Cannabinoid inhibition of guinea-pig intestinal peristalsis via inhibition of excitatory and activation of inhibitory neural pathways

Heinemann, Ákos; Shahbazian, Anaid; Holzer, Peter

doi:10.1016/s0028-3908(99)00056-8

Cited by 68 publications

(61 citation statements)

References 27 publications

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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: 86%

“…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: 79%

“…Conversely, in preparations of stomach from mouse and guinea pig, no effect of cannabinoids on NANC relaxation was evident, suggesting that there may be considerable species differences (25,34). In studies by Heinemann et al (15) using intraluminal distension of the guinea pig ileum, the antiperistaltic effects of methanandamide were found to be inhibited by apamin and a NOS inhibitor, N-nitro-L-arginine methyl ester, suggesting a facilitatory role of cannabinoids on descending relaxation. These studies were, however, based on measurement of effect on the peristaltic pressure threshold rather than direct examination of the descending relaxation pathway.…”

Section: Discussionmentioning

confidence: 97%

“…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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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

See 2 more Smart Citations

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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show abstract

“…Therefore, to date, the guinea pig ileum has been the standard in vitro bioassay for screening cannabinoids on the small intestine. The in vitro studies on this tissue have focussed on the ability of cannabinoids to inhibit either the peristaltic reflex in segments of whole ileum (Heinemann et al, 1999;Izzo et al, 2000), synaptic transmission (Lopez-Redondo et al, 1997), or the low frequency electrical field simulation (EFS)-evoked release of neurotransmitters (Coutts and Pertwee, 1997;Mang et al, 2001;Begg et al, 2002a,b) or subsequent contraction of the longitudinal Coutts and Pertwee, 1997;Mang et al, 2001) or circular (Izzo et al, 1998) smooth muscle layers.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological characterization of cannabinoid receptor activity in the rat‐isolated ileum myenteric plexus‐longitudinal muscle preparation

Makwana

Molleman

Parsons

2010

British J Pharmacology

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Background and purpose: Cannabinoid effects on intestinal transit are commonly evaluated in rats. We characterized the cannabinoid receptors mediating the inhibitory effect of 5- Contractions to exogenous ACh were not altered. These observations extended to the guinea pig ileum MPLM. Conclusions and implications:The rat MPLM contains CB1 receptors and at least two non-CB1-non-CB2-non-TRPV1 receptors attenuating EFS-evoked ACh-mediated contractions in an EFS frequency-dependent pre-synaptic and stereo-specific manner. Augmentation of the twitches by rimonabant may be through antagonism of an endocannabinoid tone or inverse agonism, whereas inhibition of the rebound contractions involved partial agonism.

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Assessment of Intestinal Peristalsis in Vitro

Pozzoli

Poli

2012

CP Toxicology

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The protocol detailed in this unit is designed to assess intestinal peristaltic motility in the isolated small intestine in vitro and to measure the effects of drugs able to interfere with gut propulsive activity. The procedure is based on Trendelenburg's classic technique, described at the beginning of the 20th century in the isolated guinea pig ileum and, later on, extended to other intestinal preparations from the same animal and other animal species. This unit illustrates the basic procedures for setting up the intestinal preparation, recording peristalsis under near-physiologic conditions, and testing the pharmaco-toxicological effects of drugs and pollutants on the contractile behavior of the gut wall. The protocol allows evaluating the action of drugs affecting sensory and/or motor neurons of the enteric nervous system and how these neurons control the development of the motor program of the gut wall. This model can be exploited to investigate novel compounds undergoing preclinical development and both inhibitors and stimulants of gastrointestinal peristaltic activity, as well as environmental or alimentary pollutants, like xenobiotics and naturally-occurring toxins, endowed with noxious activity with regard to digestive functions.

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Cannabinoid inhibition of guinea-pig intestinal peristalsis via inhibition of excitatory and activation of inhibitory neural pathways

Cited by 68 publications

References 27 publications

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

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

Pharmacological characterization of cannabinoid receptor activity in the rat‐isolated ileum myenteric plexus‐longitudinal muscle preparation

Assessment of Intestinal Peristalsis in Vitro

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