Role of Nectin-1/c-Src Signaling in the Analgesic Effect of GDNF on a Rat Model of Chronic Constrictive Injury.

Neuropathic pain results from nerve injury and is one of the most refractory disorders. Recently, many studies reported that glial cell-derived neurotrophic factor (GDNF) exhibited potent analgesic effects, but the underlying mechanisms still remain unknown. In addition to the classical GDNF-GFRα1-Ret pathway, GDNF can bind to adhesion proteins such as E-cadherin and NCAM via GFRα1 in a Ret-independent way. In this study, we aimed to examine whether the adhesion protein nectin-1 and its downstream protein c-Src are involved in neuropathic pain. We found that nectin-1 was expressed in the superficial dorsal horn of the spinal cord and that it was increased after chronic constrictive injury (CCI). Intrathecal administration of nectin-1 siRNA attenuated neuropathic pain induced by CCI via interference of the expression of nectin-1. Furthermore, we found that GDNF can downregulate the phosphorylation level of nectin-1-associated c-Src without changing the expression level of nectin-1. In summary, these data suggest that nectin-1 is involved in neuropathic pain, and that GDNF exerts analgesic effects by directly or indirectly regulating nectin-1/c-Src signaling. These findings may lead to a new target for the treatment of neuropathic pain.