Anti-CNR1 monoclonal antibody, clone 2G0

There is clear evidence that CB2, historically referred to as the peripheral cannabinoid receptor, mediates many of the immune modulatory effects of cannabinoids. However, cannabinoid receptors cannot be classified simply as central or peripheral since CB2 has been shown to play a role in the central nervous system (CNS) and CB1 mediates many immune system effects. Although Cnr1 mRNA and CB1 protein expression is lower than Cnr2 mRNA or CB2 protein expression in cells of the immune system, several studies have shown direct modulation of immune function via CB1 by endogenous and exogenous cannabinoids in T cells, innate cells, and to a lesser extent, B cells. In addition, indirect, but CB1-dependent, mechanisms of immune modulation exist. In fact, the mechanism by which cannabinoids attenuate neuroinflammation via CB1 is likely a combination of immune suppression and neuroprotection. Although many studies demonstrate that agonists for CB1 are immune suppressive and anti-inflammatory, CB1 antagonists also exhibit anti-inflammatory properties. Overall, the data demonstrate that many of the immune modulatory effects of cannabinoids are mediated via CB1. (C) 2012 Elsevier Inc. All rights reserved.

BACKGROUND & AIMS: Cannabinoid receptors are located on cholinergic neurons. Genetic variants that affect endocannabinoid metabolism are associated with colonic transit in patients with irritable bowel syndrome (IBS) with diarrhea. We compared the effects of dronabinol, a nonselective agonist of the cannabinoid receptor, with those of placebo on colonic motility and sensation in patients with IBS, and examined the effects of IBS subtype and specific genetic variants in cannabinoid mechanisms. METHODS: Seventy-five individuals with IBS (35 with IBS with constipation, 35 with IBS with diarrhea, and with 5 IBS alternating) were randomly assigned to groups that were given 1 dose of placebo or 2.5 mg or 5.0 mg dronabinol. We assessed left colonic compliance, motility index (MI), tone, and sensation during fasting and after a meal. We analyzed the single nucleotide polymorphisms CNR1 rs806378, fatty acid amide hydrolase (FAAH) rs324420, and MGLL rs4881. RESULTS: In all patients, dronabinol decreased fasting proximal left colonic MI compared with placebo (overall P=.05; for 5 mg dronabinol, P=.046), decreased fasting distal left colonic MI (overall P=.08; for 5 mg, P=.13), and increased colonic compliance (P=.058). The effects of dronabinol were greatest in patients with IBS with diarrhea or IBS alternating (proximal colonic MI, overall P=.022; compliance, overall P=.03). Dronabinol did not alter sensation or tone. CNR1 rs806378 (CC vs CT/TT) appeared to affect fasting proximal MI in all patients with IBS (P=.075). Dronabinol affected fasting distal MI in patients, regardless of FAAH rs324420 variant (CA/AA vs CC) (P=.046); the greatest effects were observed among IBS with constipation patients with the FAAH CC variant (P=.045). Dronabinol affected fasting proximal MI in patients with IBS with diarrhea or alternating with the variant FAAH CA/AA (P=.013). CONCLUSIONS: In patients with IBS with diarrhea or alternating, dronabinol reduces fasting colonic motility; FAAH and CNR1 variants could influence the effects of this drug on colonic motility.