Selective sigma-1 receptor antagonists: an emerging strategy for the treatment of neuropathic pain

J.M. Vela. Esteve, Drug Discovery and Preclinical Development. 08041 Barcelona, Spain

The sigma-1 receptor (σ1R) is a molecular chaperone that modulates the activity of several receptors and ion channels and whose activity is regulated by ligands in an agonist-antagonist manner. Recent findings identify σ1R as a constituent of the mechanisms modulating activity-induced sensitization in pain pathways and point to σ1R as a new target for neuropathic pain. Knockout mice for the σ1R showed attenuated pain responses in the formalin test and mechanical hypersensitivity did not develop following capsaicin sensitization or nerve injury. In addition, mice lacking σ1R 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. Pharmacologically, activation of σ1R has been found to promote whereas antagonists inhibit pain-related behaviours in sensitizing conditions including neuropathic pain in rodents. S1RA, a high affinity and selective σ1R antagonist, has been found to reduce pain behaviours when administered systemically to wild-type mice exposed to chemical sensitization of pain pathways (intraplantar formalin and capsaicin injection) or suffering from neuropathic pain induced by partial sciatic nerve ligation. No tolerance to the antiallodynic and antihyperalgesic effects was noticed following repeated S1RA administration to nerve-injured mice. In addition, ex vivo binding experiments demonstrated a significant correlation between the extent of CNS σ1R occupancy and the antinociceptive effect. As a mechanistic correlate, electrophysiological data point to a modulatory effect of S1RA on spinal hyperexcitability arising from repetitive nociceptive stimulation, such as that expected to come on following nerve injury, capsaicin or formalin sensitization. These findings contribute to the converging evidence identifying the σ1R as a modulator of activity-induced spinal sensitization and pain hypersensitivity, and point to σ1R antagonists as a potential novel strategy for the treatment of neuropathic pain.