Mediation of opioid analgesia by a truncated 6-transmembrane GPCR Journal Article
| Authors: | Lu, Z.; Xu, J.; Rossi, G. C.; Majumdar, S.; Pasternak, G. W.; Pan, Y. X. |
| Article Title: | Mediation of opioid analgesia by a truncated 6-transmembrane GPCR |
| Abstract: | The generation of potent opioid analgesics that lack the side effects of traditional opioids may be possible by targeting truncated splice variants of the μ-opioid receptor. μ-Opioids act through GPCRs that are generated from the Oprm1 gene, which undergoes extensive alternative splicing. The most abundant set of Oprm1 variants encode classical full-length 7 transmembrane domain (7TM) μ-opioid receptors that mediate the actions of the traditional μ-opioid drugs morphine and methadone. In contrast, 3-iodobenzoyl-6β-naltrexamide (IBNtxA) is a potent analgesic against thermal, inflammatory, and neuropathic pain that acts independently of 7TM μ-opioid receptors but has no activity in mice lacking a set of 6TM truncated μ-opioid receptor splice variants. Unlike traditional opioids, IBNtxA does not depress respiration or result in physical dependence or reward behavior, suggesting it acts through an alternative μ-opioid receptor target. Here we demonstrated that a truncated 6TM splice variant, mMOR-1G, can rescue IBNtxA analgesia in a μ-opioid receptor-deficient mouse that lacks all Oprm1 splice variants, ablating μ-opioid activity in these animals. Intrathecal administration of lentivirus containing the 6TM variant mMOR-1G restored IBNtxA, but not morphine, analgesia in Oprm1-deficient animals. Together, these results confirm that a truncated 6TM GPCR is both necessary and sufficient for IBNtxA analgesia. |
| Keywords: | controlled study; exon; nonhuman; protein domain; mouse; opiate; animal experiment; animal model; alternative rna splicing; drug dependence; methadone; morphine; analgesia; neuropathic pain; g protein coupled receptor; mu opiate receptor; fentanyl; diamorphine; lentivirinae; virus expression; antibody labeling; buprenorphine; prostaglandin f2 alpha; ketazocine; priority journal; article; lentivirus infection |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 125 |
| Issue: | 7 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2015-07-01 |
| Start Page: | 2626 |
| End Page: | 2630 |
| Language: | English |
| DOI: | 10.1172/jci81070 |
| PROVIDER: | scopus |
| PUBMED: | 26011641 |
| PMCID: | PMC4563690 |
| DOI/URL: | |
| Notes: | Export Date: 3 August 2015 -- Source: Scopus |
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