannabis use was categorised into never, former (0 day in the past 30 days), infrequent (1-2 days), occasional (3-19 days) and frequent (20-30 days) use. Recent GIT illness was defined as experiencing GIT illness with vomiting or diarrhoea that started in the 30 days prior to NHANES. Logistic regression was used to regress GIT illness on cannabis use, adjusting for potential confounders.
Results:
Compared to never use, frequent cannabis use was associated with higher odds of GIT illness (OR = 1.4; 95% confidence interval 1.04, 1.9). There were no associations between former, infrequent or occasional cannabis use and GIT illness.
Discussion and conclusions:
Frequent cannabis use is associated with GIT illnesses in a large cross-sectional study of US residents. It is possible that frequent cannabis use adversely affects GIT health, consistent with clinical case reports. Alternatively, patients with GIT illness might self-medicate with cannabis given its antiemetic properties. Prospective studies are needed to understand the effects of cannabis use on GIT health.
Endogenous and exogenous cannabinoids modulate many physiological and pathological processes by binding classical cannabinoid receptors 1 (CB1) or 2 (CB2) or non-cannabinoid receptors. Cannabinoids are known to exert antiproliferative, apoptotic, anti-migratory and anti-invasive effect on cancer cells by inducing or inhibiting various signaling cascades. In this chapter, we specifically emphasize the latest research works about the alterations in endocannabinoid system (ECS) components in malignancies and cancer cell proliferation, migration, invasion, angiogenesis, autophagy, and death by cannabinoid administration, emphasizing their mechanism of action, and give a future perspective for clinical use.
Postoperative nausea and vomiting is an increasingly common and distressing problem faced by patients undergoing anesthesia that negatively affects their recovery and wellbeing and can result in significant increases in healthcare costs. Effective treatment strategies and relevant, up-to-date guidance are essential to manage postoperative nausea and vomiting in the perioperative setting. This practical, concise guide to the subject offers information on the history and mechanisms of postoperative nausea and vomiting, assessing and identifying risk factors, providing appropriate pharmacological and non-pharmacological treatment options, and implementing successful management strategies to tackle this issue. As a uniquely comprehensive study of the topic that provides much more detail than a chapter in a general anaesthesia textbook, this is an invaluable resource for anesthetists and physicians managing patients post-surgery.
Postoperative nausea and vomiting is an increasingly common and distressing problem faced by patients undergoing anesthesia that negatively affects their recovery and wellbeing and can result in significant increases in healthcare costs. Effective treatment strategies and relevant, up-to-date guidance are essential to manage postoperative nausea and vomiting in the perioperative setting. This practical, concise guide to the subject offers information on the history and mechanisms of postoperative nausea and vomiting, assessing and identifying risk factors, providing appropriate pharmacological and non-pharmacological treatment options, and implementing successful management strategies to tackle this issue. As a uniquely comprehensive study of the topic that provides much more detail than a chapter in a general anaesthesia textbook, this is an invaluable resource for anesthetists and physicians managing patients post-surgery.
Postoperative nausea and vomiting is an increasingly common and distressing problem faced by patients undergoing anesthesia that negatively affects their recovery and wellbeing and can result in significant increases in healthcare costs. Effective treatment strategies and relevant, up-to-date guidance are essential to manage postoperative nausea and vomiting in the perioperative setting. This practical, concise guide to the subject offers information on the history and mechanisms of postoperative nausea and vomiting, assessing and identifying risk factors, providing appropriate pharmacological and non-pharmacological treatment options, and implementing successful management strategies to tackle this issue. As a uniquely comprehensive study of the topic that provides much more detail than a chapter in a general anaesthesia textbook, this is an invaluable resource for anesthetists and physicians managing patients post-surgery.
Postoperative nausea and vomiting is an increasingly common and distressing problem faced by patients undergoing anesthesia that negatively affects their recovery and wellbeing and can result in significant increases in healthcare costs. Effective treatment strategies and relevant, up-to-date guidance are essential to manage postoperative nausea and vomiting in the perioperative setting. This practical, concise guide to the subject offers information on the history and mechanisms of postoperative nausea and vomiting, assessing and identifying risk factors, providing appropriate pharmacological and non-pharmacological treatment options, and implementing successful management strategies to tackle this issue. As a uniquely comprehensive study of the topic that provides much more detail than a chapter in a general anaesthesia textbook, this is an invaluable resource for anesthetists and physicians managing patients post-surgery.
Postoperative nausea and vomiting is an increasingly common and distressing problem faced by patients undergoing anesthesia that negatively affects their recovery and wellbeing and can result in significant increases in healthcare costs. Effective treatment strategies and relevant, up-to-date guidance are essential to manage postoperative nausea and vomiting in the perioperative setting. This practical, concise guide to the subject offers information on the history and mechanisms of postoperative nausea and vomiting, assessing and identifying risk factors, providing appropriate pharmacological and non-pharmacological treatment options, and implementing successful management strategies to tackle this issue. As a uniquely comprehensive study of the topic that provides much more detail than a chapter in a general anaesthesia textbook, this is an invaluable resource for anesthetists and physicians managing patients post-surgery.
Postoperative nausea and vomiting is an increasingly common and distressing problem faced by patients undergoing anesthesia that negatively affects their recovery and wellbeing and can result in significant increases in healthcare costs. Effective treatment strategies and relevant, up-to-date guidance are essential to manage postoperative nausea and vomiting in the perioperative setting. This practical, concise guide to the subject offers information on the history and mechanisms of postoperative nausea and vomiting, assessing and identifying risk factors, providing appropriate pharmacological and non-pharmacological treatment options, and implementing successful management strategies to tackle this issue. As a uniquely comprehensive study of the topic that provides much more detail than a chapter in a general anaesthesia textbook, this is an invaluable resource for anesthetists and physicians managing patients post-surgery.
Postoperative nausea and vomiting is an increasingly common and distressing problem faced by patients undergoing anesthesia that negatively affects their recovery and wellbeing and can result in significant increases in healthcare costs. Effective treatment strategies and relevant, up-to-date guidance are essential to manage postoperative nausea and vomiting in the perioperative setting. This practical, concise guide to the subject offers information on the history and mechanisms of postoperative nausea and vomiting, assessing and identifying risk factors, providing appropriate pharmacological and non-pharmacological treatment options, and implementing successful management strategies to tackle this issue. As a uniquely comprehensive study of the topic that provides much more detail than a chapter in a general anaesthesia textbook, this is an invaluable resource for anesthetists and physicians managing patients post-surgery.
Postoperative nausea and vomiting is an increasingly common and distressing problem faced by patients undergoing anesthesia that negatively affects their recovery and wellbeing and can result in significant increases in healthcare costs. Effective treatment strategies and relevant, up-to-date guidance are essential to manage postoperative nausea and vomiting in the perioperative setting. This practical, concise guide to the subject offers information on the history and mechanisms of postoperative nausea and vomiting, assessing and identifying risk factors, providing appropriate pharmacological and non-pharmacological treatment options, and implementing successful management strategies to tackle this issue. As a uniquely comprehensive study of the topic that provides much more detail than a chapter in a general anaesthesia textbook, this is an invaluable resource for anesthetists and physicians managing patients post-surgery.
Postoperative nausea and vomiting is an increasingly common and distressing problem faced by patients undergoing anesthesia that negatively affects their recovery and wellbeing and can result in significant increases in healthcare costs. Effective treatment strategies and relevant, up-to-date guidance are essential to manage postoperative nausea and vomiting in the perioperative setting. This practical, concise guide to the subject offers information on the history and mechanisms of postoperative nausea and vomiting, assessing and identifying risk factors, providing appropriate pharmacological and non-pharmacological treatment options, and implementing successful management strategies to tackle this issue. As a uniquely comprehensive study of the topic that provides much more detail than a chapter in a general anaesthesia textbook, this is an invaluable resource for anesthetists and physicians managing patients post-surgery.
Postoperative nausea and vomiting is an increasingly common and distressing problem faced by patients undergoing anesthesia that negatively affects their recovery and wellbeing and can result in significant increases in healthcare costs. Effective treatment strategies and relevant, up-to-date guidance are essential to manage postoperative nausea and vomiting in the perioperative setting. This practical, concise guide to the subject offers information on the history and mechanisms of postoperative nausea and vomiting, assessing and identifying risk factors, providing appropriate pharmacological and non-pharmacological treatment options, and implementing successful management strategies to tackle this issue. As a uniquely comprehensive study of the topic that provides much more detail than a chapter in a general anaesthesia textbook, this is an invaluable resource for anesthetists and physicians managing patients post-surgery.
Postoperative nausea and vomiting is an increasingly common and distressing problem faced by patients undergoing anesthesia that negatively affects their recovery and wellbeing and can result in significant increases in healthcare costs. Effective treatment strategies and relevant, up-to-date guidance are essential to manage postoperative nausea and vomiting in the perioperative setting. This practical, concise guide to the subject offers information on the history and mechanisms of postoperative nausea and vomiting, assessing and identifying risk factors, providing appropriate pharmacological and non-pharmacological treatment options, and implementing successful management strategies to tackle this issue. As a uniquely comprehensive study of the topic that provides much more detail than a chapter in a general anaesthesia textbook, this is an invaluable resource for anesthetists and physicians managing patients post-surgery.
Postoperative nausea and vomiting is an increasingly common and distressing problem faced by patients undergoing anesthesia that negatively affects their recovery and wellbeing and can result in significant increases in healthcare costs. Effective treatment strategies and relevant, up-to-date guidance are essential to manage postoperative nausea and vomiting in the perioperative setting. This practical, concise guide to the subject offers information on the history and mechanisms of postoperative nausea and vomiting, assessing and identifying risk factors, providing appropriate pharmacological and non-pharmacological treatment options, and implementing successful management strategies to tackle this issue. As a uniquely comprehensive study of the topic that provides much more detail than a chapter in a general anaesthesia textbook, this is an invaluable resource for anesthetists and physicians managing patients post-surgery.
Postoperative nausea and vomiting is an increasingly common and distressing problem faced by patients undergoing anesthesia that negatively affects their recovery and wellbeing and can result in significant increases in healthcare costs. Effective treatment strategies and relevant, up-to-date guidance are essential to manage postoperative nausea and vomiting in the perioperative setting. This practical, concise guide to the subject offers information on the history and mechanisms of postoperative nausea and vomiting, assessing and identifying risk factors, providing appropriate pharmacological and non-pharmacological treatment options, and implementing successful management strategies to tackle this issue. As a uniquely comprehensive study of the topic that provides much more detail than a chapter in a general anaesthesia textbook, this is an invaluable resource for anesthetists and physicians managing patients post-surgery.
Overview
Dramatic progress has been made in the prevention and treatment of chemotherapy‐induced nausea and vomiting (CINV), especially since the introduction of the 5‐HT3 receptor antagonists (5HT3 RAs) in the early 1990s and the 2003 introduction of the NK‐1 receptor antagonist (NK1 RA), aprepitant. Recent surveys indicate the need for heightened awareness of the frequency and severity of acute and especially delayed CINV. Fortunately, new agents have been added to the antiemetic arsenal to further enhance the efficacy of antiemetic prophylaxis. Complementary therapies such as acupuncture, and mind–body interventions appear promising in controlling nausea, and are being explored further. Appropriate implementation of guidelines for prophylaxis based on patient risk factors and the specific chemotherapy agents used will ensure that fewer patients experience these most distressing of side effects.
The cannabis plant contains around 60 aromatic hydrocarbon compounds known as cannabinoids, including delta-9-tetrahydocannabinol (THC), which is primarily psychotropic; cannabidiol (CBD), efficacious in inflammation, motility and analgesia; and cannabigerol, the effect of which is still to be determined. Cannabis has been used to ameliorate a variety of gastrointestinal disorders including abdominal pain, nausea, vomiting, diarrhea/constipation, manifestations of inflammation within the gastrointestinal system, and dysmotility.This chapter reviews the endocannabinoid system as it relates to the gastrointestinal tract and associated organs, followed by specific indications based on disease entities. Appreciating that the reliability and reproducibility of clinical trials of medical cannabis on the gastrointestinal system are poor due to the lack of standardization of cannabinoid products, there are promising results that show potential benefits in a select group of patients.KeywordsCannabisGastrointestinal tractIrritable bowel syndromeInflammatory bowel diseasePancreas
The management of visceral pain in patients with disorders of gut-brain interaction, notably irritable bowel syndrome, presents a considerable clinical challenge, with few available treatment options. Patients are increasingly using cannabis and cannabinoids to control abdominal pain. Cannabis acts on receptors of the endocannabinoid system, an endogenous system of lipid mediators that regulates gastrointestinal function and pain processing pathways in health and disease. The endocannabinoid system represents a logical molecular therapeutic target for the treatment of pain in irritable bowel syndrome. Here, we review the physiological and pathophysiological functions of the endocannabinoid system with a focus on the peripheral and central regulation of gastrointestinal function and visceral nociception. We address the use of cannabinoids in pain management, comparing them to other treatment modalities, including opioids and neuromodulators. Finally, we discuss emerging therapeutic candidates targeting the endocannabinoid system for the treatment of pain in irritable bowel syndrome.
Hot-water bathing activities are reported by most cannabinoid hyperemesis syndrome (CHS) patients. Although considered a supportive factor for CHS diagnosis, these behaviors are also reported by many cyclic vomiting syndrome (CVS) patients thus reflecting nonspecificity for CHS. Excessive hot bathing provides relief of nausea and vomiting in these conditions, but can cause cutaneous thermal injury. Nausea is associated with reduced core temperatures, an effect attenuated by antiemetic therapy. The endocannabinoid system participates in thermoregulation; in animals, low doses of Δ⁹-tetrahydrocannabinol raise body temperature while higher doses cause decreases. Proposed mechanisms for benefits of hot-water exposure in CHS and CVS include activation of temperature-sensitive neurons in the skin and gut, diversion of blood flow from splanchnic viscera to the skin, and direct hypothalamic warming. Capsaicin decreases CHS attack intensity possibly by action on transient receptor potential cation channel subfamily V member 1 pathways, which also are activated by heat exposure.
Cannabinoid hyperemesis syndrome (CHS) was first described in 2004 as a cyclic vomiting illness in cannabis users. It is a puzzling condition because cannabis is a well characterized antiemetic. Cannabis acts through cannabinoid receptors of the endocannabinoid system, which is expressed throughout the body, including the gut-brain axis, where it influences neural, immune, and epithelial mechanisms involved in digestive and defensive functions of the gut. This chapter outlines the pathways of the gut-brain axis involved in nausea and emesis that are regulated by cannabinoid receptors and examines the cannabinoid receptor biology that is central to an understanding of the emetic and antiemetic actions of cannabis. In the final section, potential mechanisms for development of CHS are described based on preclinical literature, case studies, and clinical findings that constitute our understanding of this condition. Chronic cannabis consumption is the precipitating factor for CHS development in susceptible individuals. Many factors may contribute to mechanisms of CHS, including downregulation of cannabinoid-1 receptors, hypothalamic–pituitary–adrenal axis dysregulation, concomitant mood disorders, and altered endocannabinoid system genetics or epigenetics. Evidence for these potential mechanisms is limited. Future research aimed at understanding CHS pathophysiology is required to provide a better understanding of the biology and epidemiology of this debilitating condition.
Conducted 3 experiments with 50 male Sprague-Dawley rats to examine whether Ss could learn different responses to tastes paired with different types of discomfort. Ss were trained to avoid a sugar solution through pairing with LiCl toxicosis (upper gastrointestinal tract discomfort), shock (peripheral pain), or high levels of lactose (lower gastrointestinal tract discomfort). Among Ss matched for strength of avoidance of the sugar solution, only the LiCl group showed orofacial responses indicative of distaste; the other groups continued to show positive orofacial responses to the sugar solution. These results, in conjunction with recent results on humans, are interpreted to represent a distinction between food rejection based primarily on unpalatability (distaste) and food rejection based primarily on anticipated negative consequences of ingestion (danger). Results also support the hypothesis that upper gastrointestinal distress (most probably nausea) plays a special role in negative palatability shifts (acquired distastes). These results have implications for the understanding of predispositions in learning and suggest important differences in the quality of different types of associations. (42 ref)
Control rats rapidly learned to avoid drinking either a sucrose solution (Experiment 1) or a NaCl solution (Experiment 2) when the taste was paired with illness. These rats also produced aversive reactivity to each of these solutions in a taste reactivity test. Rats that lacked gustatory cortex (GC) learned to avoid drinking sucrose and NaCl, albeit at a slower rate than control rats. GC rats failed to display aversive reactivity to these tastes. The GC rats did show normal aversive reactivity to a strong quinine HCl solution during additional tests. It is suggested that the avoidance developed by GC rats did not entail a palatability shift of the conditional stimulus as it did in control rats. This altered learning strategy may account for the consistent learning deficits found in GC rats trained to avoid tastes.
[This corrects the article on p. e60537 in vol. 8.].
The vomiting (emetic) reflex is documented in numerous mammalian species, including primates and carnivores, yet
laboratory rats and mice appear to lack this response. It is unclear whether these rodents do not vomit because of
anatomical constraints (e.g., a relatively long abdominal esophagus) or lack of key neural circuits. Moreover, it is unknown whether laboratory rodents are representative of Rodentia with regards to this reflex. Here we conducted behavioral testing of members of all three major groups of Rodentia; mouse-related (rat, mouse, vole, beaver), Ctenohystrica (guinea pig, nutria), and squirrel-related (mountain beaver) species. Prototypical emetic agents, apomorphine (sc), veratrine (sc), and copper sulfate (ig), failed to produce either retching or vomiting in these species (although other behavioral effects, e.g., locomotion, were noted). These rodents also had anatomical constraints, which could limit the efficiency of vomiting should it be attempted, including reduced muscularity of the diaphragm and stomach geometry that is not well structured for moving contents towards the esophagus compared to species that can vomit (cat, ferret, and musk shrew). Lastly, an in situ brainstem preparation was used to make sensitive measures of mouth, esophagus, and shoulder muscular movements, and phrenic nerve activity–key features of emetic episodes. Laboratory mice and rats failed to display any of the common coordinated actions of these indices after typical emetic stimulation resiniferatoxin and vagal afferent stimulation) compared to musk shrews. Overall the results suggest that the inability to vomit is a general property of Rodentia and that an absent brainstem neurological component is the most likely cause. The implications of these findings for the utility of rodents as models in the area of emesis research are discussed.
The endocannabinoid system was revealed following the understanding of the mechanism of action of marijuana's major psychotropic principle, Δ(9)-tetrahydrocannabinol, and includes two G-protein-coupled receptors (GPCRs; the cannabinoid CB1 and CB2 receptors), their endogenous ligands (the endocannabinoids, the best studied of which are anandamide and 2-arachidonoylglycerol (2-AG)), and the proteins that regulate the levels and activity of these receptors and ligands. However, other minor lipid metabolites different from, but chemically similar to, anandamide and 2-AG have also been suggested to act as endocannabinoids. Thus, unlike most other GPCRs, cannabinoid receptors appear to have more than one endogenous agonist, and it has been often wondered what could be the physiological meaning of this peculiarity. In 1999, it was proposed that anandamide might also activate other targets, and in particular the transient receptor potential of vanilloid type-1 (TRPV1) channels. Over the last decade, this interaction has been shown to occur both in peripheral tissues and brain, during both physiological and pathological conditions. TRPV1 channels can be activated also by another less abundant endocannabinoid, N-arachidonoyldopamine, but not by 2-AG, and have been proposed by some authors to act as ionotropic endocannabinoid receptors. This article will discuss the latest discoveries on this subject, and discuss, among others, how anandamide and 2-AG differential actions at TRPV1 and cannabinoid receptors contribute to making this signalling system a versatile tool available to organisms to fine-tune homeostasis.
A taste associated with emetic drugs produces conditioned disgust reactions in rats (predominantly gaping), unlike nonemetic drugs that can still produce conditioned taste avoidance but not conditioned disgust. That difference suggests nausea is a prerequisite for learning disgust reactions to tastes. Depletion of forebrain serotonin (5-HT) by 5,7-dihydroxytryptamine (5,7-DHT) lesions of the dorsal raphe nucleus and median raphe nucleus prevents LiCl-induced conditioned disgust reactions (Limebeer et al., 2004). Here we demonstrate that partial depletion of 5-HT in the insular cortex (IC) prevents LiCl-induced conditioned disgust reactions. Furthermore, a double dissociation occurred in the partial regulation of disgust and taste avoidance by selective 5-HT(3) receptor antagonism/agonism in the posterior (granular) region of the IC and the anterior (dorsal agranular) region of the IC, respectively. Intracranial administration of the 5-HT(3) receptor antagonist, ondansetron (OND), to the posterior IC impaired the establishment of LiCl-induced conditioned gaping reactions, but not LiCl-induced conditioned taste avoidance (CTA). Likewise, posterior IC administration of the 5-HT(3) receptor agonist m-chlorophenylbiguanide (mCPBG) enhanced the establishment of LiCl-induced conditioned gaping and produced conditioned gaping on its own (which was prevented by intracranially administered OND), with no effect on CTA. On the other hand, anterior IC administration of OND partially reduced the establishment of LiCl-induced CTA, and mCPBG produced a weak CTA, both without effect on gaping. These results suggest that activation of 5-HT(3) receptors in the posterior IC is important for the production of nausea-induced conditioned disgust reactions, while activation of 5-HT(3) receptors in the anterior IC are involved in the production of CTA.
We review information about the potential mechanisms underlying nausea and vomiting in pregnancy (NVP), food cravings, and/or aversions in pregnancy. In addition to providing overviews about genetic predispositions and hormonal associations with appetite sensations and NVP, we review two functional explanations: the "maternal and embryo protection" and the "placental growth and development" hypotheses. We conclude with a discussion about the kinds of data that would enable us to better evaluate the relative advantages and disadvantages of NVP across disparate resource and ecological conditions.
The psychoactive constituent in cannabis, Δ(9)-tetrahydrocannabinol (THC), was isolated in the mid-1960s, but the cannabinoid receptors, CB1 and CB2, and the major endogenous cannabinoids (anandamide and 2-arachidonoyl glycerol) were identified only 20 to 25 years later. The cannabinoid system affects both central nervous system (CNS) and peripheral processes. In this review, we have tried to summarize research-with an emphasis on recent publications-on the actions of the endocannabinoid system on anxiety, depression, neurogenesis, reward, cognition, learning, and memory. The effects are at times biphasic-lower doses causing effects opposite to those seen at high doses. Recently, numerous endocannabinoid-like compounds have been identified in the brain. Only a few have been investigated for their CNS activity, and future investigations on their action may throw light on a wide spectrum of brain functions. Expected final online publication date for the Annual Review of Psychology Volume 64 is November 30, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
Buspirone, a partial 5HT(1A) agonist and D(2) and D(3) antagonist, has shown promising antiemetic efficacy when given parenterally in animal models, but its efficacy for the prevention of postoperative nausea and vomiting (PONV) is unknown.
To study the efficacy and dose-responsiveness of intravenous buspirone for the prevention of PONV.
A randomised, double-blind, placebo-controlled study was performed in adults at moderate to high PONV risk undergoing surgery with a general anaesthetic. Patients were randomised to receive an intravenous dose of buspirone (0.3, 1.0, 2.0, 3.0 mg) or placebo at the end of surgery. The primary endpoint was the cumulative 24-h PONV incidence (i.e. any nausea and/or vomiting). Vomiting included retching. Nausea was defined as a score of ≥4 on an 11-point verbal rating scale running from zero (no nausea) to ten (the worst nausea imaginable).
A total of 257 patients received the study drug and fulfilled the criteria for inclusion in the primary efficacy and safety analyses. With placebo, the mean 24-h PONV incidence was 49.0 % (90 % confidence interval [CI] 37.5-60.5 %). With buspirone, that incidence ranged from a mean of 40.8 % (29.3-52.4 %) in the 1 mg arm to 58.0 % (46.5-69.5 %) in the 0.3 mg arm (P > 0.05 for all comparisons). There was no difference between placebo and buspirone at any dose for any other efficacy endpoint, nor in the number or severity of adverse events or any other safety measures.
We were unable to show that intravenous single-dose buspirone, at the tested dose-range, was effective at preventing PONV in surgical adult patients. The present study emphasises the difficulty in extrapolating from animal models of emesis to clinical efficacy in PONV.
Exploring the role of cannabinoid CB(2) receptors in the brain, we present evidence of CB(2) receptor molecular and functional interaction with cannabinoid CB(1) receptors. Using biophysical and biochemical approaches, we discovered that CB(2) receptors can form heteromers with CB(1) receptors in transfected neuronal cells and in rat brain pineal gland, nucleus accumbens, and globus pallidus. Within CB(1)-CB(2) receptor heteromers expressed in a neuronal cell model, agonist co-activation of CB(1) and CB(2) receptors resulted in a negative cross-talk in Akt phosphorylation and neurite outgrowth. Moreover, one specific characteristic of CB(1)-CB(2) receptor heteromers consists of both the ability of CB(1) receptor antagonists to block the effect of CB(2) receptor agonists and, conversely, the ability of CB(2) receptor antagonists to block the effect of CB(1) receptor agonists, showing a bidirectional cross-antagonism phenomenon. Taken together, these data illuminate the mechanism by which CB(2) receptors can negatively modulate CB(1) receptor function.
Nausea is a universal human experience. It evolves slowly over time, and brain mechanisms underlying this evolution are not well understood. Our functional magnetic resonance imaging (fMRI) approach evaluated brain activity contributing to and arising from increasing motion sickness. Subjects rated transitions to increasing nausea, produced by visually induced vection within the fMRI environment. We evaluated parametrically increasing brain activity 1) precipitating increasing nausea and 2) following transition to stronger nausea. All subjects demonstrated visual stimulus-associated activation (P < 0.01) in primary and extrastriate visual cortices. In subjects experiencing motion sickness, increasing phasic activity preceding nausea was found in amygdala, putamen, and dorsal pons/locus ceruleus. Increasing sustained response following increased nausea was found in a broader network including insular, anterior cingulate, orbitofrontal, somatosensory and prefrontal cortices. Moreover, sustained anterior insula activation to strong nausea was correlated with midcingulate activation (r = 0.87), suggesting a closer linkage between these specific regions within the brain circuitry subserving nausea perception. Thus, while phasic activation in fear conditioning and noradrenergic brainstem regions precipitates transition to strong nausea, sustained activation following this transition occurs in a broader interoceptive, limbic, somatosensory, and cognitive network, reflecting the multiple dimensions of this aversive commonly occurring symptom.
The endocannabinoid (eCB) system is widely expressed throughout the central nervous system (CNS) and the functionality of type-1 cannabinoid receptors in neurons is well documented. In contrast, there is little knowledge about type-2 cannabinoid receptors (CB(2)Rs) in the CNS. Here, we show that CB(2)Rs are located intracellularly in layer II/III pyramidal cells of the rodent medial prefrontal cortex (mPFC) and that their activation results in IP(3)R-dependent opening of Ca(2+)-activated Cl(-) channels. To investigate the functional role of CB(2)R activation, we induced neuronal firing and observed a CB(2)R-mediated reduction in firing frequency. The description of this unique CB(2)R-mediated signaling pathway, controlling neuronal excitability, broadens our knowledge of the influence of the eCB system on brain function.
In this work, the author explains the remarkable advances that have been made in scientific research on cannabis with the discovery of specific receptors and the existence of naturally occurring cannabis-like substances in the brain. He provides an objective and up-to-date assessment of the scientific basis for the medical use of cannabis and what risks this may entail. The recreational use of the drug and how it affects users is described along with some predictions about how attitudes to cannabis may change in the future.
The antiemetic activity and side-effects of delta-9-tetrahydrocannabinol (THC) were evaluated in 116 patients (median age 61 years) receiving combined 5-fluorouracil and semustine (methyl CCNU) therapy for gastrointestinal carcinoma. In a double-blind study, patients were randomized to receive THC, 15 mg orally three times a day, prochlorperazine, 10 mg orally three times a day, or placebo. The THC had superior antiemetic activity in comparison to placebo, but it showed no advantage over prochlorperazine. Central nervous system side-effects, however, were significantly more frequent and more severe with THC. With the dosage and schedule we used, and in our patient population of largely elderly adults, THC therapy resulted in an overall more unpleasant treatment experience than that noted with prochlorperazine or placebo. Although THC may have a role in preventing nausea and vomiting associated with cancer chemotherapy, this role must be more clearly defined before THC can be recommended for general use.
A critical review of the literature assessing the antiemetic efficacy of delta-9-tetrahydrocannabinol (THC) in patients receiving cancer chemotherapy showed considerable inconsistency in results. The equivocal nature of these results partly reflects the difficulty of doing research on antiemetic therapies, but also can be attributed to differences in the adequacy and nature of the research designs, procedures, and assessment instruments that have been used. Several factors were also identified that are seldom studied but may be important in determining whether THC will be effective: patient variables, such as chemotherapy regimen and age; pharmacologic variables, such as drug tolerance, dose, schedule, toxicity, route of administration, and drug interactions; and environmental variables associated with administration setting. The need to differentiate pharmacologically induced from conditioned nausea and vomiting was also pointed out. We believe that THC does have antiemetic efficacy, but the lack of controlled research does not allow precise knowledge of its true effectiveness and toxicity. Well-controlled trials are needed to help answer some of these questions.
Enhancement of the endocannabinoid (EC) system may reduce anticipatory nausea (AN).
The experiments evaluated the potential of the dual fatty acid amide hydrolase (FAAH)/monoacylglycerol lipase (MAGL) inhibitor, JZL195, on its own and combined with anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) to reduce contextually elicited gaping, a measure of AN in rats.
Following four context lithium chloride (LiCl) pairings, rats were injected with vehicle (VEH) or JZL195 (10 mg kg(-1), intraperitoneally) 105 min before an injection of VEH, 2-AG (1.25 mg kg(-1)), or AEA (5.0 mg kg(-1)). Fifteen minutes later, all rats were placed in the LiCl-paired context for 5 min and in a different context for a 15-min locomotor test. Whole brains were extracted for EC analysis. The potential of the CB1 antagonist, SR141716, to reverse the suppression of AN by both JZL195 and AEA and of the CB2 antagonist, AM630, to reverse the suppression of AN by JZL195 was then evaluated.
JZL195 suppressed gaping and elevated AEA, palmitoylethanolamine, and oleoylethanolamide. As the suppression of gaping was reversed by SR141716, but not by AM630, the effect was CB1 mediated. The suppressive effect of JZL195 on gaping, as well as elevation of AEA and 2-AG, was amplified by pretreatment with either AEA or 2-AG. On its own, AEA, but not 2-AG, also suppressed gaping-an effect that was also prevented by CB1 antagonism.
JZL195 reduces AN primarily by acting as a FAAH inhibitor, but MAGL inhibition is also indicated.
We aimed to determine the potential of various doses of metoclopramide (MCP, a dopamine antagonist) to reduce lithium chloride (LiCl)-induced conditioned gaping (a nausea-induced behaviour) in rats, using the taste reactivity test We then evaluated whether an ineffective low dose of cannabidiolic acid (CBDA, 0.1μg/kg, Rock et al., 2013), the potent acidic precursor of cannabidiol (CBD, a non-psychoactive component of cannabis) could enhance the anti-nausea effects of an ineffective low dose of MCP. MCP (3.0mg/kg) reduced conditioned gaping responses. Coadministration of ineffective doses of MCP (0.3mg/kg) and CBDA (0.1μg/kg) enhanced the suppression of conditioned gaping, over that of either drug alone, without interfering with conditioned taste avoidance. MCP dose-dependently reduced nausea-induced conditioned gaping in rats. As well the suppression of conditioned gaping was enhanced when ineffective doses of MCP and CBDA were coadministered. These data suggest that CBDA could be a powerful adjunct treatment to anti-emetic regimens for chemotherapy-induced nausea.
To understand how anandamide transport inhibition impacts the regulation of nausea and vomiting and the receptor level mechanism of action involved. In light of recent characterization of an anandamide transporter, FAAH-1-like anandamide transporter (FLAT), to provide behavioral support for anandamide cellular reuptake as a facilitated transport process.
The systemic administration of the anandamide transport inhibitor ARN272 was used to evaluate the prevention of LiCl-induced nausea-induced behaviour (conditioned gaping) in rats, and LiCl-induced emesis in shrews (Suncus murinus). The mechanism of how prolonging anandamide availability acts to regulate nausea in rats was explored by the antagonism of CB1 receptors with the systemic co-administration of SR141716.
The systemic administration of ARN272 produced a dose-dependent suppression of nausea-induced conditioned gaping in rats, and produced a dose-dependent reduction of vomiting in shrews. The systemic co-administration of SR141716 with ARN272 (at 3.0 mg.kg(-1) ) in rats produced a complete reversal of ARN272-suppressed gaping at 1.0 mg.kg(-1) . SR141716 alone did not differ from VEH.
These results suggest that anandamide transport inhibition by the compound ARN272 tonically activates CB1 receptors and as such produces a type of indirect agonism to regulate toxin-induced nausea and vomiting. The results also provide behavioral evidence in support of a facilitated transport mechanism used in the cellular reuptake of anandamide.
We evaluated the anti-emetic and anti-nausea properties of the acid precursor of Δ(9) -tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), and to determine its mechanism of action in these animal models.
We investigated the effect of THCA on lithium chloride- (LiCl) induced conditioned gaping (nausea-induced behaviour) to a flavour, and context (a model of anticipatory nausea, AN) in rats, and on LiCl-induced vomiting in Suncus murinus. Furthermore, we investigated THCA's ability to induce hypothermia and suppress locomotion [rodent tasks to assess cannabinoid1 (CB1 ) receptor agonist-like activity], and measured plasma and brain THCA and THC levels. We also determined whether THCA's effect could be blocked by pretreatment with SR141716 (SR, a CB1 receptor antagonist).
In rats, THCA (0.05 and/or 0.5 mg/kg) suppressed LiCl-induced conditioned gaping to a flavour and context; the latter effect blocked by the CB1 receptor antagonist, SR, but not by the 5-HT1A receptor antagonist, WAY100635. In S. murinus, THCA (0.05 and 0.5 mg/kg) reduced LiCl-induced vomiting; an effect that was reversed with SR. A comparatively low dose of THC (0.05 mg/kg) did not suppress conditioned gaping to a LiCl-paired flavour or context. THCA did not induce hypothermia or reduce locomotion, indicating non-CB1 agonist-like effects. THCA, but not THC was detected in plasma samples.
THCA potently reduced conditioned gaping in rats and vomiting in S. murinus; effects that were blocked by SR.. These data suggest that THCA may be a more potent alternative to THC in the treatment of nausea and vomiting.
We have determined the effect of forskolin, an adenyl cyclase agonist, and 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, on the accumulation and cyto-toxicity of cisplatin (DDP) In 2008 human ovarian carcinoma cells. In DDP-sensitive 2008 cells, forskolin and IBMX caused 2.1-fold and 2.3-fold Increases, respectively, in the short-term accumulation of DDP relative to untreated cells. The inactive analogue, 1,9-dideoxyforskolin, decreased DDP accumulation. Forskolin and IBMX also increased accumulation in A2780 cells. Neither forskolin nor IBMX had any effect on DDP accumulation in DDP-resistant 2008 cells, the effects were detectable as early as I min and persisted at 60 min. The concentrations for half-maximal stimulation of DDP accumulation were approximately 0.2 μM for forskolin and 0.2 mM for IBMX. Forskolin caused marked increases in cAMP levels in both sensitive and resistant 2008 cells within I min, although there were differences in the subsequent time-courses of the response. Both 2008 cell types had identical cAMP-dependent protein kinase (PKA) activity. These results suggest that there is a target downstream of PKA that is an Important participant in DDP accumulation, and that this target is defective of missing in DDP-resistant cells. Following a 1-hr exposure to drugs, forskolin and IBMX at concentrations that were by themselves completely non-toxic increased the slopes of the clonogenic survival vs. DDP concentration curves in 2008 cells 1.9-fold and 3.3-fold, respectively. In DDP-resistant 2008 cells, however, forskolin and IBMX increased the slopes only 1.2 and 2.6-fold, respectively. These effects of forskolin and IBMX on DDP cytotoxicity did not directly correlate with the effects on the 1-hr DDP accumulation which suggested that, in addition to modulating DDP accumulation, these agents increase the cytotoxicity of the intracellular platinum. The results indicate that modulation of cAMP levels can have important effects on DDP accumulation and cytotoxicity in 2008 cells and that these effects are significantly diminished in DDP-resistant cells.
The aim of this review is to provide an overview of the physiological basis, clinical picture and treatment options for motion sickness. Motion sickness is a well-known nausea and vomiting syndrome in otherwise healthy people. The physical signs of motion sickness occur in both humans and animals during travel by sea, automobile or airplane and in space. Furthermore, some other special situations, such as simulators, the cinema and video games, have been described as causing pseudomotion sickness. Children between 2 and 12 years old are most susceptible to motion sickness, and women are more frequently affected than men. Predisposing factors include menstruation, pregnancy, migraines and possibly a side difference in the mass of otoconia in the vestibular organs. Therapy is directed towards decreasing conflicting sensory input, accelerating the process of adaptation and controlling nausea and vomiting. To control these vegetative symptoms, scopolamine and antihistamines are the most effective drugs.
The endocannabinoid signaling system regulates diverse physiologic processes and has attracted considerable attention as a potential pharmaceutical target for treating diseases, such as pain, anxiety/depression, and metabolic disorders. The principal ligands of the endocannabinoid system are the lipid transmitters N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), which activate the two major cannabinoid receptors, CB1 and CB2. Anandamide and 2-AG signaling pathways in the nervous system are terminated by enzymatic hydrolysis mediated primarily by the serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. In this review, we will discuss the development of FAAH and MAGL inhibitors and their pharmacological application to investigate the function of anandamide and 2-AG signaling pathways in preclinical models of neurobehavioral processes, such as pain, anxiety, and addiction. We will place emphasis on how these studies are beginning to discern the different roles played by anandamide and 2-AG in the nervous system and the resulting implications for advancing endocannabinoid hydrolase inhibitors as next-generation therapeutics.
To determine the minimally effective dose of cannabidiolic acid (CBDA) that effectively reduces lithium chloride (LiCl)-induced conditioned gaping reactions (nausea-induced behaviour) in rats and to determine if these low systemic doses of CBDA (5–0.1 μg·kg−1) relative to those of CBD could potentiate the anti-nausea effects of the classic 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, ondansetron (OND).
We investigated the efficacy of low doses of CBDA to suppress acute nausea, assessed by the establishment of conditioned gaping to a LiCl-paired flavour in rats. The potential of threshold and subthreshold doses of CBDA to enhance the reduction of nausea-induced conditioned gaping by OND were then determined.
CBDA (at doses as low as 0.5 μg·kg−1) suppressed nausea-induced conditioned gaping to a flavour. A low dose of OND (1.0 μg·kg−1) alone reduced nausea-induced conditioned gaping, but when it was combined with a subthreshold dose of CBDA (0.1 μg·kg−1) there was an enhancement in the suppression of LiCl-induced conditioned gaping.
CBDA potently reduced conditioned gaping in rats, even at low doses and enhanced the anti-nausea effect of a low dose of OND. These findings suggest that combining low doses of CBDA and OND will more effectively treat acute nausea in chemotherapy patients.
Type-1 cannabinoid receptors (CB1) are expressed in different neuronal populations in the mammalian brain. In particular, CB1 receptors on GABAergic or glutamatergic neurons exert different functions and display different pharmacological properties in vivo. This suggests the existence of neuronal type-specific signalling pathways activated by different subpopulations of CB1 receptors. In this study, we analysed CB1 expression, binding and signalling in the hippocampus of conditional mutant mice, bearing CB1 deletion in GABAergic (GABA-CB1-KO mice) or cortical glutamatergic neurons (Glu-CB1-KO mice). Compared to their wild type littermates, Glu-CB1-KO displayed a small decrease of CB1 mRNA amount, immunoreactivity and [³H]CP55,940 binding. Conversely, GABA-CB1-KO mice showed a drastic reduction of these parameters, confirming that CB1 is present at much higher density on hippocampal GABAergic interneurons than glutamatergic neurons. Surprisingly, however, saturation analysis of HU210-stimulated [(35) S]GTPγS binding demonstrated that "glutamatergic" CB1 receptors are more efficiently coupled to G protein signalling than "GABAergic" ones. Thus, the minority of CB1 receptors on glutamatergic neurons are paradoxically several fold more strongly coupled to G protein signalling than "GABAergic" CB1 receptors. This selective signalling mechanism raises the possibility of designing novel cannabinoid ligands that differentially activate only a subset of physiological effects of CB1 stimulation, thereby optimizing therapeutic action. © 2013 The Authors Journal of Neurochemistry © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12137.
Although a universally accepted definition is lacking, mild traumatic brain injury and concussion are classified by transient loss of consciousness, amnesia, altered mental status, a Glasgow Coma Score of 13 to 15, and focal neurologic deficits following an acute closed head injury. Most patients recover quickly, with a predictable clinical course of recovery within the first one to two weeks following traumatic brain injury. Persistent physical, cognitive, or behavioral postconcussive symptoms may be noted in 5 to 20 percent of persons who have mild traumatic brain injury. Physical symptoms include headaches, dizziness, and nausea, and changes in coordination, balance, appetite, sleep, vision, and hearing. Cognitive and behavioral symptoms include fatigue, anxiety, depression, and irritability, and problems with memory, concentration and decision making. Women, older adults, less educated persons, and those with a previous mental health diagnosis are more likely to have persistent symptoms. The diagnostic workup for subacute to chronic mild traumatic brain injury focuses on the history and physical examination, with continuing observation for the development of red flags such as the progression of physical, cognitive, and behavioral symptoms, seizure, progressive vomiting, and altered mental status. Early patient and family education should include information on diagnosis and prognosis, symptoms, and further injury prevention. Symptom-specific treatment, gradual return to activity, and multidisciplinary coordination of care lead to the best outcomes. Psychiatric and medical comorbidities, psychosocial issues, and legal or compensatory incentives should be explored in patients resistant to treatment.
Background and purpose:
To evaluate the ability of cannabidiolic acid (CBDA) to reduce nausea and vomiting and enhance 5-HT(1A) receptor activation in animal models.
Experimental approach:
We investigated the effect of CBDA on (i) lithium chloride (LiCl)-induced conditioned gaping to a flavour (nausea-induced behaviour) or a context (model of anticipatory nausea) in rats; (ii) saccharin palatability in rats; (iii) motion-, LiCl- or cisplatin-induced vomiting in house musk shrews (Suncus murinus); and (iv) rat brainstem 5-HT(1A) receptor activation by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and mouse whole brain CB(1) receptor activation by CP55940, using [³⁵S]GTPγS-binding assays.
Key results:
In shrews, CBDA (0.1 and/or 0.5 mg·kg⁻¹ i.p.) reduced toxin- and motion-induced vomiting, and increased the onset latency of the first motion-induced emetic episode. In rats, CBDA (0.01 and 0.1 mg·kg⁻¹ i.p.) suppressed LiCl- and context-induced conditioned gaping, effects that were blocked by the 5-HT(1A) receptor antagonist, WAY100635 (0.1 mg·kg⁻¹ i.p.), and, at 0.01 mg·kg⁻¹ i.p., enhanced saccharin palatability. CBDA-induced suppression of LiCl-induced conditioned gaping was unaffected by the CB₁ receptor antagonist, SR141716A (1 mg·kg⁻¹ i.p.). In vitro, CBDA (0.1-100 nM) increased the E(max) of 8-OH-DPAT.
Conclusions and implications:
Compared with cannabidiol, CBDA displays significantly greater potency at inhibiting vomiting in shrews and nausea in rats, and at enhancing 5-HT(1A) receptor activation, an action that accounts for its ability to attenuate conditioned gaping in rats. Consequently, CBDA shows promise as a treatment for nausea and vomiting, including anticipatory nausea for which no specific therapy is currently available.
Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a nonretrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. In this Review, we focus on new advances in synaptic endocannabinoid signaling in the mammalian brain. The emerging picture not only reinforces endocannabinoids as potent regulators of synaptic function but also reveals that endocannabinoid signaling is mechanistically more complex and diverse than originally thought.
Migraine is a neurovascular disorder characterized by recurrent unilateral headaches accompanied by nausea, vomiting, photophobia and phonophobia. Current theories suggest that the initiation of a migraine attack involves a primary event in the central nervous system (CNS), probably involving a combination of genetic changes in ion channels and environmental changes, which renders the individual more sensitive to environmental factors; this may, in turn, result in a wave of cortical spreading depression (CSD) when the attack is initiated. Genetically, migraine is a complex familial disorder in which the severity and the susceptibility of individuals are most likely governed by several genes that vary between families. Early PET studies have suggested the involvement of a migraine active region in the brainstem. Migraine headache is associated with trigeminal nerve activation and calcitonin gene-related peptide (CGRP) release from the trigeminovascular system. Administration of triptans (5-HT(1B/1D) receptor agonists) causes the headache to subside and the levels of CGRP to normalize. Moreover, administration of CGRP receptor antagonists aborts the headache. Recent immunohistochemical and pharmacological results suggest that the trigeminal system has receptors for CGRP; further, 5-HT(1B/1D) receptors, which inhibit the action of CGRP in pain transmission when activated, have been demonstrated. This offers an explanation for the treatment response. The present review provides an updated analysis of the basic mechanisms involved in the pathophysiology of migraine and the various pharmacological approaches (including 5-HT(1B/1D) receptor agonists, CGRP receptor antagonists and glutamate receptor antagonists) that have shown efficacy for the acute treatment of this disorder.
Acute administration of Δ(9)-tetrahydrocannabinol (THC) or exposure to marijuana smoke impairs short-term spatial memory in water maze tasks through a CB(1) receptor mechanism of action. N-Arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG) are endogenous cannabinoids that are predominantly metabolized by the respective enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Although the MAGL inhibitor JZL184 enhances short-term synaptic plasticity, it has yet to be evaluated in the Morris water maze. Previous research demonstrated that simultaneous, complete blockade of FAAH and MAGL produces full blown THC-like effects. Thus, in the following studies we tested whether dual blockade of FAAH and MAGL would impair learning in a repeated acquisition Morris water maze task. Mice treated with the dual FAAH/MAGL inhibitor JZL195 (20 mg/kg) as well as JZL184-treated FAAH -/- mice displayed robust deficits in Morris water maze performance that were similar in magnitude to THC-treated mice. While 20 or 40 mg/kg impaired water maze performance in FAAH -/- mice, only the high dose of JZL184 disrupted performance in FAAH +/+ mice. The memory impairing effects of JZL184 were blocked by the CB(1) receptor antagonist rimonabant. Neither JZL184 nor JZL195 impaired performance in a cued version of the water maze task, arguing against the notion that sensorimotor or motivational deficits accounted for the impaired acquisition performance. JZL184 increased 2-AG levels in the hippocampus, prefrontal cortex, and cerebellum to a similar degree in FAAH -/- and +/+ mice. FAAH -/- mice, regardless of drug treatment, possessed elevated AEA levels in each brain region assessed. The results of this study reveal that concomitant increases in AEA and 2-AG disrupt short-term spatial memory performance in a manner similar to that of THC.
The behavioral CRs elicited by a drug-paired contextual cue in rats were measured in a series of experiments. The first three
experiments measured the pattern of CRs elicited by a lithiumand an amphetamine-paired CS chamber. The final experiment measured
the pattern of URs elicited by lithium or amphetamine when administered in the same chamber. The suppression of grooming-related
activities (body washing, face washing, and/or scratching) appeared as a nonspecific effect of both drug USs that was capable
of becoming conditioned to the contextual chamber cue. A number of other behaviors differed among conditions, which provides
evidence that contextual cue-drug associations are drug-specific. Of the behaviors that differed between the two US drug conditions,
lithium CRs showed evidence of behavioral activation (enhanced rearing and limb flicking), but amphetamine CRs showed evidence
of behavioral suppression (line crossing, rearing, and shaking). The UR patterns shared some similar and some dissimilar elements
of the CR patterns elicited by the CS chamber for both lithium and amphetamine; in fact, by the activity and rearing measures,
the URs and CRs were opposite in direction. The results exclusively supported neither stimulus substitution nor conditioned
compensatory response accounts of Pavlovian conditioning; instead, each process appears to have accounted for different components
of the overall CR pattern.
Cannabis has been used for centuries in the medicinal treatment of gastrointestinal disorders. Endogenous cannabinimimetic substances such as 2-arachidonylglycerol have been isolated from gut homogenates and CB1-cannabinoid binding sites have been identified in small intestine. In this study, CB1-cannabinoid receptors (CB1-R) were immunohistochemically localized within the enteric nervous system of the pig, an omnivorous species whose digestive tract is functionally similar to humans. Two anti-CB1-R antisera, raised against N-terminal epitopes in the human CB1-R, were employed to localize receptor immunoreactivity by secondary immunofluorescence. CB1-R immunoreactivity was observed in the myenteric and submucosal ganglionated plexuses of porcine ileum and colon. In the ileum, all CB1-R-immunoreactive neurons coexpressed immunoreactivity to the cholinergic marker, choline acetyltransferase (ChAT). CB1-R/ChAT-immunoreactive neurons appeared to be in close apposition to ileal Peyer's patches, submucosal blood vessels, and intestinal crypts. In the distal colon, CB1-R-immunoreactive neurons also expressed immunoreactivity to ChAT, albeit less frequently than in ileum. Immunoreactivity to vasoactive intestinal peptide or nitric oxide synthase was not colocalized in ileal or colonic CB1-R-immunoreactive neurons. These studies indicate that CB1-R are present in cholinergic neurons in the porcine enteric nervous system. The potential roles of these receptors in intestinal motility and epithelial transport, host defense and visceral pain transmission are discussed.
What is already known about this subject:
• Cannabis based medicines are registered as a treatment for various indications, such as pain and spasms in multiple sclerosis (MS) patients, and anorexia and nausea in patients with HIV or receiving cancer treatment. • the pharmacokinetics of the various administration routes of cannabis and cannabis based medicines are variable and dosing is hard to regulate.
What this study adds:
• Namisol is a new tablet containing pure THC (>98%) that has a beneficial pharmacokinetic profile after oral administration. • Namisol gives a quick onset of pharmacodynamic effects in healthy volunteers, which implies a rapid initiation of therapeutic effects in patients.
Aims:
Among the main disadvantages of currently available Δ(9) -tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of Namisol®.
Methods:
This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomized, crossover study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5 and 8.0 mg or matching placebo in a randomized, crossover, rising dose study during panel II. PD measurements were body sway; visual analogue scales (VAS) mood, psychedelic and heart rate. THC and 11-OH-THC population PK analysis was performed.
Results:
Sublingual administration showed a flat concentration profile compared with oral administration. Oral THC apparent t(1/2) was 72-80 min, t(max) was 39-56 min and C(max) 2.92-4.69 ng ml(-1) . THC affected body sway (60.8%, 95% CI 29.5, 99.8), external perception (0.078 log mm, 95% CI 0.019, 0.137), alertness (-2.7 mm, 95% CI -4.5, -0.9) feeling high (0.256 log mm, 95% CI 0.093, 0.418) and heart rate (5.6 beats min(-1) , 95% CI 2.7, 6.5). Namisol® was well tolerated.
Conclusions:
Oral Namisol® showed promising PK and PD characteristics. Variability and t(max) of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations.
Background and purpose:
Conditioned gaping reactions reflect nausea-induced behaviour in rats. Cannabinoid 1 receptor (CB(1) ) agonists interfere with the establishment of nausea-induced conditioned gaping; however, it is not known if their effects are mediated by an action at peripheral or central CB(1) receptors.
Experimental approach:
We utilized the conditioned gaping model of nausea to evaluate the effect of peripheral and central administration of the peripherally restricted CB(1) agonist, CB13, on the establishment of LiCl-induced gaping in rats. We further evaluated the ability of HU-210 administered to the gustatory insular cortex (GIC) or visceral insular cortex (VIC) to interfere with LiCl-induced conditioned gaping and determined if this effect was mediated by CB(1) receptors.
Key results:
Central, but not peripheral, CB13 suppressed LiCl-induced conditioned gaping. Central administration of the potent CB(1) agonist, HU-210, delivered to the VIC, but not the GIC, suppressed the establishment of LiCl-induced gaping reactions, but not LiCl-induced suppression of hedonic reactions or conditioned taste avoidance. This pattern of results suggests that HU-210 delivered to the VIC prevented LiCl-induced nausea, but not learning per se. The suppression of LiCl-induced conditioned gaping by HU-210 was mediated by CB(1) receptors because it was prevented by co-administration of CB(1) antagonist/inverse agonist, AM-251, into the VIC. A high dose of AM-251 (20 µg) administered alone into the VIC did not produce conditioned gaping reactions.
Conclusions and implications:
The nausea-relieving effects of CB(1) agonists, but not the nausea-inducing effects of CB(1) inverse agonists, are mediated, at least in part, by their action at the VIC in rats.
BACKGROUND: Nicotine is the principal component of tobacco smoke, resulting in addiction, and recent evidence suggests that damage to the insular cortex (insula) disrupts tobacco addiction in human smokers. However, the effect of an inactivation of this structure in an animal model of nicotine addiction has yet to be evaluated. METHODS: To study this question, we investigated the effects of reversible inactivation of the granular insula by local injection of a gamma-aminobutyric acid agonists mixture (baclofen/muscimol) on nicotine self-administration (SA) under fixed and progressive ratio and on reinstatement of nicotine seeking induced by nicotine priming or nicotine-associated cues in rats. We also evaluated the effects of granular insula inactivation on food SA and relapse as a control. RESULTS: The inactivation of the granular insula decreased nicotine SA under both fixed and progressive ratios without affecting the SA of food under the same schedules of reinforcement. This inactivation also prevented the reinstatement, after extinction, of nicotine seeking induced by nicotine-associated cues or nicotine priming without modifying the reinstatement of food seeking. CONCLUSIONS: Our study indicates that the integrity of the granular insula is necessary for exhibiting motivation to take nicotine and to relapse to nicotine seeking but not for consuming food pellets or to relapse for food seeking. Indeed, it might be interesting to study the effect of methods that are able to modulate the activity of the insula--such as repetitive transcranial magnetic stimulation or deep brain stimulation--on tobacco addiction and relapse in humans.
Despite being regarded as a hippie science for decades, cannabinoid research has finally found its well-deserved position in mainstream neuroscience. A series of groundbreaking discoveries revealed that endocannabinoid molecules are as widespread and important as conventional neurotransmitters such as glutamate or GABA, yet they act in profoundly unconventional ways. We aim to illustrate how uncovering the molecular, anatomical, and physiological characteristics of endocannabinoid signaling has revealed new mechanistic insights into several fundamental phenomena in synaptic physiology. First, we summarize unexpected advances in the molecular complexity of biogenesis and inactivation of the two endocannabinoids, anandamide and 2-arachidonoylglycerol. Then, we show how these new metabolic routes are integrated into well-known intracellular signaling pathways. These endocannabinoid-producing signalosomes operate in phasic and tonic modes, thereby differentially governing homeostatic, short-term, and long-term synaptic plasticity throughout the brain. Finally, we discuss how cell type- and synapse-specific refinement of endocannabinoid signaling may explain the characteristic behavioral effects of cannabinoids.
Cannabis is the most commonly used illicit substance worldwide. Cannabinoids or cannabinoid receptor agonists are often used to treat nausea, vomiting, and anorexia. However, in recent years, several medical journals have published reports of patients with nausea and vomiting thought to be induced by chronic cannabis use.
The authors seek to inform readers about Cannabinoid Hyperemesis Syndrome (CHS).
The authors describe four patients with chronic cannabis abuse, episodic, intractable nausea and vomiting, and compulsive hot water bathing. Previous cases of CHS are reviewed, pathophysiology is hypothesized, and difficulties with making the diagnosis are discussed.
CHS should be strongly considered in the differential diagnosis of patients with intractable vomiting and/or compulsive hot water bathing.
The distribution in the rat brain of fatty acid amide hydrolase (FAAH) an enzyme that catalyzes the hydrolysis of the endogenous cannabinoid anandamide was studied by immunohistochemistry. An immunopurified, polyclonal antibody to the C terminal region of FAAH was used in these studies. The large principal neurons, such as pyramidal cells in the cerebral cortex, the pyramidal cells the hippocampus, Purkinje cells in the cerebellar cortex and the mitral cells in the olfactory bulb, showed the strongest FAAH immunoreactivity. These FAAH-containing principal neurons except the mitral cells in the olfactory bulb are in close proximity with cannabinoid CB1 receptors as revealed by our previous immunohistochemical study. Moderately or lightly stained FAAH-containing neurons were also found in the amygdala, the basal ganglia, the deep cerebellar nuclei, the ventral posterior nuclei of the thalamus, the optic layer and the intermediate white layer of the superior colliculus and the red nucleus in the midbrain, and motor neurons of the spinal cord. These data demonstrate that FAAH is heterogeneously distributed and this distribution exhibits considerable, although not complete, overlap with the distribution of cannabinoid CB1 receptors in rat brain.
Two experiments investigating the effects of poisoning on the consumption of non-nutritive substances are reported. In the first experiment, rats were poisoned with lithium chloride or Red Squill and offered a choice between food and soil. In the second experiment, rats were poisoned with cyclophosphamide and offered a choice between food and kaolin. Following treatment, poisoned rats in both experiments increased their consumption of the non-nutritive substances. Additionally, rats poisoned with logarithmic doses consumed amounts of the non-nutritive substances proportionate to the amount of poison administered. It was suggested that increased pica is an illness-response behavior of the rat, analogous to vomiting in other species, which can be used as an easily quantifiable behavioral assay of noxious drug effects.
A series of experiments were performed with adult CD-1 male mice to evaluate the antiemetic effects of several compounds using the conditioned taste aversion procedure. The antiemetics were administered IP immediately prior to a 30-min conditioning trial in which a novel tasting solution (0.3% saccharin) was presented to the subjects. The emetics, apomorphine and the cancer chemotherapeutic drug cyclophosphamide, were given IP immediately after the conditioning trial at doses that induced taste aversions. Three days later the mice received a two bottle preference test (saccharin vs. water) and the percent saccharin consumed of the total fluid intake was calculated. Doses of the phenothiazine antiemetic prochlorperazine (1 and 3 mg/kg) attenuated the aversions produced by 0.3 and 1.0 mg/kg apomorphine. Doses of drugs currently approved or under clinical investigation as antiemetics in conjunction with cancer chemotherapy, i.e., prochlorperazine (1.0 mg/kg), Δ9-tetrahydrocannabinol (0.3 and 1.0 mg/kg) and nabilone (0.01 and 0.03 mg/kg), significantly attenuated the taste aversions induced by cyclophosphamide. Levonantradol at doses of 0.03 and 0.06 mg/kg, however, did not attenuate cyclophosphamide-induced taste aversions. Conditioned taste aversions produced by emetic drugs warrants investigation as a model for evaluating potential antiemetics.
The presence of central cannabinoid receptor (CB1), involving the N-terminal 14 amino acid peptide, was demonstrated in the rat brain by immunohistochemistry. Intensely stained neurons were observed in the principal neurons of the hippocampus, striatum, substantia nigra, cerebellar cortex, including the Purkinje cells. Moderate CB1-IR cell bodies and fibers were present in the olfactory bulb, cingulate, entorhinal and piriform cortical areas, amygdala and nucleus accumbens. The perivascular glial fibers have shown moderate to high density CB1-IR in olfactoric and limbic structures. Low density was detected in the thalamus and hypothalamus and area postrema. The CB1 receptor was widely distributed in the forebrain and sparsely in the hindbrain.These new data support the view that the endogenous cannabinoids play an important role in different neuronal functions as neuromodulators or neurotransmitters.
We investigated involvement of the autonomic nervous system in gastric motor and cardiovascular responses to Δ9-tetrahydrocannabinol (Δ9-THC) in anesthetized rats. Intravenously administered Δ9-THC evoked long-lasting decreases in intragastric pressure and pyloric contractility, bradycardia, and hypotension. The changes in gastric motor function and bradycardia were abolished by vagotomy and ganglionic blockade, whereas spinal cord transection prevented the hypotensive response. Administered intravenously alone, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, a putative cannabinoid CB1 receptor antagonist, evoked transient decrease in intragastric pressure, and hypertension that was associated with bradycardia. However, this agent completely blocked the gastric motor and cardiovascular responses to intravenous Δ9-THC. Application of Δ9-THC to the dorsal surface of the medulla resulted in small and short-lasting decreases in gastric motor and cardiovascular function. We conclude that the decrease in gastric motor function and bradycardia are partially due to an action of Δ9-THC in the dorsal medulla and that intact vagal nerves are required. The hypotension was mediated through sympathetic pathways. Both gastric motor and cardiovascular effects of peripherally administered Δ9-THC seem to be mediated through cannabinoid CB1 receptors.