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Mediation of opioid analgesia by a truncated 6-transmembrane GPCR
Zhigang Lu, … , Gavril W. Pasternak, Ying-Xian Pan
Zhigang Lu, … , Gavril W. Pasternak, Ying-Xian Pan
Published May 26, 2015
Citation Information: J Clin Invest. 2015;125(7):2626-2630. https://doi.org/10.1172/JCI81070.
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Brief Report Genetics Neuroscience Therapeutics

Mediation of opioid analgesia by a truncated 6-transmembrane GPCR

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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.

Authors

Zhigang Lu, Jin Xu, Grace C. Rossi, Susruta Majumdar, Gavril W. Pasternak, Ying-Xian Pan

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Figure 1

Gene-targeting exons 1 and 11 in the Oprm1 gene.

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Gene-targeting exons 1 and 11 in the Oprm1 gene.
(A) Schematic of the ta...
(A) Schematic of the targeting strategy. The coding and its adjacent intron regions of exons 1 and 11 were replaced with the tdTomato/BGHpolyA (tdT/pA)/PGK-Neo (neo) and ZsGree/SVpolyA (ZsG/pA) cassettes, respectively. The expected EcoRV-digested fragment lengths for WT and targeted alleles are indicated by arrows. The 5′ probe is indicated by a short line. LoxP and Flp sites are shown by triangles and diamonds, respectively. P, PI-SecI; E, EcoRV. (B) Southern blot analysis with the 5′ probe. (C) RT-PCR using RNAs from brain and appropriate primers. Each line represents data from 1 mouse. +/+, WT; +/–, heterozygous; –/–, homozygous.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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