title: Potentiation of morphine-induced mechanical antinociception by σ₁ receptor inhibition: role of peripheral σ₁ receptors.
abstract: We studied the modulation of morphine-induced mechanical antinociception and side effects by σ₁ receptor inhibition. Both wild-type (WT) and σ₁ receptor knockout (σ₁-KO) mice showed similar responses to paw pressure (100-600 g). The systemic (subcutaneous) or local (intraplantar) administration of σ₁ antagonists (BD-1063, BD-1047, NE-100 and S1RA) was devoid of antinociceptive effects in WT mice. However, σ₁-KO mice exhibited an enhanced mechanical antinociception in response to systemic morphine (1-16 mg/kg). Similarly, systemic treatment of WT mice with σ₁ antagonists markedly potentiated morphine-induced antinociception, and its effects were reversed by the selective σ₁ agonist PRE-084. Although the local administration of morphine (50-200 μg) was devoid of antinociceptive effects in WT mice, it induced dose-dependent antinociception in σ₁-KO mice. This effect was limited to the injected paw. Enhancement of peripheral morphine antinociception was replicated in WT mice locally co-administered with σ₁ antagonists and the opioid. None of the σ₁ antagonists tested enhanced morphine-antinociception in σ₁-KO mice, confirming a σ₁-mediated action. Morphine-induced side-effects (hyperlocomotion and inhibition of gastrointestinal transit) were unaltered in σ₁-KO mice. These results cannot be explained by a direct interaction of σ₁ ligands with μ-opioid receptors or adaptive changes of μ-receptors in σ₁-KO mice, given that [(3)H]DAMGO binding in forebrain, spinal cord, and hind-paw skin membranes was unaltered in mutant mice, and none of the σ₁ drugs tested bound to μ-opioid receptors. These results show that σ₁ receptor inhibition potentiates morphine-induced mechanical analgesia but not its acute side effects, and that this enhanced analgesia can be induced at peripheral level.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Granada, Avenida de Madrid 11, 18012 Granada, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez-Fernández
authors.forename: Francisco Rafael
authors.initials: FR
authors.lastname: Nieto
authors.forename: Rafael
authors.initials: R
authors.lastname: González-Cano
authors.forename: Antonia
authors.initials: A
authors.lastname: Artacho-Cordón
authors.forename: Lucía
authors.initials: L
authors.lastname: Romero
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Montilla-García
authors.forename: Daniel
authors.initials: D
authors.lastname: Zamanillo
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Baeyens
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Entrena
authors.forename: Enrique José
authors.initials: EJ
authors.lastname: Cobos
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004357:Drug Synergism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005769:Gastrointestinal Motility / Q000187:drug effects; D006614:Hindlimb / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D016548:Prosencephalon / Q000378:metabolism; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D014316:Tritium; D000097605:Sigma-1 Receptor
chemical_list: D000701:Analgesics, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine; D017480:Receptors, sigma; D014316:Tritium; D000097605:Sigma-1 Receptor