Wang Jing, Liu Yani, Hu Fang, Yang Jiuyong, Guo Xiaoyu, Hou Xingming, Ju Chuanxia, Wang KeWei
Department of Pharmacology, School of Pharmacy at Qingdao University Medical College, Qingdao, China (J.W., Y.L., F.H., J.Y., X.G., X.H., C.J., K.W.); Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, China (Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.)
Department of Pharmacology, School of Pharmacy at Qingdao University Medical College, Qingdao, China (J.W., Y.L., F.H., J.Y., X.G., X.H., C.J., K.W.); Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, China (Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.).
J Pharmacol Exp Ther. 2021 Apr;377(1):20-28. doi: 10.1124/jpet.120.000357. Epub 2021 Jan 11.
Treatment of chronic pain remains an unmet medical need. The neuronal voltage-gated potassium Kv7/KCNQ/M channel has been implicated as a therapeutic target for chronic pain. However, whether pharmacological activation of the Kv7 channel can alleviate pain remains elusive. In this study, we show that selective activation of native M-currents by a novel channel opener SCR2682 reduces repetitive firings of dorsal root ganglia (DRG) sensory neurons. Intraperitoneal administration of SCR2682 relieves mechanical allodynia and thermal hyperalgesia in rat models of pain induced by complete Freund's adjuvant (CFA) or spared nerve injury (SNI) in a dose-dependent manner without affecting locomotor activity. The antinociceptive efficacy of SCR2682 can be reversed by the channel-specific blocker XE991. Furthermore, SCR2682 increases Kv7.2/KCNQ2 mRNA and protein expression in DRG neurons from rats in the SNI model of neuropathic pain. Taken together, pharmacological activation of neuronal Kv7 channels by opener SCR2682 can alleviate pain in rats, thus possessing therapeutic potential for chronic pain or hyperexcitability-related neurologic disorders. SIGNIFICANCE STATEMENT: A novel voltage-gated potassium Kv7 channel opener SCR2682 inhibits action potential firings in dorsal root ganglia sensory neurons and exhibits efficacy in antinociception, thus possessing a developmental potential for treatment of chronic pain or epilepsy.
慢性疼痛的治疗仍然是一项未被满足的医疗需求。神经元电压门控钾通道Kv7/KCNQ/M被认为是慢性疼痛的治疗靶点。然而，Kv7通道的药理学激活是否能减轻疼痛仍不清楚。在本研究中，我们发现新型通道开放剂SCR2682对天然M电流的选择性激活可减少背根神经节（DRG）感觉神经元的重复放电。腹腔注射SCR2682可剂量依赖性地减轻完全弗氏佐剂（CFA）或保留神经损伤（SNI）诱导的大鼠疼痛模型中的机械性异常性疼痛和热痛觉过敏，且不影响运动活性。通道特异性阻滞剂XE991可逆转SCR2682的镇痛效果。此外，SCR2682可增加神经病理性疼痛SNI模型大鼠DRG神经元中Kv7.2/KCNQ2的mRNA和蛋白表达。综上所述，开放剂SCR2682对神经元Kv7通道的药理学激活可减轻大鼠疼痛，因此对慢性疼痛或与过度兴奋相关的神经疾病具有治疗潜力。意义声明：新型电压门控钾通道Kv7开放剂SCR2682抑制背根神经节感觉神经元的动作电位发放，并具有镇痛效果，因此具有治疗慢性疼痛或癫痫的开发潜力。
