The mechanism underlying the pain symptoms associated with chemotherapeutic-induced peripheral neuropathy (CIPN) is poorly understood. Transient receptor potential ankyrin 1 (TRPA1), TRP vanilloid 4 (TRPV4), TRPV1, and oxidative stress have been implicated in several rodent models of CIPN-evoked allodynia. Thalidomide causes a painful CIPN in patients via an unknown mechanism. Surprisingly, the pathway responsible for such proalgesic response has not yet been investigated in animal models. Here, we reveal that a single systemic administration of thalidomide and its derivatives, lenalidomide and pomalidomide, elicits prolonged (~ 35 days) mechanical and cold hypersensitivity in C57BL/6J mouse hind paw. Pharmacological antagonism or genetic deletion studies indicated that both TRPA1 and TRPV4, but not TRPV1, contribute to mechanical allodynia, whereas cold hypersensitivity was entirely due to TRPA1. Thalidomide per se did not stimulate recombinant and constitutive TRPA1 and TRPV4 channels in vitro, which, however, were activated by the oxidative stress byproduct, hydrogen peroxide. Systemic treatment with an antioxidant attenuated mechanical and cold hypersensitivity, and the increase in oxidative stress in hind paw, sciatic nerve, and lumbar spinal cord produced by thalidomide. Notably, central (intrathecal) or peripheral (intraplantar) treatments with channel antagonists or an antioxidant revealed that oxidative stress-dependent activation of peripheral TRPA1 mediates cold allodynia and part of mechanical allodynia. However, oxidative stress-induced activation of central TRPV4 mediated the residual TRPA1-resistant component of mechanical allodynia. Targeting of peripheral TRPA1 and central TRPV4 may be required to attenuate pain associated with CIPN elicited by thalidomide and related drugs.

中文翻译：

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氧化应激通过靶向外周TRPA1和中枢TRPV4介导沙利度胺引起的疼痛

与化疗引起的周围神经病（CIPN）相关的疼痛症状的潜在机制知之甚少。瞬态受体电位锚蛋白1（TRPA1），TRP香草酸4（TRPV4），TRPV1和氧化应激已被CIPN诱发的异常性疼痛的几种啮齿动物模型牵连。沙利度胺通过未知机制导致患者痛苦的CIPN。令人惊讶的是，尚未在动物模型中研究引起这种镇痛反应的途径。在这里，我们揭示了沙利度胺及其衍生物来那度胺和泊马利度胺的单一系统性给药在C57BL / 6J小鼠后爪中引起了延长的（〜35天）机械和冷超敏反应。药理拮抗作用或基因缺失研究表明，TRPA1和TRPV4均可引起机械性异常性疼痛，而TRPV1则不起作用。而冷超敏反应完全归因于TRPA1。沙利度胺本身并未在体外刺激重组和组成型TRPA1和TRPV4通道，但是这些通道被氧化应激副产物过氧化氢激活。用抗氧化剂进行的全身治疗减弱了机械和寒冷的超敏反应，并且沙利度胺产生的后爪，坐骨神经和腰脊髓的氧化应激增加。值得注意的是，用通道拮抗剂或抗氧化剂进行的中央（鞘内）或外周（足底内）治疗显示，外周TRPA1的氧化应激依赖性激活介导了冷异常性疼痛和机械性异常性疼痛的一部分。但是，氧化应激诱导的中央TRPV4的激活介导了机械性异常性疼痛的残留TRPA1抗性成分。