Amir Ron, Argoff Charles E, Bennett Gary J, Cummins Theodore R, Durieux Marcel E, Gerner Peter, Gold Michael S, Porreca Frank, Strichartz Gary R
Department of Cell and Animal Biology, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
J Pain. 2006 May;7(5 Suppl 3):S1-29. doi: 10.1016/j.jpain.2006.01.444.
Clinical and experimental data indicate that changes in the expression of voltage-gated sodium channels play a key role in the pathogenesis of neuropathic pain and that drugs that block these channels are potentially therapeutic. Clinical and experimental data also suggest that changes in voltage-gated sodium channels may play a role in inflammatory pain, and here too sodium-channel blockers may have therapeutic potential. The sodium-channel blockers of interest include local anesthetics, used at doses far below those that block nerve impulse propagation, and tricyclic antidepressants, whose analgesic effects may at least partly be due to blockade of sodium channels. Recent data show that local anesthetics may have pain-relieving actions via targets other than sodium channels, including neuronal G protein-coupled receptors and binding sites on immune cells. Some of these actions occur with nanomolar drug concentrations, and some are detected only with relatively long-term drug exposure. There are 9 isoforms of the voltage-gated sodium channel alpha-subunit, and several of the isoforms that are implicated in neuropathic and inflammatory pain states are expressed by somatosensory primary afferent neurons but not by skeletal or cardiovascular muscle. This restricted expression raises the possibility that isoform-specific drugs might be analgesic and lacking the cardiotoxicity and neurotoxicity that limit the use of current sodium-channel blockers.
Changes in the expression of neuronal voltage-gated sodium channels may play a key role in the pathogenesis of both chronic neuropathic and chronic inflammatory pain conditions. Drugs that block these channels may have therapeutic efficacy with doses that are far below those that impair nerve impulse propagation or cardiovascular function.
临床和实验数据表明，电压门控钠通道表达的变化在神经性疼痛的发病机制中起关键作用，且阻断这些通道的药物具有潜在治疗作用。临床和实验数据还表明，电压门控钠通道的变化可能在炎性疼痛中起作用，钠通道阻滞剂在此也可能具有治疗潜力。所关注的钠通道阻滞剂包括局部麻醉药，其使用剂量远低于阻断神经冲动传导的剂量，以及三环类抗抑郁药，其镇痛作用可能至少部分归因于对钠通道的阻断。最近的数据表明，局部麻醉药可能通过钠通道以外的靶点发挥止痛作用，包括神经元G蛋白偶联受体和免疫细胞上的结合位点。其中一些作用在纳摩尔药物浓度下就会出现，有些则仅在相对长期的药物暴露后才能检测到。电压门控钠通道α亚基有9种亚型，与神经性和炎性疼痛状态相关的几种亚型由躯体感觉初级传入神经元表达，而骨骼肌或心血管肌肉则不表达。这种有限的表达增加了一种可能性，即亚型特异性药物可能具有镇痛作用，且缺乏限制当前钠通道阻滞剂使用的心脏毒性和神经毒性。
神经元电压门控钠通道表达的变化可能在慢性神经性疼痛和慢性炎性疼痛病症的发病机制中起关键作用。阻断这些通道的药物可能在远低于损害神经冲动传导或心血管功能剂量的情况下具有治疗效果。
