In-vivo Modulation of Gastrointestinal Motility by Cannabinoid Drugs (original) (raw)
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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).
The Gastrointestinal Pharmacology of Cannabinoids: Focus on Motility
Pharmacology, 2012
The marijuana plant Cannabis sp. and its derivatives and analogues, known as cannabinoids (CBs), induce many effects throughout the whole body. Herein we briefly review the gastrointestinal (GI) pharmacology of CBs, with special focus on motor function. Some drugs are available to treat nausea and emesis, and evidences in humans and animal models suggest that other GI motility alterations (gastro-oesophageal reflux, inflammatory bowel conditions or paralytic ileus) might benefit from modifications of the CB tone throughout the gut. However, central and peripheral (including GI) side effects may occur upon acute and chronic CB administration. Hopefully, the ongoing worldwide intense research on CBs will soon provide new, safer CB-based medicines.
Neurogastroenterology & Motility, 2007
Cannabinoid-1 (CB1) receptor activation affects gastrointestinal propulsion in vivo. It was our aim to further characterize the involved myenteric mechanisms in vivo and in vitro. In CB1 )/) mice and wild-type littermates we performed in vivo transit experiments by charcoal feeding and in vitro electrophysiological recordings in mouse small intestinal smooth muscle. Ascending neuronal contraction (ANC) following electrical field stimulation was studied in rat ileum in a partitioned organ bath separating the aboral stimulation site from the oral recording site. The knockout animals displayed an accelerated upper gastrointestinal transit compared to control animals. The CB1 receptor antagonist AM251 stimulated the force of the ANC in a concentration dependent manner when added in the oral chamber. Anandamide significantly inhibited the ANC when added in the oral chamber. Neither AM251 nor anandamide had an influence on the contraction latency. No effects were observed when drugs were added in the aboral chamber, proving a CB1 mediated action on the neuromuscular junction. Resting membrane potentials and neuronal induced inhibitory junction potentials in CB1 )/) mice were unchanged as compared to wild type. However, the electrophysiological slow waves were more sensitive to blockade of Ca 2+ channels in CB1 )/) mice. Our data strongly suggest a physiological involvement of the CB-1 receptor in the regulation of small intestinal motility. Therefore, CB1 receptors are a promising target for the treatment of motility disorders.
In vitro functional evidence of neuronal cannabinoid CB 1 receptors in human ileum
British Journal of Pharmacology, 1998
We investigated the eect of the cannabinoid agonist (+)WIN-55212-2 on human ileum longitudinal smooth muscle preparations, either electrically stimulated or contracted by carbachol. Electrical ®eld stimulation mostly activated cholinergic neurons, since atropine and tetrodotoxin (TTX), alone or coincubated, reduced twitch responses to a similar degree (85%). (+)WIN-55212-2 concentrationdependently inhibited twitch responses (IC 50 73 nM), but had no additive eect with atropine or TTX. The cannabinoid CB 1 receptor antagonist SR 141716 (pA 2 8.2), but not the CB 2 receptor antagonist, SR 144528, competitively antagonized twitch inhibition by (+)WIN-55212-2. Atropine but not (+)WIN-55212-2 or TTX prevented carbachol-induced tonic contraction.
Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine
British Journal of Pharmacology, 1996
A9-tetrahydrocannabinol (THC) and cannabinol each inhibited electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation of guinea-pig small intestine in a concentration-related manner. The IC50 values of these cannabinoids, respectively 3.45, 3.46, 30.61, 162.94, 214.63, and 3913.5 nM, correlate well with previously obtained potency values for displacement of [3H]-CP 55,940 from cannabinoid binding sites. 2 Electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation were also inhibited by AM 630 (6-iodo-pravadoline) and by WIN 55,212-2 (IC50= 1923.0 and 5.54 nM, respectively). The present finding that AM 630 is an agonist, contrasts with a previous observation that it behaves as a cannabinoid receptor antagonist in the mouse isolated vas deferens. 3 SR141716A produced dose-related parallel rightward shifts in the log concentration-response curves of CP 55,940, WIN 55,212-2, THC and AM 630 for inhibition of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation. SR141716A (1 giM) did not reverse the inhibitory effects of normorphine and clonidine on electrically-evoked contractions or potentiate the contractile response to acetylcholine. 4 Doses of naloxone and yohimbine that reversed the inhibitory effects of normorphine or clonidine on electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation did not affect the inhibitory response to WIN 55,212-2. 5 Electrically-evoked release of acetylcholine from strips of myenteric plexus-longitudinal muscle was decreased by 200 nM CP 55,940 and this inhibitory effect was almost completely reversed by 1 LM SR141716A. Acetylcholine-induced contractions were not affected by 200 nM CP 55,940. 6 These results support the hypothesis that guinea-pig small intestine contains prejunctional cannabinoid CB1 receptors through which cannabinoids act to inhibit electrically-evoked contractions by reducing release of the contractile transmitter, acetylcholine. 7 THC was found to be more susceptible to antagonism by SR141716A than CP 55,940 or AM 630, raising the possibility that guinea-pig small intestine contains more than one type of cannabinoid receptor. 8 At concentrations of 10 nM and above, SR141716A produced small but significant increases in the amplitude of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation suggesting that this tissue may release an endogenous cannabinoid receptor agonist or that some cannabinoid receptors in this tissue are precoupled and that SR141716A can reduce the number of receptors in this state.
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, 2010
Background and purpose: Cannabinoid receptor agonists reduce intestinal propulsion in rodents through the CB1 receptor. In addition to its antagonistic activity at this receptor, rimonabant (N-(piperidino)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxyamide) alone augments intestinal transit. Using rat and guinea-pig ileum MPLM (myenteric plexus-longitudinal muscle) preparations, we investigated whether the latter effect was through inverse agonism or antagonism of endocannabinoid agonist(s).Experimental approach: Inverse agonism was investigated by comparing the maximal enhancement of electrically evoked contractions of the MPLM by two CB1 receptor antagonists, AM 251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) and O-2050 [(6aR,10aR)-3-(1-methanesulphonylamino-4-hexyn-6-yl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6-H-dibenzo[b,d]pyran], with that produced by rimonabant. To reveal ongoing endocannabinoid activity, effects of inhibiting endocannabinoid hydrolysis by fatty acid amide hydrolase (FAAH) using AA-5HT (arachidonyl-5-hydroxytryptamine), PMSF (phenylmethylsulphonyl fluoride) or URB-597 (3′-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate), or putative uptake using VDM-11 [(5Z,8Z,11Z,14Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide] was evaluated.Key results: The presence of CB1 receptors was revealed by antagonism of exogenous anandamide, arachidonylethanolamide (AEA) and WIN 55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] by rimonabant. The rank order of potentiation of contractions was AM 251 > rimonabant > O-2050. Neither the FAAH inhibitors nor VDM-11 affected electrically evoked contractions. Each FAAH inhibitor increased the potency of AEA but not WIN 55,212-2. VDM-11 did not alter the inhibitory effect of AEA.Conclusions and implications: The different levels of maximal potentiation of contractions by the CB1 receptor antagonists suggest inverse agonism. The potentiation of the action of AEA by the FAAH inhibitors showed that FAAH was present. The lack of effect of FAAH inhibitors and VDM-11 alone on electrically evoked contractions, and on the potency of exogenous AEA suggests that pharmacologically active endocannabinoids were not released and the endocannabinoid transporter was absent. Thus, the CB1 receptor antagonists behave as inverse agonists.This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x
Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, 2015
Cannabinoids have been traditionally used for the treatment of gastrointestinal (GI) symptoms, but the associated central effects, through cannabinoid-1 receptors (CB1R), constitute an important drawback. Our aims were to characterize the effects of the recently developed highly potent long-acting megagonist AM841 on GI motor function and to determine its central effects in rats. Male Wistar rats were used for in vitro and in vivo studies. The effect of AM841 was tested on electrically induced twitch contractions of GI preparations (in vitro) and on GI motility measured radiographically after contrast administration (in vivo). Central effects of AM841 were evaluated using the cannabinoid tetrad. The non-selective cannabinoid agonist WIN 55,212-2 (WIN) was used for comparison. The CB1R (AM251) and CB2R (AM630) antagonists were used to characterize cannabinoid receptor-mediated effects of AM841. AM841 dose-dependently reduced in vitro contractile activity of rat GI preparations via CB...