Broad-spectrum analgesic efficacy of IBNtxA is mediated by exon 11-associated splice variants of the mu-opioid receptor gene

Pain. 2014 Oct;155(10):2063-70. doi: 10.1016/j.pain.2014.07.014. Epub 2014 Aug 2.


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: Chronic pain; Splice variants; Synergy; Transgenic; mRNA expression; mu-Opioid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Analgesics, Opioid / therapeutic use*
  • Animals
  • Exons*
  • Female
  • Hot Temperature
  • Male
  • Mice
  • Mice, Knockout
  • Naltrexone / analogs & derivatives*
  • Naltrexone / pharmacology
  • Naltrexone / therapeutic use
  • Pain / drug therapy*
  • Pain Threshold / drug effects
  • Protein Isoforms*
  • Receptors, Opioid, mu / genetics*


  • Analgesics, Opioid
  • Protein Isoforms
  • Receptors, Opioid, mu
  • iodobenzoylnaltrexamide
  • Naltrexone