Department of Molecular Neuroscience, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan.
PLoS One. 2021 Apr 29;16(4):e0251013. doi: 10.1371/journal.pone.0251013. eCollection 2021.
Neuropathic pain refers to pain caused by lesions or diseases of the somatosensory nervous system that is characteristically different from nociceptive pain. Moreover, neuropathic pain occurs in the maxillofacial region due to various factors and is treated using tricyclic antidepressants and nerve block therapy; however, some cases do not fully recover. Netrin is a secreted protein crucially involved in neural circuit formation during development, including cell migration, cell death, neurite formation, and synapse formation. Recent studies show Netrin-4 expressed in the dorsal horn of the spinal cord is associated with chronic pain. Here we found involvement of Netrin-4 in neuropathic pain in the maxillofacial region. Netrin-4, along with one of its receptors, Unc5B, are expressed in the caudal subnucleus of the trigeminal spinal tract nucleus. Inhibition of its binding by anti-Netrin-4 antibodies not only shows a behavioral analgesic effect but also neuronal activity suppression. There was increased Netrin-4 expression at 14 days after infraorbital nerve injury. Our findings suggest that Netrin-4 induced by peripheral nerve injury causes neuropathic pain via Unc5B.
神经病理性疼痛是指由躯体感觉神经系统的损伤或疾病引起的疼痛，其特征与伤害性疼痛不同。此外，由于各种因素，面部区域会出现神经病理性疼痛，并采用三环类抗抑郁药和神经阻滞疗法进行治疗；然而，有些病例并未完全康复。Netrin 是一种在发育过程中对神经回路形成至关重要的分泌蛋白，包括细胞迁移、细胞死亡、神经突形成和突触形成。最近的研究表明，脊髓背角表达的 Netrin-4 与慢性疼痛有关。在这里，我们发现 Netrin-4 参与了面部区域的神经病理性疼痛。Netrin-4 及其受体之一 Unc5B 在三叉神经脊束核的尾亚核中表达。用抗 Netrin-4 抗体抑制其结合不仅表现出行为镇痛作用，还能抑制神经元活动。眶下神经损伤后 14 天，Netrin-4 的表达增加。我们的研究结果表明，外周神经损伤诱导的 Netrin-4 通过 Unc5B 引起神经病理性疼痛。
