Chemotherapy induced peripheral neuropathy (CIPN) is a frequent, disabling side effect of anticancer drugs. Oxaliplatin, a platinum compound used in the treatment of advanced colorectal cancer, often leads to a form of CIPN characterized by mechanical and cold hypersensitivity. Current therapies for CIPN are ineffective, often leading to the cessation of treatment. Transient receptor potential ankyrin 1 (TRPA1) is a polymodal, non-selective cation-permeable channel expressed in nociceptors, activated by physical stimuli and cellular stress products. TRPA1 has been linked to the establishment of CIPN and other painful neuropathic conditions. Sigma-1 receptor is an endoplasmic reticulum chaperone known to modulate the function of many ion channels and receptors. S1RA, a highly selective antagonist of Sigma-1 receptor has shown effectiveness in a phase II clinical trial for oxaliplatin CIPN. However, the mechanisms involved in the beneficial effects of S1RA are little understood. We combined biochemical and biophysical (i.e. intermolecular FRET) techniques to demonstrate the interaction between Sigma-1 receptor and human TRPA1. Pharmacological antagonism of Sigma-1R impaired the formation of this molecular complex and the trafficking of functional TRPA1 to the plasma membrane. Using patch-clamp electrophysiological recordings we found that antagonists of Sigma-1 receptor, including S1RA, exert a marked inhibition on plasma membrane expression and function of human TRPA1 channels. In TRPA1-expressing mouse sensory neurons, S1RA reduced inward currents and the firing of actions potentials in response to TRPA1 agonists. Finally, in a mouse experimental model of oxaliplatin neuropathy, systemic treatment with a S1RA prevented the development of painful symptoms by a mechanism involving TRPA1. In summary, the modulation of TRPA1 channels by Sigma-1 receptor antagonists suggests a new strategy for the prevention and treatment of CIPN and could inform the development of novel therapeutics for neuropathic pain.

中文翻译：

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Sigma-1 受体对 TRPA1 的调节可预防奥沙利铂诱导的疼痛性周围神经病变

化疗引起的周围神经病变 (CIPN) 是抗癌药物常见的致残性副作用。奥沙利铂是一种用于治疗晚期结直肠癌的铂化合物，通常会导致一种以机械和冷超敏反应为特征的 CIPN。目前针对 CIPN 的治疗无效，常常导致治疗停止。瞬时受体电位锚蛋白 1 (TRPA1) 是一种多模式、非选择性阳离子可渗透通道，在伤害感受器中表达，由物理刺激和细胞应激产物激活。TRPA1 与 CIPN 和其他疼痛性神经病症的建立有关。Sigma-1 受体是一种内质网分子伴侣，已知可调节许多离子通道和受体的功能。S1RA, 一种高度选择性的 Sigma-1 受体拮抗剂在奥沙利铂 CIPN 的 II 期临床试验中显示出有效性。然而，S1RA 有益作用所涉及的机制知之甚少。我们结合生物化学和生物物理学（即分子间 FRET）技术来证明 Sigma-1 受体与人类 TRPA1 之间的相互作用。Sigma-1R 的药理学拮抗作用损害了这种分子复合物的形成以及功能性 TRPA1 向质膜的运输。使用膜片钳电生理记录，我们发现 Sigma-1 受体拮抗剂（包括 S1RA）对质膜表达和人 TRPA1 通道的功能具有显着抑制作用。在表达 TRPA1 的小鼠感觉神经元中，S1RA 减少内向电流和响应 TRPA1 激动剂的动作电位发射。最后，在奥沙利铂神经病变的小鼠实验模型中，S1RA 的全身治疗通过涉及 TRPA1 的机制阻止了疼痛症状的发展。总之，Sigma-1 受体拮抗剂对 TRPA1 通道的调节提出了一种预防和治疗 CIPN 的新策略，并可能为开发神经性疼痛的新疗法提供信息。