title: Broad-spectrum analgesic efficacy of IBNtxA is mediated by exon 11-associated splice variants of the mu-opioid receptor gene.
abstract: μ-Opioids remain vastly important for the treatment of pain, and would represent ideal analgesics if their analgesic effects could be separated from their many side effects. A recently synthesized compound, iodobenzoylnaltrexamide (IBNtxA), acting at 6-transmembrane (6-TM) splice variants of the μ-opioid receptor gene, was shown to have potent analgesic actions against acute, thermal pain accompanied by a vastly improved side-effect profile compared to 7-TM-acting drugs such as morphine. Whether such analgesia can be seen in longer-lasting and nonthermal algesiometric assays is not known. The current study demonstrates potent and efficacious IBNtxA inhibition of a wide variety of assays, including inflammatory and neuropathic hypersensitivity and spontaneous pain. We further demonstrate the dependence of such analgesia on 6-TM μ-opioid receptor variants using isobolographic analysis and the testing of Oprm1 (the μ-opioid receptor gene) exon 11 null mutant mice. Finally, the effect of nerve damage (spared nerve injury) and inflammatory injury (complete Freund's adjuvant) on expression of μ-opioid receptor variant genes in pain-relevant central nervous system loci was examined, revealing a downregulation of the mMOR-1D splice variant in the dorsal root ganglion after spared nerve injury. These findings are supportive of the potential value of 6-TM-acting drugs as novel analgesics.
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Wieskopf
authors.affiliation: Department of Neurology and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Ying-Xian
authors.initials: YX
authors.lastname: Pan
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Marcovitz
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Tuttle
authors.affiliation: Department of Neurology and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Susruta
authors.initials: S
authors.lastname: Majumdar
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Pidakala
authors.affiliation: Department of Neurology and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada. Electronic address: jeffrey.mogil@mcgill.ca.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D005091:Exons; D005260:Female; D006358:Hot Temperature; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy*; D017288:Pain Threshold / Q000187:drug effects; D020033:Protein Isoforms; D017450:Receptors, Opioid, mu / Q000235:genetics*
chemical_list: D000701:Analgesics, Opioid; D020033:Protein Isoforms; D017450:Receptors, Opioid, mu; C570718:iodobenzoylnaltrexamide; D009271:Naltrexone
keywords: Chronic pain; Splice variants; Synergy; Transgenic; mRNA expression; mu-Opioid
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