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Novel pharmacology of the inhibitory effects of JWH015 in the mouse gastrointestinal tract

The effects of cannabinoid (CB) receptor activation and the role of endocannabinoids in the gastrointestinal (GI) tract are fairly extensive. However, our understanding of the receptor pharmacology of CBs is still quite rudimentary. JWH015 has been considered as an agonist of a newly identified CB –like receptor, GPR55, and also as a CB2 agonist. The role of CB2 and GPR55 receptors in GI motility are not known. In this study we examined the effect of JWH015 on the neurogenic contractions in the ileum strips from wild type, CB1−/ minus;, CB2−/− and GPR55−/− knockout mice. JWH015 (10 nM – 10μM) inhibited field‐stimulation evoked cholinergic contractions in longitudinal muscle preparations from ileum and colon (pD2: 7±0.1; Emax: 95±2%). Gene deletion of CB1 or CB2 receptors did not significantly shift the dose –response curves suggesting no role of these receptors in the JWH015 effects. In the GPR55−/− mice, there were no significant differences in the JWH015 effects at lower concentrations, however, the Emax was significantly (P<0.05) decreased (46 ± 10% vs 73±5%). Western blots demonstrated the expression of GPR55 in the mouse ileum. The lack of effect of GPR55−/− on the JWH015 effects at lower concentrations suggest that GPR55 is not the main receptor that mediates JWH015 effects in the gut. These studies suggest that JWH015 acts on a non‐CB1, non‐CB2, non‐GPR55 receptor in the mouse ileum and colon. Supported by DA0240009