Morphine induces desensitization of insulin receptor signaling

Mol Cell Biol. 2003 Sep;23(17):6255-66. doi: 10.1128/mcb.23.17.6255-6266.2003.

Abstract

Morphine analgesia is mediated principally by the micro -opioid receptor (MOR). Since morphine and other opiates have been shown to influence glucose homeostasis, we investigated the hypothesis of direct cross talk between the MOR and the insulin receptor (IR) signaling cascades. We show that prolonged morphine exposure of cell lines expressing endogenous or transfected MOR, IR, and the insulin substrate 1 (IRS-1) protein specifically desensitizes IR signaling to Akt and ERK cascades. Morphine caused serine phosphorylation of the IR and impaired the formation of the signaling complex among the IR, Shc, and Grb2. Morphine also resulted in IRS-1 phosphorylation at serine 612 and reduced tyrosine phosphorylation at the YMXM p85-binding motifs, weakening the association of the IRS-1/p85 phosphatidylinositol 3-kinase complex. However, the IRS-1/Grb2 complex was unaffected by chronic morphine treatment. These results suggest that morphine attenuates IR signaling to Akt by disrupting the IRS-1-p85 interaction but inhibits signaling to ERK by disruption of the complex among the IR, Shc, and Grb2. Finally, we show that systemic morphine induced IRS-1 phosphorylation at Ser612 in the hypothalamus and hippocampus of wild type, but not MOR knockout, mice. Our results demonstrate that opiates can inhibit insulin signaling through direct cross talk between the downstream signaling pathways of the MOR and the IR.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Adaptor Proteins, Vesicular Transport*
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Binding Sites
  • Brain / drug effects
  • Brain / metabolism
  • CHO Cells
  • Cricetinae
  • Enzyme Inhibitors / pharmacology
  • GRB2 Adaptor Protein
  • Insulin / metabolism
  • Insulin / pharmacology
  • Insulin Receptor Substrate Proteins
  • Male
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism
  • Morphine / pharmacology*
  • Phosphatidylinositol 3-Kinases / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / drug effects
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases*
  • Proteins / drug effects
  • Proteins / metabolism
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptor, Insulin / drug effects*
  • Receptor, Insulin / metabolism
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / genetics
  • Receptors, Opioid, mu / metabolism*
  • Serine / metabolism
  • Shc Signaling Adaptor Proteins
  • Signal Transduction / drug effects*
  • Src Homology 2 Domain-Containing, Transforming Protein 1

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Analgesics, Opioid
  • Enzyme Inhibitors
  • GRB2 Adaptor Protein
  • Grb2 protein, mouse
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Phosphoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Opioid, mu
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Serine
  • Morphine
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases