Cannabinoid and nicotinic acetylcholine receptors are strongly associated with algesia.Previous studies in our laboratory have reported inhibitory effects of synthetic cannabinoid WIN55,212-2 on nicotine-activated currents(Inic),but the underlying mechanisms remain poorly understood.The present study used whole-cell patch clamp techniques to investigate the modulatory effects of synthetic cannabinoid WIN55,212-2 on Inic in cultured rat trigeminal ganglion neurons.The results revealed several major findings:WIN55,212-2 inhibited Inic in rat trigeminal ganglion neurons.In addition,when WIN55,212-2(3 μmol/L) was applied simultaneously with nicotine(100 μmol/L),the inhibition of WIN55,212-2 on Inic was reversible,concentration-dependent and voltage-independent.This effect was not mediated by CB1,CB2 or VR1 receptors;neither the selective CB1 receptor antagonist AM281,CB2 receptor antagonist AM630 nor VR1 receptor antagonist capsazepine reduced the inhibitory effect of WIN55,212-2.Further,the inhibition of nicotinic responses by WIN55,212-2 was not sensitive to the membrane permeable cyclic adenosine monophosphate(cAMP) analog 8-Br-cAMP.The G-protein inhibitor GDP-β-S(1 mmol/L) did not block the inhibitory effects of WIN55,212-2 on Inic,excluding the involvement of G-protein mediation.The results suggested that WIN55,212-2 inhibits Inic directly via the neuronal nicotinic acetylcholine receptor,and that this inhibition is non-competitive.WIN55,212-2 did not act as an open channel blocker of the neuronal nicotinic acetylcholine receptor,and did not affect the desensitization of Inic.The results suggest that nicotine receptors may be physically plugged from outside the membrane by drugs containing WIN55,212-2. Cannabinoid and nicotinic acetylcholine receptors are strongly associated with algesia. Previous studies in our laboratory have reported inhibitory effects of synthetic cannabinoid WIN55, 212-2 on nicotine-activated currents (Inic), but the underlying mechanisms remain poorly understood. The present study used whole -cell patch clamp techniques to investigate the modulatory effects of synthetic cannabinoid WIN55, 212-2 on Inic in cultured rat trigeminal ganglion neurons. The results reveals several major findings: WIN55, 212-2 inhibited Inic in rat trigeminal ganglion neurons. In addition, when WIN55, 212-2 (3 μmol / L) was applied simultaneously with nicotine (100 μmol / L), the inhibition of WIN55, 212-2 on Inic was reversible, concentration-dependent and voltage- independent. This effect was not mediated by CB1, CB2 or VR1 receptors; neither the selective CB1 receptor antagonist AM281, CB2 receptor antagonist AM630 nor VR1 receptor antagonist capsazepine reduced the inhibitory effect of WIN55, 212-2. , the inhibition of nicotinic responses by WIN55,212-2 was not sensitive to the membrane permeable cyclic adenosine monophosphate (cAMP) analog 8-Br-cAMP. The G-protein inhibitor GDP-β-S (1 mmol / L) did not block the inhibitory effects of WIN55, 212-2 on Inic, excluding the involvement of G-protein mediation. The results suggested that WIN55, 212-2 inhibits Inicially via the neuronal nicotinic acetylcholine receptor, and that this inhibition is non-competitive. WIN55, 212-2 did not act as an open channel blocker of the neuronal nicotinic acetylcholine receptor, and did not affect the desensitization of Inic. The results suggest that nicotine receptors may be physically plugged from outside the membrane by drugs containing WIN 55, 212- 2.