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

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

Immunohistochemical localization of the sigma1 receptor in Schwann cells of rat sciatic nerve.

The sigma-1 (sigma(1)) receptors can bind different psychotropic drugs and have been implicated in schizophrenia, depression and dementia. The cloning of the sigma(1)-receptor has allowed to obtain specific antibodies and, in a recent immunohistochemical study, we demonstrated that, in addition to neurons, the sigma(1)-receptor is located in oligodendrocytes [Brain Res. 961 (2003) 92.]. In the present study using in vivo and in vitro techniques, we demonstrate the localization of the sigma(1)-receptor in Schwann cells. Double immunofluorescence studies showed that sigma(1)-receptor co-localized with S100 protein, a specific marker of Schwann cells, in both rat sciatic nerve Schwann cells and Schwann cells in cultures. The sigma(1)-receptor immunoreactivity was seen in the cytoplasm and paranodal region formed by these cells, but not in myelin itself. The presence of sigma(1)-receptor in oligodendrocytes and Schwann cells is discussed on the basis on recent findings involving this receptor in lipid metabolism, compartmentalization and transport to the plasma membrane, thus suggesting a role for sigma(1)-receptor signaling in myelination.

Immunohistochemical localization of the sigma1-receptor in oligodendrocytes in the rat central nervous system.

By using a new polyclonal antibody raised against a 21-amino acid peptide sequence corresponding to the fragment 138-157 of the cloned rat sigma(1)-receptor, we demonstrated by immunoperoxidase and double immunofluorescence techniques, that rat oligodendrocytes express the sigma(1)-receptor. Experiments in vivo and in vitro showed that sigma(1)-receptor colocalized with specific markers of progenitor (A2B5) and mature oligodendrocytes (GalC, RIP). These results suggest that sigma(1)-receptor in oligodendrocytes might be involved in myelination by direct implication in cholesterol biosynthesis or by interaction with endogenous ligands such as neurosteroids.