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Research ArticleNeuropharmacology

Opioid-Induced Signaling and Antinociception Are Modulated by the Recently Deorphanized Receptor, GPR171

Max V. McDermott, Leela Afrose, Ivone Gomes, Lakshmi A. Devi and Erin N. Bobeck
Journal of Pharmacology and Experimental Therapeutics October 2019, 371 (1) 56-62; DOI: https://doi.org/10.1124/jpet.119.259242
Max V. McDermott
Department of Biology, Utah State University, Logan, Utah (M.V.M., L.A., E.N.B.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (I.G., L.A.D.)
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Leela Afrose
Department of Biology, Utah State University, Logan, Utah (M.V.M., L.A., E.N.B.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (I.G., L.A.D.)
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Ivone Gomes
Department of Biology, Utah State University, Logan, Utah (M.V.M., L.A., E.N.B.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (I.G., L.A.D.)
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Lakshmi A. Devi
Department of Biology, Utah State University, Logan, Utah (M.V.M., L.A., E.N.B.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (I.G., L.A.D.)
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Erin N. Bobeck
Department of Biology, Utah State University, Logan, Utah (M.V.M., L.A., E.N.B.) and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (I.G., L.A.D.)
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Abstract

ProSAAS is one of the most widely expressed proteins throughout the brain and was recently found to be upregulated in chronic fibromyalgia patients. BigLEN is a neuropeptide that is derived from ProSAAS and was recently discovered to be the endogenous ligand for the orphan G protein-coupled receptor GPR171. Although BigLEN-GPR171 has been found to play a role in feeding and anxiety behaviors, it has not yet been explored in pain and opioid modulation. The purpose of this study was to evaluate this novel neuropeptide-receptor system in opioid-induced antinociception. We found that GPR171 is expressed in GABAergic neurons within the periaqueductal gray, which is a key brain area involved in pain modulation and opioid functions. We also found that, although the GPR171 agonist and antagonist do not have nociceptive effects on their own, they oppositely regulate morphine-induced antinociception with the agonist enhancing and antagonist reducing antinociception. Lastly, we showed that the GPR171 antagonist or receptor knockdown decreases signaling by the mu-opioid receptor, but not the delta-opioid receptor. Taken together, these results suggest that antagonism of the GPR171 receptor reduces mu opioid receptor signaling and morphine-induced antinociception, whereas the GPR171 agonist enhances morphine antinociception, suggesting that GPR171 may be a novel target toward the development of pain therapeutics.

SIGNIFICANCE STATEMENT GPR171 is a recently deorphanized receptor that is expressed within the periaqueductal gray and can regulate mu opioid receptor signaling and antinociception. This research may contribute to the development of new therapeutics to treat pain.

Footnotes

    • Received April 19, 2019.
    • Accepted July 10, 2019.
  • This work was supported by National Institutes of Health [Grants DA0886 and NS026880 to L.A.D. and by a Young Investigator Grant from Brain and Behavior Research Foundation to E.N.B.

  • https://doi.org/10.1124/jpet.119.259242.

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

  • Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 371 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 371, Issue 1
1 Oct 2019
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Research ArticleNeuropharmacology

GPR171 Regulates Opioid Signaling and Antinociception

Max V. McDermott, Leela Afrose, Ivone Gomes, Lakshmi A. Devi and Erin N. Bobeck
Journal of Pharmacology and Experimental Therapeutics October 1, 2019, 371 (1) 56-62; DOI: https://doi.org/10.1124/jpet.119.259242

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Research ArticleNeuropharmacology

GPR171 Regulates Opioid Signaling and Antinociception

Max V. McDermott, Leela Afrose, Ivone Gomes, Lakshmi A. Devi and Erin N. Bobeck
Journal of Pharmacology and Experimental Therapeutics October 1, 2019, 371 (1) 56-62; DOI: https://doi.org/10.1124/jpet.119.259242
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