Tobori Shota, Tamada Kosei, Uemura Nagi, Sawada Kyoko, Kakae Masashi, Nagayasu Kazuki, Nakagawa Takayuki, Mori Yasuo, Kaneko Shuji, Shirakawa Hisashi
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Department of Clinical Pharmacology and Pharmacotherapy, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama 640-8156, Japan.
Proc Natl Acad Sci U S A. 2025 Mar 18;122(11):e2416828122. doi: 10.1073/pnas.2416828122. Epub 2025 Mar 13.
Neuropathic pain is a debilitating chronic condition mainly caused by peripheral nerve injury. However, the cellular and molecular mechanisms underlying this condition remain unclear. Transient receptor potential canonical 3 (TRPC3), a TRP channel that is activated by downstream of the Gq-phospholipase C (PLC) axis, is expressed in the somatosensory system. Therefore, the present study investigated its pathophysiological role in neuropathic pain following peripheral nerve injury. Here, partial sciatic nerve ligation (pSNL) elicited mechanical and thermal hypersensitivity in wild-type mice, which was suppressed in TRPC3-KO mice. In situ hybridization revealed that TRPC3 is predominantly expressed in neurons in the spinal dorsal horn. Furthermore, spinal dorsal horn neuron-specific downregulation using miRNA attenuated pSNL-induced mechanical hypersensitivity. Spinal TRPC3 activation elicited acute mechanical hypersensitivity. Moreover, its genetic ablation reduced the mechanical hypersensitivity caused by spinal NKR or PLC activation. These findings demonstrate that TRPC3 in spinal dorsal horn neurons facilitates the development of neuropathic pain. Therefore, TRPC3 may be a promising therapeutic target for neuropathic pain caused by peripheral nerve injury.
神经性疼痛是一种主要由外周神经损伤引起的使人衰弱的慢性疾病。然而，这种疾病背后的细胞和分子机制仍不清楚。瞬时受体电位香草酸亚型3（TRPC3）是一种由Gq-磷脂酶C（PLC）轴下游激活的TRP通道，在体感系统中表达。因此，本研究调查了其在周围神经损伤后神经性疼痛中的病理生理作用。在此，部分坐骨神经结扎（pSNL）在野生型小鼠中引发机械性和热超敏反应，而在TRPC3基因敲除小鼠中这种反应受到抑制。原位杂交显示，TRPC3主要在脊髓背角的神经元中表达。此外，使用微小RNA对脊髓背角神经元进行特异性下调可减轻pSNL诱导的机械性超敏反应。脊髓TRPC3激活引发急性机械性超敏反应。此外，其基因缺失减少了由脊髓神经激肽受体（NKR）或PLC激活引起的机械性超敏反应。这些发现表明，脊髓背角神经元中的TRPC3促进了神经性疼痛的发展。因此，TRPC3可能是治疗由外周神经损伤引起的神经性疼痛的一个有前景的治疗靶点。
