Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS
Autor: | Grace C. Rossi, Valerie Le Rouzic, Jin Xu, Susruta Majumdar, Gavril W. Pasternak, Gina F. Marrone, Zhigang Lu, Ying-Xian Pan, Steven G. Grinnell |
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Rok vydání: | 2016 |
Předmět: |
Male
0301 basic medicine Mice 129 Strain medicine.medical_treatment Analgesic Receptors Opioid mu Pharmacology IBNtxA Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Pain Management Protein Isoforms Receptor Pain Measurement G protein-coupled receptor Mice Knockout Multidisciplinary Morphine business.industry Biological Sciences Naltrexone Protein Structure Tertiary Analgesics Opioid Mice Inbred C57BL Alternative Splicing Transmembrane domain 030104 developmental biology Opioid Female Cannabinoid Analgesia μ-opioid receptor business 030217 neurology & neurosurgery medicine.drug |
Zdroj: | Proceedings of the National Academy of Sciences. 113:3663-3668 |
ISSN: | 1091-6490 0027-8424 |
DOI: | 10.1073/pnas.1523894113 |
Popis: | 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. |
Databáze: | OpenAIRE |
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