Local uncoordinated gene 5H2 contributes to nerve injury‐induced mechanical allodynia associated to its role in autophagy

Abstract

Lesions of the peripheral nerves can lead to lifelong neuropathic pain (NP). Autophagic deficiency in the Schwann cells (SCs) is an early event in the origin of NP chronification. Uncoordinated gene 5H2 (UNC5H2), one of the repulsive netrin receptors, mediated the effect of netrin‐1 on autophagic activation and cell survival in endothelial cells. However, itsrole on autophagy regulation in peripheral nervesduring NP process remains unidentified.Chronic constriction injury (CCI) of the left sciatic nerve was induced in Sprague‐Dawley rats, and UNC5H2 small interfering RNA was transfected to the ipsilateral sciatic nerve immediatelyafter injury. Mechanical allodynia was assessed. Sciatic UNC5H2 and netrin‐1 protein levels wereinvestigated. Autophagy in the ipsilateral sciatic nerves was evaluated by detecting punctate light chain 3(LC3) and autophagosomes, as well asthe levels of LC3 II, p62 and phosphorylated UNC51‐like kinase (ULK1). After CCI, UNC5H2 of the sciatic nerves was upregulated, exclusively expressed in SCs. Small interfering RNA transfectionresulted in significant decrease of UNC5H2 and netrin‐1 protein, leading to exaggeration of mechanical allodynia through 14 days after CCI. Autophagy was activated but autophagic influx was interfered within a weekafter CCI,shown by the elevatedlevels of both LC3II and p62, which was further deteriorated with UNC5H2 knockdown. In addition, the injury‐induced augmentation of phosphorylated ULK1 was significantly diminished by UNC5H2 knockdown. Altogether, the results suggest that local UNC5H2 of the peripheral nerve plays a significant role inthe process of injury‐induced mechanical allodynia, probably associated to its contribution to autophagic regulation.