The Gastrointestinal Pharmacology of Cannabinoids: Focus on Motility (original) (raw)
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In‐vivo Modulation of Gastrointestinal Motility by Cannabinoid Drugs
Pharmacy and …, 2000
In-vivo studies have shown that cannabinoid receptor agonists decreased gastrointestinal motility through activation of cannabinoid CB 1 receptors, while SR141716A, a cannabinoid CB 1 -receptor antagonist, increased intestinal motility. Both central and peripheral cannabinoid CB 1 ...
The Role of Cannabinoids in Regulation of Nausea and Vomiting, and Visceral Pain
Current Gastroenterology Reports, 2015
Marijuana derived from the plant Cannabis sativa has been used for the treatment of many gastrointestinal (GI) disorders, including anorexia, emesis, abdominal pain, diarrhea, and others. However, its psychotropic side effects have often limited its use. Several cannabinoid receptors, which include the cannabinoid receptor 1 (CB1), CB2, and possibly GPR55, have been identified throughout the GI tract. These receptors may play a role in the regulation of food intake, nausea and emesis, gastric secretion and gastroprotection, GI motility, ion transport, visceral sensation, intestinal inflammation, and cell proliferation in the gut. However, the regulation of nausea and vomiting by cannabinoids and the endocannabinoid system has shed new knowledge in this field. Thus far, despite evidence of visceral sensitivity inhibition in animal models, data in irritable bowel syndrome (IBS) patients is scarce and not supportive. Furthermore, many compounds that either act directly at the receptor or increase (or reduce) ligand availability have the potential to affect other brain functions and cause side effects. Novel drug targets such as FAAH and monoacylglycerol lipase (MAGL) inhibitors appear to be promising in animal models, but more studies are necessary to prove their efficiency. The promise of emerging drugs that are more selective and peripherally acting suggest that, in the near future, cannabinoids will play a major role in managing an array of GI diseases.
Δ9-Tetrahydrocannabinol inhibits gastric motility in the rat through cannabinoid CB1 receptors
European Journal of Pharmacology, 1999
We investigated involvement of the autonomic nervous system in gastric motor and cardiovascular responses to D 9 -tetrahydrocanna-Ž 9 . 9 binol D -THC in anesthetized rats. Intravenously administered D -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, Ž . Ž . Ž . N-piperidin-1-yl -5-4-chlorophenyl -1-2,4-dichlorophenyl -4-methyl-1H-pyrazole-3-carboxamide, a putative cannabinoid CB receptor 1 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 D 9 -THC. Application of D 9 -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 D 9 -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 D 9 -THC seem to be mediated through cannabinoid CB receptors. q 1999 Elsevier Science B.V. All rights reserved. 1 9 Ž
Cannabinoid pharmacology and therapy in gut disorders
Biochemical Pharmacology, 2018
Cannabis sp. and their products (marijuana, hashish…), in addition to their recreational, industrial and other uses, have a long history for their use as a remedy for symptoms related with gastrointestinal diseases. After many reports suggesting these beneficial effects, it was not surprising to discover that the gastrointestinal tract expresses endogenous cannabinoids, their receptors, and enzymes for their synthesis and degradation, comprising the so-called endocannabinoid system. This system participates in the control of tissue homeostasis and important intestinal functions like motor and sensory activity, nausea, emesis, the maintenance of the epithelial barrier integrity, and the correct cellular microenvironment. Thus, different cannabinoid-related pharmacological agents may be useful to treat the main digestive pathologies. To name a few examples, in irritable bowel syndrome they may normalize dysmotility and reduce pain, in inflammatory bowel disease they may decrease inflammation, and in colorectal cancer, apart from alleviating some symptoms, they may play a role in the regulation of the cell niche. This review summarizes the main recent findings on the role of cannabinoid receptors, their synthetic or natural ligands and their metabolizing enzymes in normal gastrointestinal function and in disorders including irritable bowel syndrome, inflammatory bowel disease, colon cancer and gastrointestinal chemotherapy-induced adverse effects (nausea/vomiting, constipation, diarrhea).
Neurogastroenterology & Motility, 2010
Background In the absence of pathology, cannabinoid-induced depression of gastrointestinal (GI) motility is thought to be mediated primarily by CB1 receptors, whereas the role of CB2 receptors is still unclear. The aim of this work was to radiographically analyze the acute effect of the mixed cannabinoid agonist WIN 55,212-2 (WIN) on GI motor function in the rat, focusing on the involvement of CB1 and CB2 receptors. Methods Male Wistar rats received different doses of WIN and both psychoactivity (cannabinoid tetrad) and GI motility (radiographic analysis) were tested. The duration of WIN effect on GI motility was also radiographically analyzed. Finally, the involvement of the different cannabinoid receptors on WINinduced alterations of GI motility was analyzed by the previous administration of selective CB1 (AM251) and CB2 (SR144528 or AM630) antagonists. After administration of contrast medium, alterations in GI motility were quantitatively evaluated in serial radiographs by assigning a compounded value to each region of the GI tract. Key Results Low, analgesic doses of WIN delayed intestinal transit, but high, psychoactive doses were required to delay gastric emptying. Acute WIN effects on GI motility were confined to the first few hours after administration. AM251 partially counteracted the effect of WIN on GI motility. Surprisingly, SR144528 (but not AM630) enhanced WIN-induced delayed gastric emptying. Conclusions & Inferences X-ray analyses confirm that cannabinoids inhibit GI motility via CB1 receptors; in addition, cannabinoids could influence motility through interaction with a SR144528-sensitive site. Further studies are needed to verify if such site of action is the CB2 receptor.
British Journal of Pharmacology, 2001
1 We have studied the eect of cannabinoid agonists (CP 55,940 and cannabinol) on intestinal motility in a model of intestinal in¯ammation (induced by oral croton oil in mice) and measured cannabinoid receptor expression, endocannabinoids (anandamide and 2-arachidonylglycerol) and anandamide amidohydrolase activity both in physiological and pathophysiological states. 2 CP 55,940 (0.03 ± 10 nmol mouse 71 ) and cannabinol (10 ± 3000 nmol mouse 71 ) were more active in delaying intestinal motility in croton oil-treated mice than in control mice. These inhibitory eects were counteracted by the selective cannabinoid CB 1 receptor antagonist SR141716A (16 nmol mouse 71 ). SR141716A (1 ± 300 nmol mouse 71 ), administered alone, increased intestinal motility to the same extent in both control and croton oil-treated mice 3 Croton oil-induced intestinal in¯ammation was associated with an increased expression of CB 1 receptor, an unprecedented example of up-regulation of cannabinoid receptors during in¯ammation. 4 High levels of anandamide and 2-arachidonylglycerol were detected in the small intestine, although no dierences were observed between control and croton oil-treated mice; by contrast anandamide amidohydrolase activity increased 2 fold in the in¯amed small intestine. 5 It is concluded that in¯ammation of the gut increases the potency of cannabinoid agonists possibly by`up-regulating' CB 1 receptor expression; in addition, endocannabinoids, whose turnover is increased in in¯amed gut, might tonically inhibit intestinal motility. This work was supported by Co®nanziamento Murst and Enrico and Enrica Sovena Foundation (Roma). SR141716A and SR144528 were a kind gift from SANOFI (Montpellier, France).
Cannabis and the Gastrointestinal Tract
Journal of Pharmacy & Pharmaceutical Sciences
Cannabis has been used for its medicinal purposes since ancient times. Its consumption leads to the activation of Cannabis receptors CB1 and CB2 that, through specific mechanisms can lead to modulation and progression of inflammation or repair. The novel findings are linked to the medical use of Cannabis in gastrointestinal (GI) system. PURPOSE: The objective of the present paper is to elucidate the role of Cannabis consumption in GI system. An additional aim is to review the information on the function of Cannabis in non-alcoholic fatty liver disease (NAFLD). METHODS AND RESULTS: This review summarizes the recent findings on the role of cannabinoid receptors, their synthetic or natural ligands, as well as their metabolizing enzymes in normal GI function and its disorders, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and possible adverse events. The synergism or antagonism between Cannabis’ active ingredients and the “entourage” plays a role in the effi...
Endocannabinoids and the gastrointestinal tract: what are the key questions?
British Journal of Pharmacology, 2009
Cannabinoid (CB 1) receptor activation acts neuronally, reducing GI motility, diarrhoea, pain, transient lower oesophageal sphincter relaxations (TLESRs) and emesis, and promoting eating. CB 2 receptor activation acts mostly via immune cells to reduce inflammation. What are the key questions which now need answering to further understand endocannabinoid pathophysiology? GPR55. Does this receptor have a GI role? Satiety, Nausea, Vomiting, Gastro-Oesophageal Reflux, Gastric Emptying. Endocannabinoids acting at CB 1 receptors can increase food intake and body weight, exert anti-emetic activity, reduce gastric acid secretion and TLESRs; CB 2 receptors may have a small role in emesis. Question 1: CB 1 receptor activation reduces emesis and gastric emptying but the latter is associated with nausea. How is the paradox explained? Q2: Do non-CB receptor actions of endocannabinoids (for example TRPV1) also modulate emesis? Q3: Is pathology necessary (gastritis, gastrooesophageal reflux) to observe CB 2 receptor function? Intestinal Transit and Secretion. Reduced by endocannabinoids at CB 1 receptors, but not by CB 2 receptor agonists. Q1: Do the effects of endocannabinoids rapidly diminish with repeat-dosing? Q2: Do CB 2 receptors need to be pathologically upregulated before they are active? Inflammation. CB 1 , CB 2 and TRPV1 receptors may mediate an ability of endocannabinoids to reduce GI inflammation or its consequences. Q1: Are CB 2 receptors upregulated by inflammatory or other pathology? Pain. Colonic bacterial flora may upregulate CB 2 receptor expression and thereby increase intestinal sensitivity to noxious stimuli. Q1: Are CB 2 receptors the interface between colonic bacteria and enteric-or extrinsic nerve sensitivity? Relevance of endocannabinoids to humans. Perhaps apart from appetite, this is largely unknown.