Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury

Sigma-1 receptor (sigma R-1) is expressed in key CNS areas involved in nociceptive processing but only limited information is available about its functional role. in the present study we investigated the relevance of sigma R-1 in modulating nerve injury-evoked pain. For this purpose, wild-type mice and mice lacking the sigma R-1 gene were exposed to partial sciatic nerve ligation and neuropathic pain-related behaviors were investigated. To explore underlying mechanisms, spinal processing of repetitive nociceptive stimulation and expression of extracellular signal-regulated kinase (ERK) were also investigated. Sensitivity to noxious heat of homozygous sigma R-1 knockout mice did not differ from wild-type mice. Baseline values obtained in sigma R-1 knockout mice before nerve injury in the plantar, cold-plate and von Frey tests were also indistinguishable from those obtained in wild-type mice. However, cold and mechanical allodynia did not develop in sigma R-1 null mice exposed to partial sciatic nerve injury. Using isolated spinal cords we found that mice lacking sigma R-1 showed reduced wind-up responses respect to wild-type mice, as evidenced by a reduced number of action potentials induced by trains of C-fiber intensity stimuli. In addition, in contrast to wild-type mice, sigma R-1 knockout mice did not show increased phosphorylation of ERK in the spinal cord after sciatic nerve injury. Both wind-up and ERK activation have been related to mechanisms of spinal cord sensitization. Our findings identify sigma R-1 as a constituent of the mechanisms modulating activity-induced sensitization in pain pathways and point to sigma R-1 as a new potential target for drugs designed to alleviate neuropathic pain. (C) 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.