Pharmacological properties of S1RA, a new sigma‐1 receptor antagonist that inhibits neuropathic pain and activity‐induced spinal sensitization

<jats:p><jats:bold>BACKGROUND AND PURPOSE</jats:bold> The sigma‐1 (σ<jats:sub>1</jats:sub>) receptor is a ligand‐regulated molecular chaperone that has been involved in pain, but there is limited understanding of the actions associated with its pharmacological modulation. Indeed, the selectivity and pharmacological properties of σ<jats:sub>1</jats:sub> receptor ligands used as pharmacological tools are unclear and the demonstration that σ<jats:sub>1</jats:sub> receptor antagonists have efficacy in reversing central sensitization‐related pain sensitivity is still missing.</jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH</jats:bold> The pharmacological properties of a novel σ<jats:sub>1</jats:sub> receptor antagonist (S1RA) were first characterized. S1RA was then used to investigate the effect of pharmacological antagonism of σ<jats:sub>1</jats:sub> receptors on <jats:italic>in vivo</jats:italic> nociception in sensitizing conditions and on <jats:italic>in vitro</jats:italic> spinal cord sensitization in mice. Drug levels and autoradiographic, <jats:italic>ex vivo</jats:italic> binding for σ<jats:sub>1</jats:sub> receptor occupancy were measured to substantiate behavioural data.</jats:p><jats:p><jats:bold>KEY RESULTS</jats:bold> Formalin‐induced nociception (both phases), capsaicin‐induced mechanical hypersensitivity and sciatic nerve injury‐induced mechanical and thermal hypersensitivity were dose‐dependently inhibited by systemic administration of S1RA. Occupancy of σ<jats:sub>1</jats:sub> receptors in the CNS was significantly correlated with the antinociceptive effects. No pharmacodynamic tolerance to the antiallodynic and antihyperalgesic effect developed following repeated administration of S1RA to nerve‐injured mice. As a mechanistic correlate, electrophysiological recordings demonstrated that pharmacological antagonism of σ<jats:sub>1</jats:sub> receptors attenuated the wind‐up responses in spinal cords sensitized by repetitive nociceptive stimulation.</jats:p><jats:p><jats:bold>CONCLUSIONS AND IMPLICATIONS</jats:bold> These findings contribute to evidence identifying the σ<jats:sub>1</jats:sub> receptor as a modulator of activity‐induced spinal sensitization and pain hypersensitivity, and suggest σ<jats:sub>1</jats:sub> receptor antagonists as potential novel treatments for neuropathic pain.</jats:p>