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

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 pa...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-04, Vol.118 (16), p.1
Main Authors: Kandasamy, Ram, Hillhouse, Todd M, Livingston, Kathryn E, Kochan, Kelsey E, Meurice, Claire, Eans, Shainnel O, Li, Ming-Hua, White, Andrew D, Roques, Bernard P, McLaughlin, Jay P, Ingram, Susan L, Burford, Neil T, Alt, Andrew, Traynor, John R
Format: Article
Language:English
Subjects:
Allosteric properties
Analgesia
Analgesics
Animal models
Antagonists
Arrestin
Biological Sciences
Constipation
Enkephalin (methionine)
Enkephalins
Hypotheses
Inflammation
Life Sciences
Methionine
Modulators
Morphine
Narcotics
Neurons and Cognition
Opioid receptors (type mu)
Pain
Pain perception
Peptides
Periaqueductal gray area
Place preference conditioning
Proteins
Receptors
Reinforcement
Side effects
γ-Aminobutyric acid
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2000017118