Nalfurafine is a G-protein biased agonist having significantly greater bias at the human than rodent form of the kappa opioid receptor

Cell Signal. 2017 Apr;32:59-65. doi: 10.1016/j.cellsig.2017.01.016. Epub 2017 Jan 11.


Nalfurafine is a moderately selective kappa opioid receptor (KOR) analgesic with low incidence of dysphoric side effects in clinical development for the treatment of uremic pruritis. The basis for its reduced dysphoric effect compared to other KOR agonists is not clear, but prior studies suggest that the aversive properties of KOR agonists require p38α MAPK activation through an arrestin-dependent mechanism. To determine whether nalfurafine is a functionally selective KOR agonist, we measured its potency to activate the G protein-dependent early phase of Extracellular Signal-Regulated Kinase (ERK1/2) phosphorylation and the arrestin-dependent late phase of p38 MAPK signaling. Nalfurafine was approximately 250 fold more potent for ERK1/2 activation as compared to p38 MAPK activation in human KOR (hKOR) expressing HEK293 cells, and approximately 20 fold more potent for ERK1/2 activation than p38 activation in rodent KOR (rKOR) expressing HEK293 cells. The 10-fold greater G-bias at the hKOR than rKOR was unexpected, however the G protein biased effect of nalfurafine is consistent with its reduced dysphoric effects in human and rodent models. Although nalfurafine is reported to have low receptor selectivity in radioligand binding assays, its antinociceptive effect was blocked by the selective KOR antagonist norbinaltorphimine. Nalfurafine pretreatment also resulted in a KOR-dependent and mu opioid receptor-independent reduction in scratching induced by 5'-GNTI. These findings suggest that nalfurafine is a functionally selective KOR agonist and that KOR agonists able to selectively activate G protein signaling without activating p38α MAPK may have therapeutic potential as non-dysphoric antipruritic analgesics.

Keywords: Biased signaling; Dysphoria; Kappa opioid receptor; p38 MAPK.

MeSH terms

  • Animals
  • Drug Tolerance
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GTP-Binding Proteins / agonists*
  • GTP-Binding Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Morphinans / pharmacology*
  • Morphinans / therapeutic use
  • Pruritus / drug therapy
  • Pruritus / pathology
  • Receptors, Opioid, kappa / agonists*
  • Receptors, Opioid, kappa / metabolism
  • Receptors, Opioid, mu / metabolism
  • Signal Transduction / drug effects
  • Spiro Compounds / pharmacology*
  • Spiro Compounds / therapeutic use
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Morphinans
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Spiro Compounds
  • TRK 820
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • GTP-Binding Proteins