Silos-Santiago Inmaculada
Vertex Pharmaceuticals Inc, San Diego, CA 92121, USA.
Curr Opin Investig Drugs. 2008 Jan;9(1):83-9.
Neuropathic pain, a persistent chronic pain resulting from damage to the central or peripheral nervous system, is a condition that severely affects the quality-of-life of millions of individuals worldwide. The treatment of neuropathic pain is still an unmet medical need; however, recent advances in our understanding of mechanisms underlying the perception and transmission of painful stimuli offer significant potential for improvement of therapies directed to neuropathic pain. Ectopic activity in damaged and dysfunctional sensory afferents is believed to have a role in the generation and maintenance of neuropathic pain. One of the mechanisms underlying this ectopic firing involves abnormal modulation of voltage-gated sodium channels (NaVs) in the soma and axonal membranes of dorsal root ganglion (DRG) sensory neurons. In fact, NaV blockers have been clinically validated as treatments for neuropathic pain. However, current drugs are weak, non-selective inhibitors of NaVs with dose-limiting CNS and cardiovascular side effects that prevent their use in long-term therapy. Selective NaV tetrodotoxin-resistant channels (NaV 1.8 and NaV 1.9) are expressed exclusively in nociceptive neurons in the DRGs where they play a key role in normal and/or pathological pain sensation, providing an opportunity for the development of novel peripheral analgesics with a better safety profile.
神经性疼痛是一种由中枢或外周神经系统损伤引起的持续性慢性疼痛，严重影响着全球数百万人的生活质量。神经性疼痛的治疗仍是一项未被满足的医疗需求；然而，我们对疼痛刺激感知和传递机制理解的最新进展为改善针对神经性疼痛的治疗提供了巨大潜力。受损和功能失调的感觉传入神经的异位活动被认为在神经性疼痛的产生和维持中起作用。这种异位放电的潜在机制之一涉及背根神经节（DRG）感觉神经元的胞体和轴突膜中电压门控钠通道（NaVs）的异常调节。事实上，NaV阻滞剂已在临床上被证实可用于治疗神经性疼痛。然而，目前的药物是较弱的、非选择性的NaV抑制剂，具有剂量限制性的中枢神经系统和心血管副作用，这使得它们无法用于长期治疗。选择性抗河豚毒素的钠通道（NaV 1.8和NaV 1.9）仅在DRG的伤害性神经元中表达，它们在正常和/或病理性疼痛感觉中起关键作用，这为开发具有更好安全性的新型外周镇痛药提供了机会。
