Cannabinoids inhibit intestinal motility via presynaptic cannabinoid receptor type I(CB1) in enteric neurons while cannabinoid receptor type II (CB2) receptors are located mainly in immune cells. The recently deorphanized G-protein-coupled receptor, GPR55, has been proposed to be the “third” cannabinoid receptor. Although gene expression of GPR55 is evident in the gut, functional evidence for GPR55 in the gut is unknown. In this study, we tested the hypothesis that GPR55 activation inhibits neurogenic contractions in the gut.
We assessed the inhibitory effect of the atypical cannabinoid O-1602, a GPR55 agonist, in mouse colon. Isometric tension recordings in colonic tissue strips were used from either wild type, GPR55−/− or CB1−/−/CB2−/−knock-out mice.
O-1602 inhibited the electrical field-induced contractions in the colon strips from wild type and CB1−/−/CB2−/− in a concentration–dependent manner, suggesting a non-CB1/CB2-receptor mediated prejunctional effect. The concentration–dependent response of O-1602 was significantly inhibited in GPR55−/− mice. O-1602 did not relax colonic strips pre-contracted with high K+ (80 mmol/l), indicating no involvement of Ca2+channel blockade in O-1602–induced relaxation. However, 10 μmol/l O-1602 partially inhibited the exogenous acetylcholine (10 μmol/l) –induced contractions. Moreover, we also assessed the inhibitory effects of JWH 015, a CB2/GPR55 agonist on neurogenic contractions of mouse ileum. Surprisingly, the effects of JWH015 were independent of the known cannabinoid receptors.
These findings taken together suggest that activation of GPR55 leads to inhibition of neurogenic contractions in the gut, and are predominantly prejunctional.
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