Alsaloum Matthew, Higerd Grant P, Effraim Philip R, Waxman Stephen G
Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.
Center for Neuroscience & Regeneration Research, Yale University, West Haven, CT, USA.
Nat Rev Neurol. 2020 Dec;16(12):689-705. doi: 10.1038/s41582-020-00415-2. Epub 2020 Oct 27.
The effective and safe treatment of pain is an unmet health-care need. Current medications used for pain management are often only partially effective, carry dose-limiting adverse effects and are potentially addictive, highlighting the need for improved therapeutic agents. Most common pain conditions originate in the periphery, where dorsal root ganglion and trigeminal ganglion neurons feed pain information into the CNS. Voltage-gated sodium (Na) channels drive neuronal excitability and three subtypes - Na1.7, Na1.8 and Na1.9 - are preferentially expressed in the peripheral nervous system, suggesting that their inhibition might treat pain while avoiding central and cardiac adverse effects. Genetic and functional studies of human pain disorders have identified Na1.7, Na1.8 and Na1.9 as mediators of pain and validated them as targets for pain treatment. Consequently, multiple Na1.7-specific and Na1.8-specific blockers have undergone clinical trials, with others in preclinical development, and the targeting of Na1.9, although hampered by technical constraints, might also be moving ahead. In this Review, we summarize the clinical and preclinical literature describing compounds that target peripheral Na channels and discuss the challenges and future prospects for the field. Although the potential of peripheral Na channel inhibition for the treatment of pain has yet to be realized, this remains a promising strategy to achieve non-addictive analgesia for multiple pain conditions.
有效且安全地治疗疼痛是一项尚未满足的医疗需求。目前用于疼痛管理的药物往往仅部分有效，具有剂量限制性不良反应且有潜在成瘾性，这凸显了对改进治疗药物的需求。大多数常见疼痛病症起源于外周，背根神经节和三叉神经节神经元在此将疼痛信息传入中枢神经系统。电压门控钠（Na）通道驱动神经元兴奋性，其中三种亚型——Na1.7、Na1.8和Na1.9——在外周神经系统中优先表达，这表明抑制它们可能在避免中枢和心脏不良反应的同时治疗疼痛。对人类疼痛病症的遗传学和功能研究已确定Na1.7、Na1.8和Na1.9为疼痛介质，并将它们验证为疼痛治疗靶点。因此，多种Na1.7特异性和Na1.8特异性阻滞剂已进入临床试验阶段，其他一些则处于临床前开发阶段，尽管受到技术限制，但针对Na1.9的研究也可能在推进。在本综述中，我们总结了描述靶向外周钠通道化合物的临床和临床前文献，并讨论了该领域的挑战和未来前景。尽管外周钠通道抑制用于治疗疼痛的潜力尚未实现，但这仍然是一种有前景的策略，可为多种疼痛病症实现非成瘾性镇痛。
