Cannabinoid WIN 55,212-2 inhibits TRPV1 in trigeminal ganglion neurons via PKA and PKC pathways

Although the inhibitory effect of cannabinoids on transient receptor potential vanilloid 1 (TRPV1) channel may explain the efficacy of peripheral cannabinoids in antihyperalgesia and antinociceptive actions, the mechanism for cannabinoid-induced inhibition of TRPV1 in primary sensory neurons is not understood. Therefore, we explored how WIN55,212-2 (WIN, a synthetic cannabinoid) inhibited TRPV1 in rat trigeminal ganglion neurons. A “bell”-shaped concentration-dependent curve was obtained from the effects of WIN on TRPV1 channel. The maximal inhibition on capsaicin-induced current ( I cap ) by WIN was at a concentration of 10 −9 M, and at this concentration I cap was reduced by 95 ± 1.6%. When the concentration of WIN was at 10 −6 M, it displayed a stimulatory effect on I cap . In this study, several intracellular signaling transduction pathways were tested to study whether they were involved in the inhibitory effects of WIN on I cap . We found that the inhibitory effect of WIN on I cap was completely reversed by PKA antagonists H-89 and KT5720 as well as by PKC antagonists BIM and staurosporine. It was also found that the inhibitory effect was partly reversed by PKG antagonist PKGi, while G-protein antagonist GDP-βs/pertussis toxin (PTX) and PLC antagonist U-73122 had no effect on the inhibitory effect of WIN on I cap . These results suggest that several intracellular signaling transduction pathways including PKA and PKC systems underlie the inhibitory effects of WIN on I cap ; however, G protein-coupled receptors CB1 or CB2 were not involved.