ArticleProceedings of the National Academy of Sciences of the United States of America2016
Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 34 citations in OpenAlex.
- Synthesis and Pharmacology of a Morphinan-Derived Dual Mu-Kappa Opioid Receptor Agonist Analgesic.ACS chemical neuroscience · 2025Article
- GPCR Sense Communication Among Interaction Nematodes with Other Organisms.International journal of molecular sciences · 2025Review
- Buprenorphine Pharmacodynamics: A Bridge to Understanding Buprenorphine Clinical Benefits.Drugs · 2025Review
- Toward a comprehensive profiling of alternative splicing proteoform structures, interactions and functions.Current opinion in structural biology · 2025Review
- Signaling Modulation Mediated by Ligand Water Interactions with the Sodium Site at μOR.ACS central science · 2024Article
- Sex Differences in Brain Region-Specific Activation of c-Fos following Kappa Opioid Receptor Stimulation or Acute Stress in Mice.International journal of molecular sciences · 2023Article
- Exploring Pharmacological Functions of Alternatively Spliced Variants of the Mu Opioid Receptor Gene,International journal of molecular sciences · 2022Review
- Alternative Pre-mRNA Splicing of the Mu Opioid Receptor Gene,Biomolecules · 2021Review
- Constitutive signal bias mediated by the human GHRHR splice variant 1.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Kratom Alkaloids as Probes for Opioid Receptor Function: Pharmacological Characterization of Minor Indole and Oxindole Alkaloids from Kratom.ACS chemical neuroscience · 2021Article
- Interactive Mechanisms of Supraspinal Sites of Opioid Analgesic Action: A Festschrift to Dr. Gavril W. Pasternak.Cellular and molecular neurobiology · 2021Review
- Identification and characterization of novel candidate compounds targeting 6- and 7-transmembrane μ-opioid receptor isoforms.British journal of pharmacology · 2021Article
- Article
- Abuse Liability, Anti-Nociceptive, and Discriminative Stimulus Properties of IBNtxA.ACS pharmacology & translational science · 2020Article
- A Truncated Six Transmembrane Splice Variant MOR-1G Enhances Expression of the Full-Length Seven TransmembraneMolecular pharmacology · 2020Article
- Untangling the complexity of opioid receptor function.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2018Review
- Truncated μ-Opioid Receptors With 6 Transmembrane Domains Are Essential for Opioid Analgesia.Anesthesia and analgesia · 2018Article
- Breaking barriers to novel analgesic drug development.Nature reviews. Drug discovery · 2017Review
- Genetic dissociation of morphine analgesia from hyperalgesia in mice.Psychopharmacology · 2017Article
- A "tail" of opioid receptor variants.The Journal of clinical investigation · 2017Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3'-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α2-adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50, 488H, or α2-mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa1, and α2 actions from analgesia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.