Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 13; pp. 3663 - 3668
• Main Authors: Marrone, Gina F., Grinnell, Steven G., Lu, Zhigang, Rossi, Grace C., Le Rouzic, Valerie, Xu, Jin, Majumdar, Susruta, Pan, Ying-Xian, Pasternak, Gavril W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.03.2016; National Acad Sciences
• Subjects: Alternative Splicing; Analgesia; Analgesics; Analgesics, Opioid - pharmacology; Animals; Biological Sciences; Female; Humans; Male; Membranes; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Morphine - pharmacology; Naltrexone - analogs & derivatives; Naltrexone - pharmacology; Narcotics; Pain Management; Pain Measurement; Protein Isoforms - deficiency; Protein Isoforms - genetics; Protein Isoforms - physiology; Protein Structure, Tertiary; Proteins; Receptors, Opioid, mu - deficiency; Receptors, Opioid, mu - genetics; Receptors, Opioid, mu - physiology; GPCR; truncation; analgesia; mu opioid receptor; morphine
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1523894113

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.