Mu-opioid agonist inhibition of kappa-opioid receptor-stimulated extracellular signal-regulated kinase phosphorylation is dynamin-dependent in C6 glioma cells

J Neurochem. 2000 Feb;74(2):574-81. doi: 10.1046/j.1471-4159.2000.740574.x.


In previous studies we found that mu-opioids, acting via mu-opioid receptors, inhibit endothelin-stimulated C6 glioma cell growth. In the preceding article we show that the kappa-selective opioid agonist U69,593 acts as a mitogen with a potency similar to that of endothelin in the same astrocytic model system. Here we report that C6 cell treatment with mu-opioid agonists for 1 h results in the inhibition of kappa-opioid mitogenic signaling. The mu-selective agonist endomorphin-1 attenuates kappa-opioid-stimulated DNA synthesis, phosphoinositide turnover, and extracellular signal-regulated kinase phosphorylation. To investigate the role of receptor endocytosis in signaling, we have examined the effects of dynamin-1 and its GTPase-defective, dominant suppressor mutant (K44A) on opioid modulation of extracellular signal-regulated kinase phosphorylation in C6 cells. Overexpression of dynamin K44A in C6 cells does not affect kappa-opioid phosphorylation of extracellular signal-regulated kinase. However, it does block the inhibitory action on kappa-opioid signaling mediated by the kappa-opioid receptor. Our results are consistent with a growing body of evidence of the opposing actions of mu- and kappa-opioids and provide new insight into the role of opioid receptor trafficking in signaling.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzeneacetamides*
  • DNA / antagonists & inhibitors
  • DNA / biosynthesis
  • Dynamin I
  • Dynamins
  • Endothelins / pharmacology
  • GTP Phosphohydrolases / physiology*
  • Glioma / metabolism
  • Glioma / pathology
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Morphine / pharmacology
  • Oligopeptides / pharmacology
  • Phosphatidylinositols / antagonists & inhibitors
  • Phosphatidylinositols / metabolism
  • Phosphorylation / drug effects
  • Pyrrolidines / metabolism
  • Pyrrolidines / pharmacology
  • Rats
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / physiology*
  • Receptors, Opioid, mu / agonists*
  • Receptors, Opioid, mu / physiology
  • Tumor Cells, Cultured


  • Benzeneacetamides
  • Endothelins
  • Oligopeptides
  • Phosphatidylinositols
  • Pyrrolidines
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • endomorphin 1
  • endomorphin 2
  • Morphine
  • DNA
  • Mitogen-Activated Protein Kinases
  • Dynamin I
  • GTP Phosphohydrolases
  • Dynamins
  • U 69593