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Research ArticleBehavioral Pharmacology

Modulation of Peripheral μ-Opioid Analgesia by σ1 Receptors

Cristina Sánchez-Fernández, Ángeles Montilla-García, Rafael González-Cano, Francisco Rafael Nieto, Lucía Romero, Antonia Artacho-Cordón, Rosa Montes, Begoña Fernández-Pastor, Manuel Merlos, José Manuel Baeyens, José Manuel Entrena and Enrique José Cobos
Journal of Pharmacology and Experimental Therapeutics January 2014, 348 (1) 32-45; DOI: https://doi.org/10.1124/jpet.113.208272
Cristina Sánchez-Fernández
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.)
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Ángeles Montilla-García
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.)
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Rafael González-Cano
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.)
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Francisco Rafael Nieto
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.)
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Lucía Romero
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.)
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Antonia Artacho-Cordón
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.)
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Rosa Montes
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.)
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Begoña Fernández-Pastor
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.)
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Manuel Merlos
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.)
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José Manuel Baeyens
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.)
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José Manuel Entrena
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.)
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Enrique José Cobos
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.)
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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 [3H](+)-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.

Footnotes

    • Received July 24, 2013.
    • Accepted October 23, 2013.
  • This study was supported in part by the Spanish Ministry of Education and Science [Grant SAF2006-06122]; the Ministry of Science and Innovation [Grant SAF2010-15343 and predoctoral FPU grants to (C.S.-F. and R.G.-C.)]; Junta de Andalucía [Grant CTS-109]; FEDER (European Fund for Regional Development) funds, Laboratorios Esteve; the Research Program of the University of Granada (to E.J.C.); and the Spanish Center for Industrial Technological Development (Genius Pharma Project).

  • This research was done in partial fulfillment of the requirements for the doctoral thesis of Sánchez-Fernández C.

  • dx.doi.org/10.1124/jpet.113.208272.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 348 (1)
Journal of Pharmacology and Experimental Therapeutics
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1 Jan 2014
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Research ArticleBehavioral Pharmacology

Modulation of Peripheral μ-Opioid Analgesia by σ1 Receptors

Cristina Sánchez-Fernández, Ángeles Montilla-García, Rafael González-Cano, Francisco Rafael Nieto, Lucía Romero, Antonia Artacho-Cordón, Rosa Montes, Begoña Fernández-Pastor, Manuel Merlos, José Manuel Baeyens, José Manuel Entrena and Enrique José Cobos
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 32-45; DOI: https://doi.org/10.1124/jpet.113.208272

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Research ArticleBehavioral Pharmacology

Modulation of Peripheral μ-Opioid Analgesia by σ1 Receptors

Cristina Sánchez-Fernández, Ángeles Montilla-García, Rafael González-Cano, Francisco Rafael Nieto, Lucía Romero, Antonia Artacho-Cordón, Rosa Montes, Begoña Fernández-Pastor, Manuel Merlos, José Manuel Baeyens, José Manuel Entrena and Enrique José Cobos
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 32-45; DOI: https://doi.org/10.1124/jpet.113.208272
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