Broad-spectrum analgesic efficacy of IBNtxA is mediated by exon 11-associated splice variants of the mu-opioid receptor gene Journal Article
| Authors: | Wieskopf, J. S.; Pan, Y. X.; Marcovitz, J.; Tuttle, A. H.; Majumdar, S.; Pidakala, J.; Pasternak, G. W.; Mogil, J. S. |
| Article 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. |
| Keywords: | adult; controlled study; young adult; unclassified drug; exon; drug efficacy; nonhuman; mouse; animal tissue; drug inhibition; pain; gene expression; animal experiment; animal model; genetic variability; drug potency; messenger rna; splice variants; alternative rna splicing; nerve injury; chronic pain; morphine; transgenic; mu opiate receptor; analgesic agent; analgesic activity; spinal ganglion; synergy; receptor down regulation; mrna expression; iodobenzoylnaltrexamide; male; female; article; mu-opioid; neuropathic hypersensitivity; spontaneous pain; thermal pain |
| Journal Title: | Pain |
| Volume: | 155 |
| Issue: | 10 |
| ISSN: | 0304-3959 |
| Publisher: | Elsevier Science BV |
| Date Published: | 2014-10-01 |
| Start Page: | 2063 |
| End Page: | 2070 |
| Language: | English |
| DOI: | 10.1016/j.pain.2014.07.014 |
| PROVIDER: | scopus |
| PUBMED: | 25093831 |
| PMCID: | PMC4372857 |
| DOI/URL: | |
| Notes: | Export Date: 1 December 2014 -- Source: Scopus |
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