Involvement of cannabinoid receptors in gut motility and visceral perception

Abstract

From a historical perspective to the present day, all the evidence suggests that activation of cannabinoid receptors (CBRs) is beneficial for gut discomfort and pain, which are symptoms related to dysmotility and visceral perception. CBRs comprise G-protein coupled receptors that are predominantly in enteric and central neurones (CB1R) and immune cells (CB2R). In the last decade, evidence obtained from the use of selective agonists and inverse agonists/antagonists indicates that manipulation of CB1R can alter (1) sensory processing from the gut, (2) brain integration of brain-gut axis, (3) extrinsic control of the gut and (4) intrinsic control by the enteric nervous system. The extent to which activation of CB1R is most critical at these different levels is related to the region of the GI tract. The upper GI tract is strongly influenced by CB1R activation on central vagal pathways, whereas intestinal peristalsis can be modified by CB1R activation in the absence of extrinsic input. Actions at multiple levels make the CB1R a target for the treatment of functional bowel disorders, such as IBS. Since low-grade inflammation may act as a trigger for occurrence of IBS, CB2R modulation could be beneficial, but there is little supporting evidence for this yet. The challenge is to accomplish CBR activation while minimizing adverse effects and abuse liabilities. Potential therapeutic strategies involve increasing signaling by endocannabinoids (EC). The pathways involved in the biosynthesis, uptake and degradation of EC provide opportunities for modulation of CB1R and some recent evidence with inhibitors of EC uptake and metabolism suggest that these could be exploited for therapeutic gain.

Figure 1

Photomicrograph of CB1R-immunostaining in the ferret hindbrain dorsal vagal complex. Intense staining in cell bodies is noted in the area postrema (AP) and within the medial nucleus tractus solatarius (mNTS). Punctate terminal field like staining is intense in the dorsal motor nucleus of the vagus, but not within vagal motor neurones. Abbreviations: TS, tractus solitarius; V, fourth ventricle XII hypoglossal nucleus. Bar=100 μm. Reproduced with permission from Partosoedarso et al. (2003b).

Figure 2

Schema that summarizes the main site(s) of action of cannabinoids on CB1R (open arrowhead) and immunocytochemical localization of CBR1 (stipple). Arrows indicate motility effects, except H⁺ refers to gastric acid secretion and I_sc intestinal ion transport. For the upper GI tract, some evidence suggests that CBR activation could inhibit vagal afferents centrally, excitatory (Glu) and inhibitory (GABA) interneurones in the nucleus tractus solitarius and cholinergic (Ach) motor output peripherally at the cholinergic postganglionic/enteric neurons level to reduce gastric motility, acid secretion, increase volume, delay gastric emptying, and to reduce lower oesophageal sphincter relaxation. In the submucosal plexus of the small intestine, CB1R is expressed in ACh and vasoactive intestinal peptide (VIP) neurones but functionally inhibits I_sc through extrinsic primary afferents, some of which which contain the vanilloid receptor (TRPV), and act via excitatory ACh neurons. Within the myenteric plexus, CB1R inhibits contractile activity and peristalsis of the intestines via inhibition of excitatory ACh. It does not appear to act on inhibitory nitric oxide (NO) containing neurons in the myenteric plexus of the large intesting but inhibits NANC small intestinal relaxation. CB1R distribution and effects in different species may vary. See text for further details.

Figure 3

Activity-dependent depolarization of a presynaptic neurone causes neurotransmitter release, which after binding to its receptor on the postsynaptic neurone, causes calcium influx. Increased calcium activates N-acyltransferase (NAT), which results in production of N-arachidonoyl phosphatidylethanolamine. Phospholipase D (PLD) liberates anandamide (AEA) from N-arachidonoyl phosphatidylethanolamine, which then could associate with a lipid binding protein (LBP), and be transported to the anandamide membrane transporter (illustrated as a pore in the plasma membrane of the postsynaptic neurone). AEA can then bind to CB1 receptors (CB1R) on the presynaptic neurone, resulting in decreased intracellular calcium and presynaptic inhibition. AEA signaling could be inactivated by reuptake through the anandamide membrane transporter, where it could bind a LBP and be transported to microsomal membranes (illustrated as parallel lines) for degradation by fatty acid amide hydrolase (FAAH) or esterification into phospholipids (PL) and/or acyglycerols (AG).