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

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 2

Lentivirus expression in the spinal cord following intrathecal administration.

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Lentivirus expression in the spinal cord following intrathecal administr...
(A) Distribution of lentiviral-expressed mMOR-1G (lenti–mMOR-1G) and EGFP. An exon 4 antibody was used for staining mMOR-1G. Nuclei were stained with DAPI. Scale bars: 100 μm in first three columns and 10 μm in last column. (B and C) Receptor binding in the spinal cord of exon 1/exon 11 KO mice without and following lenti–mMOR-1G (percent of WT; mean ± SEM from 3–4 pooled samples. Each pool contains the spinal cord from 2–3 mice). Significant differences between WT, exon 1/exon 11 KO, and lenti–mMOR-1G groups were seen with ANOVA for 125I-IBNtxA and 3H-DAMGO (*P < 0.001) (A) but not 3H-DPDPE and 3H-U69,593 (B). For 125I-IBNtxA, the exon 1/exon 11 KO and the lenti–mMOR-1G groups differed from WT (P < 0.001) and from each other (P < 0.05; Tukey). For 3H-DAMGO, the exon 1/exon 11 KO and the lenti–mMOR-1G groups differed from WT (P < 0.001) but not from each other (P > 0.05).