Gina F Marrone1,2, Valerie Le Rouzic1, Andras Varadi1, Jin Xu1, Anjali M Rajadhyaksha2, Susruta Majumdar1, Ying-Xian Pan1, Gavril W Pasternak3,4. 1. Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA. 2. Department of Neurology and Neuroscience, Weill Cornell Medical College, 1300 York Ave, New York, NY, 10065, USA. 3. Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA. pasterng@mskcc.org. 4. Department of Neurology and Neuroscience, Weill Cornell Medical College, 1300 York Ave, New York, NY, 10065, USA. pasterng@mskcc.org.
Abstract
RATIONALE: Morphine is the prototypic mu opioid, producing its analgesic actions through traditional 7 transmembrane domain (7TM) G-protein-coupled receptors generated by the mu opioid receptor gene (Oprm1). However, the Oprm1 gene undergoes extensive alternative splicing to yield three structurally distinct sets of splice variants. In addition to the full-length 7TM receptors, it produces a set of truncated variants comprised of only 6 transmembrane domains (6TM). OBJECTIVES: This study explored the relative contributions of 7TM and 6TM variants in a range of morphine actions. METHODS: Groups of male and mixed-gender wild-type and exon 11 Oprm1 knockout mice were examined in a series of behavioral assays measuring analgesia, hyperalgesia, respiration, and reward in conditioned place preference assays. RESULTS: Loss of the 6TM variants in an exon 11 knockout (E11 KO) mouse did not affect morphine analgesia, reward, or respiratory depression. However, E11 KO mice lacking 6TM variants failed to show morphine-induced hyperalgesia, developed tolerance more slowly than wild-type mice, and did not display hyperlocomotion. CONCLUSIONS: Together, our findings confirm the established role of 7TM mu receptor variants in morphine analgesia, reward, and respiratory depression, but reveal an unexpected obligatory role for 6TM variants in morphine-induced hyperalgesia and a modulatory role in morphine tolerance and dependence.
RATIONALE: Morphine is the prototypic mu opioid, producing its analgesic actions through traditional 7 transmembrane domain (7TM) G-protein-coupled receptors generated by the mu opioid receptor gene (Oprm1). However, the Oprm1 gene undergoes extensive alternative splicing to yield three structurally distinct sets of splice variants. In addition to the full-length 7TM receptors, it produces a set of truncated variants comprised of only 6 transmembrane domains (6TM). OBJECTIVES: This study explored the relative contributions of 7TM and 6TM variants in a range of morphine actions. METHODS: Groups of male and mixed-gender wild-type and exon 11 Oprm1 knockout mice were examined in a series of behavioral assays measuring analgesia, hyperalgesia, respiration, and reward in conditioned place preference assays. RESULTS: Loss of the 6TM variants in an exon 11 knockout (E11 KO) mouse did not affect morphineanalgesia, reward, or respiratory depression. However, E11 KO mice lacking 6TM variants failed to show morphine-induced hyperalgesia, developed tolerance more slowly than wild-type mice, and did not display hyperlocomotion. CONCLUSIONS: Together, our findings confirm the established role of 7TM mu receptor variants in morphineanalgesia, reward, and respiratory depression, but reveal an unexpected obligatory role for 6TM variants in morphine-induced hyperalgesia and a modulatory role in morphine tolerance and dependence.
Entities:
Keywords:
6TM; Alternative splicing; GPCR; KNOCKOUT; MOR-1; Mu opioid; Mu opioid receptor; Truncated
Authors: Michael H Baumann; Susruta Majumdar; Valerie Le Rouzic; Amanda Hunkele; Rajendra Uprety; Xi Ping Huang; Jin Xu; Bryan L Roth; Ying-Xian Pan; Gavril W Pasternak Journal: Neuropharmacology Date: 2017-08-12 Impact factor: 5.250
Authors: Marjo Piltonen; Andrey Krokhotin; Marc Parisien; Pierre Bérubé; Haig Djambazian; Rob Sladek; Nikolay V Dokholyan; Svetlana A Shabalina; Luda Diatchenko Journal: Cell Mol Neurobiol Date: 2020-10-03 Impact factor: 5.046