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).
This study explored the relative contributions of 7TM and 6TM variants in a range of morphine actions.
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.
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.
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.
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This work was supported in part by grants from the Peter F. McManus Charitable Trust, Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, The Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center, and the National Institutes on Drug Abuse of the National Institutes of Health (DA06241 and DA07242) to GWP and DA0291122 to AMR; a core grant from the National Cancer Institute of the National Institutes of Health (CA08748) to MSKCC; and a National Science Foundation Graduate Research Fellowship Grant (DGE-1257284) to GFM. There are no competing financial interests.
All animal studies were approved by the Institutional Animal Care and Use Committee of Memorial Sloan Kettering Cancer Center and performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals in an AAALAC-accredited facility.
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Marrone, G.F., Le Rouzic, V., Varadi, A. et al. Genetic dissociation of morphine analgesia from hyperalgesia in mice. Psychopharmacology 234, 1891–1900 (2017). https://doi.org/10.1007/s00213-017-4600-2
- Mu opioid
- Mu opioid receptor
- Alternative splicing