Investigational sigma-1 receptor antagonists for the treatment of pain

Introduction: The sigma-1 receptor (σ₁R) is a ligand-regulated molecular chaperone that interacts with other proteins, including NMDA and opioid receptors, to modulate their activity. Convergent evidence indicates that σ₁R antagonists exert inhibitory effects (and agonists stimulatory effects) on pain by stepping down the intracellular signaling cascades involved in transduction of noxious stimuli and plastic changes (i.e., sensitization phenomena) associated with chronic pain states.

Areas covered: This review addresses three primary domains. The first focuses on mechanisms underlying the antinociceptive effects of σ₁R antagonists. The second addresses evidence gained using pharmacological tools and experimental drugs in the discovery phase and clinical development. Finally, the article outlines the potential benefits of σ₁R antagonists, alone or in combination, in the context of available pain therapeutics.

Expert opinion: There is a critical need for new analgesics based on new mechanisms of action. Target identification requires convincing evidence relating targets to function. In turn, target validation requires confirmation of therapeutic benefits, ideally in humans. Current preclinical evidence provides strong rationale for σ₁R antagonists in pain. The outcome of clinical studies with the most advanced investigational σ₁R antagonist, S1RA (E-52862), will be of great interest to ascertain the potential of this new therapeutic approach to pain management.