title: Modulation of peripheral μ-opioid analgesia by σ1 receptors.
abstract: We evaluated the effects of σ1-receptor inhibition on μ-opioid-induced mechanical antinociception and constipation. σ1-Knockout mice exhibited marked mechanical antinociception in response to several μ-opioid analgesics (fentanyl, oxycodone, morphine, buprenorphine, and tramadol) at systemic (subcutaneous) doses that were inactive in wild-type mice and even unmasked the antinociceptive effects of the peripheral μ-opioid agonist loperamide. Likewise, systemic (subcutaneous) or local (intraplantar) treatment of wild-type mice with the selective σ1 antagonists BD-1063 [1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride] or S1RA [4-[2-[[5-methyl-1-(2-naphthalenyl)1H-pyrazol-3-yl]oxy]ethyl] morpholine hydrochloride] potentiated μ-opioid antinociception; these effects were fully reversed by the σ1 agonist PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate) hydrochloride], showing the selectivity of the pharmacological approach. The μ-opioid antinociception potentiated by σ1 inhibition (by σ1-receptor knockout or σ1-pharmacological antagonism) was more sensitive to the peripherally restricted opioid antagonist naloxone methiodide than opioid antinociception under normal conditions, indicating a key role for peripheral opioid receptors in the enhanced antinociception. Direct interaction between the opioid drugs and σ1 receptor cannot account for our results, since the former lacked affinity for σ1 receptors (labeled with [(3)H](+)-pentazocine). A peripheral role for σ1 receptors was also supported by their higher density (Western blot results) in peripheral nervous tissue (dorsal root ganglia) than in several central areas involved in opioid antinociception (dorsal spinal cord, basolateral amygdala, periaqueductal gray, and rostroventral medulla). In contrast to its effects on nociception, σ1-receptor inhibition did not alter fentanyl- or loperamide-induced constipation, a peripherally mediated nonanalgesic opioid effect. Therefore, σ1-receptor inhibition may be used as a systemic or local adjuvant to enhance peripheral μ-opioid analgesia without affecting opioid-induced constipation.
authors.affiliation: Departments of Pharmacology (C.S.-F., A.M.-G., R.G.-C., F.R.N., L.R., A.A.-C., J.M.B., E.J.C.) and Physiology (R.M.), School of Medicine, University of Granada, Granada, Spain; Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain (C.S.-F., R.G.-C., F.R.N., R.M., J.M.B., J.M.E., E.J.C.); Animal Behavior Research Unit, Scientific Instrumentation Center, University of Granada, Granada, Spain (J.M.E.); and Drug Discovery and Preclinical Development, Barcelona, Spain (B.F.-P., M.M.).
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez-Fernández
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Montilla-García
authors.forename: Rafael
authors.initials: R
authors.lastname: González-Cano
authors.forename: Francisco Rafael
authors.initials: FR
authors.lastname: Nieto
authors.forename: Lucía
authors.initials: L
authors.lastname: Romero
authors.forename: Antonia
authors.initials: A
authors.lastname: Artacho-Cordón
authors.forename: Rosa
authors.initials: R
authors.lastname: Montes
authors.forename: Begoña
authors.initials: B
authors.lastname: Fernández-Pastor
authors.forename: Manuel
authors.initials: M
authors.lastname: Merlos
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 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D003248:Constipation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010147:Pain Measurement / Q000379:methods*; D017450:Receptors, Opioid, mu / Q000378:metabolism / Q000502:physiology*; D017480:Receptors, sigma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000097605:Sigma-1 Receptor
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor