• Dan Okura, Takafumi Horishita, Susumu Ueno, Nobuyuki Yanagihara, Yuka Sudo, Yasuhito Uezono, and Takeyoshi Sata.
• From the *Department of Anesthesiology, School of Medicine; †Department of Occupational Toxicology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, ‡Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Fukuoka; §Department of Molecular Pathology & Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo university of Science, Chiba; and ‖Cancer Pathophysiology Division, National Cancer Center Research Institute, Tokyo, Japan.
• Anesth. Analg.. 2014 Mar 1;118(3):554-62.

BackgroundAnandamide 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 α subunits, Nav1.2, Nav1.6, Nav1.7, and Nav1.8, to explore the mechanisms underlying the antinociceptive effects of anandamide.MethodsWe studied the effects of anandamide on Nav1.2, Nav1.6, Nav1.7, and Nav1.8 α subunits with β1 subunits by using whole-cell, 2-electrode, voltage-clamp techniques in Xenopus oocytes.ResultsAnandamide inhibited sodium currents of all subunits at a holding potential causing half-maximal current (V1/2) in a concentration-dependent manner. The half-maximal inhibitory concentration values for Nav1.2, Nav1.6, Nav1.7, and Nav1.8 were 17, 12, 27, and 40 μmol/L, respectively, indicating an inhibitory effect on Nav1.6, 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 α subunits, suggesting that sodium current inhibition was due to decreased activation and increased inactivation. Moreover, anandamide showed a use-dependent block in Nav1.2, Nav1.6, and Nav1.7 but not Nav1.8.ConclusionAnandamide inhibited the function of α subunits in neuronal sodium channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8. These results help clarify the mechanisms of the analgesic effects of anandamide.

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