Sigma-1 Receptor and Pain.

There is a critical need for new analgesics acting through new mechanisms of action, which could increase the efficacy respect to existing therapies and/or reduce their unwanted effects. Current preclinical evidence supports the modulatory role of the sigma-1 receptor (σR) in nociception, mainly based on the pain-attenuated phenotype of σR knockout mice and on the antinociceptive effect exerted by σR antagonists on pain of different etiology, very consistently in neuropathic pain, but also in nociceptive, inflammatory, and visceral pain. σR is highly expressed in different pain areas of the CNS and the periphery, particularly dorsal root ganglia (DRG), and interacts and modulates the functionality of different receptors and ion channels. Accordingly, antinociceptive effects of σR antagonists both acting alone and in combination with other analgesics have been reported at both central and peripheral sites. At the central level, behavioral, electrophysiological, neurochemical, and molecular findings support a role for σR antagonists in inhibiting augmented excitability secondary to sustained afferent input. Moreover, the involvement of σR in mechanisms regulating pain at the periphery has been recently confirmed. Unlike opioids, σR antagonists do not modify normal sensory mechanical and thermal sensitivity thresholds but they exert antihypersensitivity effects (antihyperalgesic and antiallodynic) in sensitizing conditions, enabling the reversal of nociceptive thresholds back to normal values. These are distinctive features allowing σR antagonists to exert a modulatory effect specifically in pathophysiological conditions such as chronic pain.