Investigational sigma-1 receptor antagonists for the treatment of pain

Expert Opin Investig Drugs. 2015;24(7):883-96. doi: 10.1517/13543784.2015.1048334. Epub 2015 Jun 3.


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.

Keywords: E-52862; analgesia; antinociception; combination therapy; opioids; pain; sigma-1 receptor.

Publication types

  • Review

MeSH terms

  • Analgesics / pharmacology
  • Analgesics / therapeutic use*
  • Animals
  • Drug Discovery
  • Humans
  • Ligands
  • Pain / drug therapy*
  • Pain / metabolism
  • Receptors, sigma / antagonists & inhibitors*
  • Receptors, sigma / metabolism


  • Analgesics
  • Ligands
  • Receptors, sigma
  • sigma-1 receptor