• Kanako Miyano, Kouichiro Minami, Toru Yokoyama, Katsuya Ohbuchi, Takuhiro Yamaguchi, Satoshi Murakami, Seiji Shiraishi, Masahiro Yamamoto, Motohiro Matoba, and Yasuhito Uezono.
• From the *Division of Cancer Pathophysiology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan; †Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan; ‡Tsumura Research Labs, Tumura & Co., Inashiki-gun, Ibaraki, Japan; §Division of Biostatistics, Tohoku University Graduate School of Medicine, Clinical Research Data Center, Tohoku University Hospital, Sendai, Miyagi, Japan; ∥Department of Palliative Medicine, Seirei Sakura Citizen Hospital, Sakura-shi, Chiba, Japan; and ¶Department of Palliative Medicine, Aomori Prefectural Central Hospital, Aomori-city, Aomori, Japan.
• Anesth. Analg.. 2015 Apr 1;120(4):790-8.

BackgroundThe transient receptor potential vanilloid 1 (TRPV1) and the transient receptor potential ankyrin 1 (TRPA1), which are expressed in sensory neurons, are polymodal nonselective cation channels that sense noxious stimuli. Recent reports showed that these channels play important roles in inflammatory, neuropathic, or cancer pain, suggesting that they may serve as attractive analgesic pharmacological targets. Tramadol is an effective analgesic that is widely used in clinical practice. Reportedly, tramadol and its metabolite (M1) bind to μ-opioid receptors and/or inhibit reuptake of monoamines in the central nervous system, resulting in the activation of the descending inhibitory system. However, the fundamental mechanisms of tramadol in pain control remain unclear. TRPV1 and TRPA1 may be targets of tramadol; however, they have not been studied extensively.MethodsWe examined whether and how tramadol and M1 act on human embryonic kidney 293 (HEK293) cells expressing human TRPV1 (hTRPV1) or hTRPA1 by using a Ca imaging assay and whole-cell patch-clamp recording.ResultsTramadol and M1 (0.01-10 μM) alone did not increase in intracellular Ca concentration ([Ca]i) in HEK293 cells expressing hTRPV1 or hTRPA1 compared with capsaicin (a TRPV1 agonist) or the allyl isothiocyanate (AITC, a TRPA1 agonist), respectively. Furthermore, in HEK293 cells expressing hTRPV1, pretreatment with tramadol or M1 for 5 minutes did not change the increase in [Ca]i induced by capsaicin. Conversely, pretreatment with tramadol (0.1-10 μM) and M1 (1-10 μM) significantly suppressed the AITC-induced [Ca]i increases in HEK293 cells expressing hTRPA1. In addition, the patch-clamp study showed that pretreatment with tramadol and M1 (10 μM) decreased the inward currents induced by AITC.ConclusionsThese data indicate that tramadol and M1 selectively inhibit the function of hTRPA1, but not that of hTRPV1, and that hTRPA1 may play a role in the analgesic effects of these compounds.

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