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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 125 Issue 7 Pg. 2626-30 (Jul 01 2015) ISSN: 1558-8238 [Electronic] United States
• PMID: 26011641 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Analgesics, Opioid
• Oprm protein, mouse
• Peptide Fragments
• Receptors, Opioid, mu
• Recombinant Proteins
• iodobenzoylnaltrexamide
• Naltrexone
• Morphine
• Methadone

Topics

• Alternative Splicing
• Analgesics, Opioid (pharmacology)
• Animals
• Exons
• Gene Targeting
• Methadone (pharmacology)
• Mice
• Mice, Knockout
• Morphine (pharmacology)
• Naltrexone (analogs & derivatives, pharmacology)
• Pain (drug therapy, physiopathology)
• Peptide Fragments (chemistry, genetics, physiology)
• Protein Structure, Tertiary
• Receptors, Opioid, mu (deficiency, genetics, physiology)
• Recombinant Proteins (chemistry, genetics, metabolism)