title: Investigational sigma-1 receptor antagonists for the treatment of pain.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: ESTEVE, Drug Discovery and Preclinical Development, Carrer Baldiri Reixac , 4-8. Parc Científic de Barcelona, 08028 Barcelona , Spain +34 93 4466244 ; +34 93 4466432 ; jvela@esteve.es.
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Vela
authors.forename: Manuel
authors.initials: M
authors.lastname: Merlos
authors.forename: Carmen
authors.initials: C
authors.lastname: Almansa
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D000700:Analgesics; D008024:Ligands; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
keywords: E-52862; analgesia; antinociception; combination therapy; opioids; pain; sigma-1 receptor