The Endocannabinoid Anandamide Inhibits -VoltageGated Sodium Channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 in Xenopus Oocytes

BACKGROUND: Anandamide is an endocannabinoid that regulates multiple physiological functions by pharmacological actions, in a manner similar to marijuana. Recently, much attention has been paid to the analgesic effect of endocannabinoids in terms of identifying new pharmacotherapies for refractory pain management, but the mechanisms of the analgesic effects of anandamide are still obscure. Voltage-gated sodium channels are believed to play important roles in inflammatory and neuropathic pain. We investigated the effects of anandamide on 4 neuronal sodium channel subunits, Na(v)1.2, Na(v)1.6, Na(v)1.7, and Na(v)1.8, to explore the mechanisms underlying the antinociceptive effects of anandamide. METHODS: We studied the effects of anandamide on Na(v)1.2, Na(v)1.6, Na(v)1.7, and Na(v)1.8 subunits with (1) subunits by using whole-cell, 2-electrode, voltage-clamp techniques in Xenopus oocytes. RESULTS: Anandamide inhibited sodium currents of all subunits at a holding potential causing half-maximal current (V-1/2) in a concentration-dependent manner. The half-maximal inhibitory concentration values for Na(v)1.2, Na(v)1.6, Na(v)1.7, and Na(v)1.8 were 17, 12, 27, and 40 mol/L, respectively, indicating an inhibitory effect on Na(v)1.6, which showed the highest potency. Anandamide raised the depolarizing shift of the activation curve as well as the hyperpolarizing shift of the inactivation curve in all subunits, suggesting that sodium current inhibition was due to decreased activation and increased inactivation. Moreover, anandamide showed a use-dependent block in Na(v)1.2, Na(v)1.6, and Na(v)1.7 but not Na(v)1.8. CONCLUSION: Anandamide inhibited the function of subunits in neuronal sodium channels Na(v)1.2, Na(v)1.6, Na(v)1.7, and Na(v)1.8. These results help clarify the mechanisms of the analgesic effects of anandamide.