title: Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization.
abstract: OBJECTIVE
  The sigma-1 (σ(1) ) 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(1) receptor ligands used as pharmacological tools are unclear and the demonstration that σ(1) receptor antagonists have efficacy in reversing central sensitization-related pain sensitivity is still missing.
  
  
  METHODS
  The pharmacological properties of a novel σ(1) receptor antagonist (S1RA) were first characterized. S1RA was then used to investigate the effect of pharmacological antagonism of σ(1) receptors on in vivo nociception in sensitizing conditions and on in vitro spinal cord sensitization in mice. Drug levels and autoradiographic, ex vivo binding for σ(1) receptor occupancy were measured to substantiate behavioural data.
  
  
  RESULTS
  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(1) 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(1) receptors attenuated the wind-up responses in spinal cords sensitized by repetitive nociceptive stimulation.
  
  
  CONCLUSIONS
  These findings contribute to evidence identifying the σ(1) receptor as a modulator of activity-induced spinal sensitization and pain hypersensitivity, and suggest σ(1) receptor antagonists as potential novel treatments for neuropathic pain.
authors.affiliation: Esteve, Drug Discovery and Preclinical Development, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Romero
authors.forename: D
authors.initials: D
authors.lastname: Zamanillo
authors.forename: X
authors.initials: X
authors.lastname: Nadal
authors.forename: R
authors.initials: R
authors.lastname: Sánchez-Arroyos
authors.forename: I
authors.initials: I
authors.lastname: Rivera-Arconada
authors.forename: A
authors.initials: A
authors.lastname: Dordal
authors.forename: A
authors.initials: A
authors.lastname: Montero
authors.forename: A
authors.initials: A
authors.lastname: Muro
authors.forename: A
authors.initials: A
authors.lastname: Bura
authors.forename: C
authors.initials: C
authors.lastname: Segalés
authors.forename: M
authors.initials: M
authors.lastname: Laloya
authors.forename: E
authors.initials: E
authors.lastname: Hernández
authors.forename: E
authors.initials: E
authors.lastname: Portillo-Salido
authors.forename: M
authors.initials: M
authors.lastname: Escriche
authors.forename: X
authors.initials: X
authors.lastname: Codony
authors.forename: G
authors.initials: G
authors.lastname: Encina
authors.forename: J
authors.initials: J
authors.lastname: Burgueño
authors.forename: M
authors.initials: M
authors.lastname: Merlos
authors.forename: J M
authors.initials: JM
authors.lastname: Baeyens
authors.forename: J
authors.initials: J
authors.lastname: Giraldo
authors.forename: J A
authors.initials: JA
authors.lastname: López-García
authors.forename: R
authors.initials: R
authors.lastname: Maldonado
authors.forename: C R
authors.initials: CR
authors.lastname: Plata-Salamán
authors.forename: J M
authors.initials: JM
authors.lastname: Vela
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D002211:Capsaicin / Q000633:toxicity; D004558:Electric Stimulation; D005557:Formaldehyde / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D009437:Neuralgia / Q000188:drug therapy*; D010147:Pain Measurement; D011720:Pyrazoles / Q000494:pharmacology*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D000097605:Sigma-1 Receptor
chemical_list: D000700:Analgesics; D002211:Capsaicin; D005557:Formaldehyde; D009025:Morpholines; D011720:Pyrazoles; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C576663:4-(2-((5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl)oxy)ethyl)morpholine