Heterologous mu-opioid receptor adaptation by repeated stimulation of kappa-opioid receptor: up-regulation of G-protein activation and antinociception

J Neurochem. 2003 Jun;85(5):1171-9. doi: 10.1046/j.1471-4159.2003.01754.x.


The present study was designed to investigate the effect of repeated administration of a selective kappa-opioid receptor agonist (1S-trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride [(-)U-50,488H] on antinociception and G-protein activation induced by mu-opioid receptor agonists in mice. A single s.c. injection of (-)U-50,488H produced a dose-dependent antinociception, and this effect was reversed by a selective kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI). Furthermore, a single s.c. pre-treatment with (-)U-50,488H had no effect on the mu-opioid receptor agonist-induced antinociception. In contrast, repeated s.c. administration of (-)U-50,488H resulted in the development of tolerance to (-)U-50,488H-induced antinociception. Under these conditions, we demonstrated here that repeated s.c. injection of (-)U-50,488H significantly enhanced the antinociceptive effect of selective mu-opioid receptor agonists endomorphin-1, endomorphin-2 and [d-Ala2,N-MePhe4,Gly-ol5] enkephalin (DAMGO). Using the guanosine-5'-o-(3-[35S]thio) triphosphate ([35S]GTP gamma S) binding assay, we found that (-)U-50,488H was able to produce a nor-BNI-reversible increase in [35S]GTP gamma S binding to membranes of the mouse thalamus, which has a high level of kappa-opioid receptors. Repeated administration of (-)U-50,488H caused a significant reduction in the (-)U-50,488H-stimulated [35S]GTP gamma S binding in this region, whereas chronic treatment with (-)U-50,488H exhibited the increase in the endomorphin-1-, endomorphin-2- and DAMGO-stimulated [35S]GTP gamma S bindings in membranes of the thalamus and periaqueductal gray. These results suggest that repeated stimulation of kappa-opioid receptors leads to the heterologous up-regulation of mu-opioid receptor functions in the thalamus and periaqueductal gray regions, which may be associated with the supersensitivity of mu-opioid receptor-mediated antinociception.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
  • Adaptation, Physiological / physiology*
  • Analgesics / pharmacology
  • Analgesics, Non-Narcotic / pharmacology
  • Analgesics, Opioid / pharmacology
  • Animals
  • Binding, Competitive / drug effects
  • Cell Membrane / chemistry
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Dose-Response Relationship, Drug
  • Drug Tolerance
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • GTP-Binding Proteins / metabolism*
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Guanosine 5'-O-(3-Thiotriphosphate) / pharmacokinetics
  • Male
  • Medulla Oblongata / chemistry
  • Mice
  • Mice, Inbred ICR
  • Oligopeptides / pharmacology
  • Pain Measurement / drug effects
  • Pons / chemistry
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / physiology*
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / physiology*
  • Thalamus / chemistry
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • Analgesics
  • Analgesics, Non-Narcotic
  • Analgesics, Opioid
  • Oligopeptides
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • endomorphin 1
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
  • GTP-Binding Proteins