Cannabinoid type 1 receptor modulates intestinal propulsion by an attenuation of intestinal motor responses within the myenteric part of the peristaltic reflex

Yuece, Birol; Sibaev, Andrei; Broedl, U. C.; Marsicano, Giovanni; Göke, Burkhard; Lutz, Beat; Allescher, H.D.; Storr, Martin

doi:10.1111/j.1365-2982.2007.00975.x

Cited by 41 publications

(45 citation statements)

References 41 publications

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“…7C) compared with the vehicle control group. In CB 1 receptordeficient mice, transit times were accelerated compared with wild-type mice, in agreement with previous reports (48). The inhibitory action of 40 mg/kg URB602 on whole gut transit was absent in these mice (Fig.…”

Section: Resultssupporting

confidence: 92%

Distribution and function of monoacylglycerol lipase in the gastrointestinal tract

Duncan

Thomas²,

Cluny³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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The endogenous cannabinoid system plays an important role in the regulation of gastrointestinal function in health and disease. Endocannabinoid levels are regulated by catabolic enzymes. Here, we describe the presence and localization of monoacylglycerol lipase (MGL), the major enzyme responsible for the degradation of 2-arachidonoylglycerol. We used molecular, biochemical, immunohistochemical, and functional assays to characterize the distribution and activity of MGL. MGL mRNA was present in rat ileum throughout the wall of the gut. MGL protein was distributed in the muscle and mucosal layers of the ileum and in the duodenum, proximal colon, and distal colon. We observed MGL expression in nerve cell bodies and nerve fibers of the enteric nervous system. There was extensive colocalization of MGL with PGP 9.5 and calretinin-immunoreactive neurons, but not with nitric oxide synthase. MGL was also present in the epithelium and was highly expressed in the small intestine. Enzyme activity levels were highest in the duodenum and decreased along the gut with lowest levels in the distal colon. We observed both soluble and membrane-associated enzyme activities. The MGL inhibitor URB602 significantly inhibited whole gut transit in mice, an action that was abolished in cannabinoid 1 receptor-deficient mice. In conclusion, MGL is localized in the enteric nervous system where endocannabinoids regulate intestinal motility. MGL is highly expressed in the epithelium, where this enzyme may have digestive or other functions yet to be determined.

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Section: Resultssupporting

confidence: 92%

Distribution and function of monoacylglycerol lipase in the gastrointestinal tract

Duncan

Thomas²,

Cluny³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…As shown in the present study and by others (15,21,28,29,35), the cannabinoids are potent inhibitors of peristaltic propulsion. This has largely been attributed to inhibition of the ascending contraction component as a result of CB-1 receptormediated inhibition of acetylcholine release.…”

Section: Discussionsupporting

confidence: 85%

“…ACh is one of the primary transmitters released from the excitatory motor neurons innervating the circular muscle layer, suggesting that cannabinoids might inhibit the ascending contraction limb of the peristaltic reflex. Previous studies by others have examined this and shown convincingly that the ascending contraction limb of the peristaltic reflex is inhibited by cannabinoids acting at cholinergic excitatory motor neurons and/or ascending excitatory interneurons (15,29,32,35). Similarly, a variety of CB-1 antagonists have been shown to enhance the ascending limb of the peristaltic reflex, suggesting a restraining influence of endocannabinoids.…”

Section: Discussionmentioning

confidence: 80%

“…In a variety of species including the human, cannabinoids have long been known to be inhibitory, slowing gut motility as well as secretion, and this has been usually attributed to the most prominent effect of cannabinoids in the gut, that is, CB-1 receptor-mediated presynaptic inhibition of acetylcholine (ACh) release (9,15,16,19,28,29,32,35). Although this mode of action is well documented, the peristaltic reflex is mediated by a complex array of enteric neurons that make up the reflex circuit.…”

mentioning

confidence: 99%

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Modulation of motor and sensory pathways of the peristaltic reflex by cannabinoids

Grider¹,

Mahavadi²,

Li³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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This effect has generally been attributed to their ability to prejunctionally inhibit release of acetylcholine from excitatory motor neurons that mediate, in part, the ascending contraction phase of the peristaltic reflex. In the present study we examined the effect of cannabinoids on the other transmitters known to participate in the peristaltic reflex using a three-compartment preparation of rat colon that allows separation of ascending contraction, descending relaxation, and the sensory components of the reflex. On addition to the orad motor compartment, anandamide decreased and AM-251, a CB-1 antagonist, increased ascending contraction and the concomitant substance P (SP) release. Similarly, on addition to the caudad motor compartment, anandamide decreased and AM-251 increased descending relaxation and the concomitant vasoactive intestinal peptide (VIP) release. On addition to the central sensory compartment, anandamide decreased and AM-251 increased both ascending contraction and SP release orad, and descending relaxation and VIP release caudad. This suggested a role for CB-1 receptors in modulation of sensory transmission that was confirmed by the demonstration that central addition of anandamide decreased and AM-251 increased release of the sensory transmitter, calcitonin gene-related peptide (CGRP). We conclude that the potent antipropulsive effect of cannabinoids is the result of inhibition of both excitatory cholinergic/tachykininergic and inhibitory VIPergic motor neurons that mediate ascending contraction and descending relaxation, respectively, as well as inhibition of the intrinsic sensory CGRP-containing neurons that initiate the peristaltic reflex underlying propulsive motility. endocannabinoid; cannabinoid receptors; enteric nervous system; peristalsis; neuropeptides ENDOGENOUS CANNABINOIDS (endocannabinoids) and their receptors are present in the gut tissues where they modulate motility, secretion, and the inflammatory response. Several endocannabinoids are synthesized on demand from fatty acids although the most commonly studied endocannabinoid is anandamide. The endocannabinoids interact mainly with two types of cannabinoid receptors designated CB-1 and CB-2, and in some cases with the TRPV1 (transient receptor potential vanilloid receptor 1 or VR-1) (24,26,36). Recently, studies also suggest that there may be an additional receptor that might mediate some actions of endocannabinoids (6,20,36).Endocannabinoids and the CB-1 and CB-2 receptors are present in the gut although much more is known about the localization of the receptors than the endocannabinoids (9, 16, 28). Both CB-1 and CB-2 receptors are present on enteric neurons that are invariably colocalized with choline acetyltransferase (ChAT) but not vasoactive intestinal peptide (VIP) or nitric oxide synthase (NOS) (8,10,19,28,29,32). Both Dogiel type I and II enteric neurons have been shown to express CB-1 receptors. The presence of cannabinoid receptors in smooth muscle is controversial although recent evidence suggests the presence of...

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“…Thus CB1 receptors also modulate intestinal propulsion by an attenuation of the peristaltic reflex (30).…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits

Camilleri

Kolar

Vázquez-Roque

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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P ϭ 0.028). There was significant association of CNR1 rs806378 (P ϭ 0.014; CC vs. CT/TT) with colonic transit in IBS-diarrhea (IBS-D) group; the TT group had the fastest colonic transit at 24 and 48 h. There was significant overall association of CNR1 rs806378 with sensation rating of gas (P ϭ 0.025), but not pain; the strongest associations for gas ratings were in IBS-D (P ϭ 0.002) and IBSalternating (P ϭ 0.025) subgroups. For CNR1 (AAT)n, gene-byphenotype interactions were observed for colonic transit at 24 (P ϭ 0.06) and 48 h (P ϭ 0.002) and gas (P ϭ 0.046, highest for IBS-D, P ϭ 0.034), but not pain sensation; the strongest association with transit was in controls, not in IBS. These data support the hypothesis that cannabinoid receptors may play a role in control of colonic transit and sensation in humans and deserve further study as potential mediators or therapeutic targets in lower functional gastrointestinal disorders.

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Cannabinoid type 1 receptor modulates intestinal propulsion by an attenuation of intestinal motor responses within the myenteric part of the peristaltic reflex

Cited by 41 publications

References 41 publications

Distribution and function of monoacylglycerol lipase in the gastrointestinal tract

Distribution and function of monoacylglycerol lipase in the gastrointestinal tract

Modulation of motor and sensory pathways of the peristaltic reflex by cannabinoids

Cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits

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