Morphine Induces Desensitization of Insulin Receptor Signaling

Cell Signaling Technology, Inc., Beverly, Massachusetts, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 10/2003; 23(17):6255-66. DOI: 10.1128/MCB.23.17.6255-6266.2003
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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.

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Available from: Chris Evans, Jun 14, 2014
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    • "We also observed that IL-1␤ interferes by the same mechanism with signaling of another neurotrophic factor NT-3 that under the experimental conditions exerted its action primarily through TrkC activation (manuscript in preparation). Scaffolding proteins are also critically involved in the regulation of insulin and IGF-1 signaling in both neurons and non-neural, peripheral tissues (Garcia-Galloway et al., 2003; Li et al., 2003; Venters et al., 2000; Zick, 2001). In neurons, the wide-ranging nature of regulation at the level of the docking proteins, such as IRS-1, is indicated by the observation that interference at the docking site is not restricted to the effect of IL-1␤ on neurotrophin signaling in cerebral cortical cells. "
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