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

Abstract

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...

Endocannabinoids

“…In vivo, inhibition of FAAH and MAGL in mouse intestine was shown to lead to increased levels of anandamide and 2-AG, respectively, also resulting in reduced motility Duncan et al 2008a;Alhouayek et al 2011). Anandamide seems to play an important role in the regulation of peristaltic reflex pathways within the ENS of rodents (Grider et al 2009). In contrast to CB 1 , the CB 2 receptor may not be involved in the physiological control of gut motility, except in the inflamed gut (Duncan et al 2008b).…”

The Gastrointestinal Pharmacology of Cannabinoids: Focus on Motility

“…In fact, all the components of the peristaltic reflex are affected, at least in the rat colon, in which CBs inhibited the ascending contraction and concomitant substance P release, the descending relaxation and concomitant vaso-active intestinal peptide release, and the sensory limb and concomitant calcitonin gene-related peptide release via CB1 receptor activation [25]. …”

Cannabinoids and their medicinal potential

“…77 Pharmacological studies have demonstrated that anandamide and various CB 1 agonists inhibit gastrointestinal motility in rodens in vivo and in isolated ileum and colon from both animals and humans. 20,80,81 In clinical trials with rimonabant for nicotine cessation or obesity, it was seen that incidence of diarrhea was higher in patients receiving rimonabant than with placebo.…”