• Jeffrey S Wieskopf, Ying-Xian Pan, Jaclyn Marcovitz, Alexander H Tuttle, Susruta Majumdar, John Pidakala, Gavril W Pasternak, and Jeffrey S Mogil.
• Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
• Pain. 2014 Oct 1; 155 (10): 206320702063-70.

Abstractμ-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.Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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