2. Academic Validation
  3. Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects

Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects

  • Proc Natl Acad Sci U S A. 2021 Apr 20;118(16):e2000017118. doi: 10.1073/pnas.2000017118.
Ram Kandasamy 1 2,  Todd M Hillhouse 1 3,  Kathryn E Livingston 1,  Kelsey E Kochan 1,  Claire Meurice 1,  Shainnel O Eans 4,  Ming-Hua Li 5,  Andrew D White 6,  Bernard P Roques 7,  Jay P McLaughlin 4,  Susan L Ingram 5,  Neil T Burford 8,  Andrew Alt 1 8 9,  John R Traynor 10 6
Affiliations

Affiliations

  • 1 Edward F. Domino Research Center, Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, 48109.
  • 2 Department of Psychology, California State University, East Bay, Hayward, CA, 94542.
  • 3 Department of Psychology, University of Wisconsin-Green Bay, Green Bay, WI, 54311.
  • 4 Department of Pharmacodynamics, University of Florida College of Pharmacy, Gainesville, FL, 32610.
  • 5 Department of Neurological Surgery, Oregon Health and Science University, Portland, OR, 97239.
  • 6 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor MI, 48109.
  • 7 Unité de Technologies Chimiques et Biologiques pour la Santé, Université Paris Descartes, Paris, Cedex 05, France.
  • 8 Lead Discovery and Optimization, Bristol-Myers Squibb, Wallingford, CT, 06492.
  • 9 Center for Chemical Genomics, Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109.
  • 10 Edward F. Domino Research Center, Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, 48109; jtraynor@umich.edu.
PMID: 33846240 DOI: 10.1073/pnas.2000017118
Abstract

Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid Peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested. Here, we show that a mu-PAM, BMS-986122, enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than β-arrestin recruitment in Chinese hamster ovary (CHO) cells expressing human mu-opioid receptors. Moreover, BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray, an important site for antinociception. We describe in vivo experiments demonstrating that the mu-PAM produces antinociception in mouse models of acute noxious heat pain as well as inflammatory pain. These effects are blocked by MOR antagonists and are consistent with the hypothesis that in vivo mu-PAMs enhance the activity of endogenous opioid Peptides. Because BMS-986122 does not bind to the orthosteric site and has no inherent agonist action at endogenously expressed levels of MOR, it produces a reduced level of morphine-like side effects of constipation, reward as measured by conditioned place preference, and respiratory depression. These data provide a rationale for the further exploration of the action and safety of mu-PAMs as an innovative approach to pain management.

Keywords

allostery; analgesia; endogenous opioid peptides; mu-opioid receptor; signaling bias.

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