Sigma-1 Receptor Antagonists: A New Class of Neuromodulatory Analgesics

The sigma-1 receptor is a unique ligand-operated chaperone present in key areas for pain control, in both the peripheral and central nervous system. Sigma-1 receptors interact with a variety of protein targets to modify their function. These targets include several G-protein-coupled receptors such as the μ-opioid receptor, and ion channels such as the N-methyl-D-aspartate receptor (NMDAR). Sigma-1 antagonists modify the chaperoning activity of sigma-1 receptor by increasing opioid signaling and decreasing NMDAR responses, consequently enhancing opioid antinociception and decreasing the sensory hypersensitivity that characterizes pathological pain conditions. However, the participation in pain relief of other protein partners of sigma-1 receptors in addition to opioid receptors and NMDARs cannot be ruled out. The enhanced opioid antinociception by sigma-1 antagonism is not accompanied by an increase in opioid side effects , including tolerance, dependence or constipation, so the use of sigma-1 antagonists may increase the therapeutic index of opioids. Furthermore, sigma-1 antagonists (in the absence of opioids) have been shown to exert antinociceptive effects in preclinical models of neuropathic pain induced by nerve trauma or chemical injury (the antineoplastic paclitaxel), and more recently in inflammatory and ischemic pain. Although most studies attributed the analgesic properties of sigma-1 antagonists to their central actions, it is now known that peripheral sigma-1 receptors also participate in their effects. Overwhelming preclinical evidence of the role of sigma-1 receptors in pain has led to the development of the first selective sigma-1 antagonist with an intended indication for pain treatment, which is currently in Phase II clinical trials.