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Research ArticleBehavioral Pharmacology

Pharmacological Properties of δ-Opioid Receptor–Mediated Behaviors: Agonist Efficacy and Receptor Reserve

Isaac J. Dripps, Ruizhuo Chen, Amanda M. Shafer, Kathryn E. Livingston, Alexander Disney, Stephen M. Husbands, John R. Traynor, Kenner C. Rice and Emily M. Jutkiewicz
Journal of Pharmacology and Experimental Therapeutics August 2020, 374 (2) 319-330; DOI: https://doi.org/10.1124/jpet.119.262717
Isaac J. Dripps
Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (I.J.D., R.C., A.M.S., K.E.L., J.R.T., E.M.J.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (A.D., S.M.H.); and Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.)
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Ruizhuo Chen
Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (I.J.D., R.C., A.M.S., K.E.L., J.R.T., E.M.J.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (A.D., S.M.H.); and Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.)
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Amanda M. Shafer
Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (I.J.D., R.C., A.M.S., K.E.L., J.R.T., E.M.J.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (A.D., S.M.H.); and Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.)
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Kathryn E. Livingston
Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (I.J.D., R.C., A.M.S., K.E.L., J.R.T., E.M.J.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (A.D., S.M.H.); and Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.)
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Alexander Disney
Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (I.J.D., R.C., A.M.S., K.E.L., J.R.T., E.M.J.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (A.D., S.M.H.); and Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.)
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Stephen M. Husbands
Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (I.J.D., R.C., A.M.S., K.E.L., J.R.T., E.M.J.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (A.D., S.M.H.); and Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.)
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John R. Traynor
Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (I.J.D., R.C., A.M.S., K.E.L., J.R.T., E.M.J.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (A.D., S.M.H.); and Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.)
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Kenner C. Rice
Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (I.J.D., R.C., A.M.S., K.E.L., J.R.T., E.M.J.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (A.D., S.M.H.); and Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.)
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Emily M. Jutkiewicz
Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (I.J.D., R.C., A.M.S., K.E.L., J.R.T., E.M.J.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (A.D., S.M.H.); and Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.)
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Abstract

δ-Opioid receptor (δ-receptor) agonists produce antihyperalgesia, antidepressant-like effects, and convulsions in animals. However, the role of agonist efficacy in generating different δ-receptor–mediated behaviors has not been thoroughly investigated. To this end, efficacy requirements for δ-receptor–mediated antihyperalgesia, antidepressant-like effects, and convulsions were evaluated by comparing the effects of the partial agonist BU48 and the full agonist SNC80 and changes in the potency of SNC80 after δ-receptor elimination. Antihyperalgesia was measured in a nitroglycerin-induced thermal hyperalgesia assay. An antidepressant-like effect was evaluated in the forced swim test. Mice were observed for convulsions after treatment with SNC80 or the δ-opioid receptor partial agonist BU48. Ligand-induced G protein activation was measured by [35S]guanosine 5′-O-[γ-thio]triphosphate binding in mouse forebrain tissue, and δ-receptor number was measured by [3H]D-Pen2,5-enkephalin saturation binding. BU48 produced antidepressant-like effects and convulsions but antagonized SNC80-induced antihyperalgesia and G protein activation. The potency of SNC80 was shifted to the right in δ-receptor heterozygous knockout mice and naltrindole-5′-isothiocyanate–treated mice, and the magnitude of potency shift differed across assays, with the largest shift occurring in the thermal hyperalgesia assay, followed by the forced swim test and then convulsion observation. Naltrindole antagonized these SNC80-induced behaviors with similar potencies, suggesting that these effects are mediated by the same type of δ-receptor. These data suggest that δ-receptor–mediated behaviors display a rank order of efficacy requirement, with antihyperalgesia having the highest requirement, followed by antidepressant-like effects and then convulsions. These findings further our understanding of the pharmacological mechanisms mediating the in vivo effects of δ-opioid receptor agonists.

SIGNIFICANCE STATEMENT δ-Opioid receptor (δ-receptor) agonists produce antihyperalgesia, antidepressant-like effects, and convulsions in animal models. This study evaluates pharmacological properties, specifically the role of agonist efficacy and receptor reserve, underlying these δ-receptor–mediated behaviors. These data suggest that δ-receptor–mediated behaviors display a rank order of efficacy requirement, with antihyperalgesia having the highest requirement, followed by antidepressant-like effects and then convulsions.

Footnotes

    • Received September 15, 2019.
    • Accepted May 18, 2020.
  • These studies were funded by a Research Starter Grant from the Pharmaceutical Research and Manufacturers of America Foundation awarded to E.M.J. Additional support was provided by National Institutes of Health National Institute on Drug Abuse Grants [R-01 DA042092] (to E.M.J.), [R-01 DA035316 ] (to J.R.T.), and [R-01 DA07315] (to S.M.H. and J.R.T.). This study was also supported in part by the Intramural Research Program of National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism (to K.C.R.).

  • This work was presented in thesis work for I.J.D. and R.C.

  • https://doi.org/10.1124/jpet.119.262717.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 374 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 374, Issue 2
1 Aug 2020
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Research ArticleBehavioral Pharmacology

Efficacy Requirements of δ-Receptor–Mediated Behaviors

Isaac J. Dripps, Ruizhuo Chen, Amanda M. Shafer, Kathryn E. Livingston, Alexander Disney, Stephen M. Husbands, John R. Traynor, Kenner C. Rice and Emily M. Jutkiewicz
Journal of Pharmacology and Experimental Therapeutics August 1, 2020, 374 (2) 319-330; DOI: https://doi.org/10.1124/jpet.119.262717

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Research ArticleBehavioral Pharmacology

Efficacy Requirements of δ-Receptor–Mediated Behaviors

Isaac J. Dripps, Ruizhuo Chen, Amanda M. Shafer, Kathryn E. Livingston, Alexander Disney, Stephen M. Husbands, John R. Traynor, Kenner C. Rice and Emily M. Jutkiewicz
Journal of Pharmacology and Experimental Therapeutics August 1, 2020, 374 (2) 319-330; DOI: https://doi.org/10.1124/jpet.119.262717
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