ArticleProceedings of the National Academy of Sciences of the United States of America2021
Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44 citing papers in PubMed, 74 citations in OpenAlex.
- Structure-guided allosteric modulation of the delta opioid receptor.Nature communications · 2026Article
- Positive allosteric modulation of the delta opioid receptor attenuates depression-like and pain-like behaviors but does not promote convulsions.The Journal of pharmacology and experimental therapeutics · 2026Article
- Molecular mechanism of allosteric modulation of opioid receptors.Signal transduction and targeted therapy · 2026Article
- Effects of the Mu Opioid Receptor Positive Allosteric Modulator BMS-986122 On Opioid Efficacy in Rat Neuropathic Pain States.bioRxiv : the preprint server for biology · 2026Article
- AI-driven quantum chemical exploration of multi-target synthetic opioid analogs for enhanced therapeutic profiles.Journal of computer-aided molecular design · 2026Article
- Discovery and dynamic pharmacology of μ-opioid receptor positive allosteric modulators.bioRxiv : the preprint server for biology · 2026Article
- Structure-based design of an opioid receptor modulator for enhanced morphine analgesia.Science advances · 2026Article
- Antidepressants and the endogenous opioid system.Biochemical pharmacology · 2025Review
- The neural circuits and signalling pathways of opioid use disorder.Nature reviews. Neuroscience · 2025Review
- Effects of two structurally diverse positive allosteric modulators on signaling bias at the μ-opioid receptor.Molecular pharmacology · 2025Article
- Mu Opioid Receptor Positive Allosteric Modulator BMS-986122 Confers Agonist-Dependent G Protein Subtype Signaling Bias.Biochemistry · 2025Article
- Peripheral Opioid Receptors in the Modulation of Inflammatory Pain: a Narrative Review.Maedica · 2025Review
- Advances in the structural understanding of opioid allostery.Trends in pharmacological sciences · 2025Review
- Insurmountable antagonism of human mu opioid receptors by buprenorphine is due to hemi-equilibrium.European journal of pharmacology · 2025Article
- Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors.Molecular pharmacology · 2024Article
- Identification of c[D-Trp-Phe-β-Ala-β-Ala], the First κ-Opioid Receptor-Specific Negative Allosteric Modulator.ACS pharmacology & translational science · 2024Article
- Signaling Modulation Mediated by Ligand Water Interactions with the Sodium Site at μOR.ACS central science · 2024Article
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- Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator.Nature communications · 2024Article
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14 authors at 7 institutions in 2 countries.
Funding
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.
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