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

Abstract 

Sigma-1 receptor (σ₁R) 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 σ₁R in modulating nerve injury-evoked pain. For this purpose, wild-type mice and mice lacking the σ₁R 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 σ₁R knockout mice did not differ from wild-type mice. Baseline values obtained in σ₁R 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 σ₁R null mice exposed to partial sciatic nerve injury. Using isolated spinal cords we found that mice lacking σ₁R 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, σ₁R 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 σ₁R as a constituent of the mechanisms modulating activity-induced sensitization in pain pathways and point to σ₁R as a new potential target for drugs designed to alleviate neuropathic pain.

Keywords: Sigma-1 receptor, Neuropathic pain, Hyperalgesia, Allodynia, Spinal cord, ERK, Wind-up, Central sensitization