Sigma-1 receptor agonists and central sensitization mechanisms

Dae-Hyun Roh1, Alvin J. Beitz2, Jang-Hern Lee3. 1Kyung Hee University, Department of Maxillofacial Tissue Regeneration, School of Dentistry, 130-701, Republic of Korea, 2University of Minnesota, Department of Veterinary and Biomedical Sciences, College of Vet. Medicine, MN55108, USA, 3Seoul National University, Department of Veterinary Physiology, College of Vet. Medicine, 151-742, Republic of Korea

The sigma-1 receptor has recently been implicated in a myriad of cellular functions and biological processes. Our previous studies have demonstrated that the spinal sigma-1 receptor plays a pro-nociceptive role in acute pain and that direct activation of spinal sigma-1 receptors by intrathecal injection of agonists enhances the nociceptive response to peripheral stimuli. This pronociceptive effect involves calcium-dependent second messenger cascades including PKC. In addition, the activation of spinal sigma-1 receptors increases PKC-dependent phosphorylation of the NMDA receptor NR1 subunit (pNR1) in the spinal cord, which results in the potentiation of intrathecal NMDA-evoked spontaneous pain behaviors. Conversely, the blockade of spinal sigma-1 receptors suppresses the development of neuropathic pain induced by sciatic nerve chronic constriction injury (CCI) and reduces the CCI-induced increase of pNR1 expression in the spinal cord. Furthermore, we have previously reported that administration of the endogenous sigma-1 receptor ligands, pregnenolone and dehydroepiandrosterone sulfate (DHEAS), produce mechanical hypersensitivity via a sigma-1 receptor-mediated increase in pNR1. We have also elucidated several novel mechanisms that underlie spinal sigma-1 receptor-induced sensitization. First, we demonstrated that sigma-1 receptor-induced pain facilitation is mediated by an increase in nNOS activity, which is closely associated with an NO-induced increase in PKC-dependent, but not PKA-dependent, pNR1 expression. Secondly we have shown that ROS is involved in sigma-1 receptor-mediated pain and the increase in pNR1 in the spinal dorsal horn, which is mediated by NOX2 activation. In addition, we determined that the increase in nNOS activity results in activation of spinal NOX2, which ultimately can increase PKC-dependent pNR1. Taken together, these findings demonstrate that the activation of spinal sigma-1 receptors via an increase in the concentration of endogenous neurosteroids contributes to acute pain sensation and to the development of chronic neuropathic pain via NMDA receptor phosphorylation. Moreover the increase in NO-ROS signalling and their subsequent interactions are closely associated with sigma-1 receptor-mediated pain. Accordingly we propose that the development of drugs that target sigma-1 receptors and/or neurosteroids may serve as novel analgesic agents that could potentially reduce or alleviate both acute pain and persistent neuropathic pain.