Shin Seung Min, Wang Fei, Qiu Chensheng, Itson-Zoske Brandon, Hogan Quinn H, Yu Hongwei
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Zablocki Veterans Affairs Medical Center, Milwaukee, WI, 53295, USA.
Gene Ther. 2022 Feb;29(1-2):1-15. doi: 10.1038/s41434-020-0157-5. Epub 2020 May 18.
The Sigma-1 receptor (σR) is highly expressed in the primary sensory neurons (PSNs) that are the critical site of initiation and maintenance of pain following peripheral nerve injury. By immunoblot and immunohistochemistry, we observed increased expression of both σR and σR-binding immunoglobulin protein (BiP) in the lumbar (L) dorsal root ganglia (DRG) ipsilateral to painful neuropathy induced by spared nerve injury (SNI). To evaluate the therapeutic potential of PSN-targeted σR inhibition at a selected segmental level, we designed a recombinant adeno-associated viral (AAV) vector expressing a small hairpin RNA (shRNA) against rat σR. Injection of this vector into the L4/L5 DRGs induced downregulation of σR in DRG neurons of all size groups, while expression of BiP was not affected. This was accompanied by attenuation of SNI-induced cutaneous mechanical and thermal hypersensitivity. Whole-cell current-clamp recordings of dissociated neurons showed that knockdown of σR suppressed neuronal excitability, suggesting that σR silencing attenuates pain by reversal of injury-induced neuronal hyperexcitability. These findings support a critical role of σR in modulating PSN nociceptive functions, and that the nerve injury-induced elevated σR activity in the PSNs can be a significant driver of neuropathic pain. Further understanding the role of PSN-σR in pain pathology may open routes to exploit this system for DRG-targeted pain therapy.
西格玛-1受体（σR）在初级感觉神经元（PSN）中高度表达，而初级感觉神经元是周围神经损伤后疼痛起始和维持的关键部位。通过免疫印迹和免疫组织化学方法，我们观察到在 spared 神经损伤（SNI）诱导的疼痛性神经病变同侧的腰（L）背根神经节（DRG）中，σR 和与 σR 结合的免疫球蛋白重链结合蛋白（BiP）的表达均增加。为了评估在选定节段水平上对 PSN 靶向的 σR 抑制的治疗潜力，我们设计了一种重组腺相关病毒（AAV）载体，该载体表达针对大鼠 σR 的小发夹 RNA（shRNA）。将该载体注射到 L4/L5 DRG 中可诱导所有大小组的 DRG 神经元中 σR 的下调，而 BiP 的表达不受影响。这伴随着 SNI 诱导的皮肤机械性和热超敏反应的减轻。对解离神经元的全细胞膜片钳记录表明，σR 的敲低抑制了神经元的兴奋性，这表明 σR 的沉默通过逆转损伤诱导的神经元过度兴奋性来减轻疼痛。这些发现支持了 σR 在调节 PSN 伤害感受功能中的关键作用，并且神经损伤诱导的 PSN 中 σR 活性升高可能是神经性疼痛的重要驱动因素。进一步了解 PSN-σR 在疼痛病理中的作用可能会为利用该系统进行 DRG 靶向疼痛治疗开辟途径。
