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Molecular and Cellular Biology, September 2003, p. 6255-6266, Vol. 23, No. 17
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.17.6255-6266.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Morphine Induces Desensitization of Insulin Receptor Signaling

Yu Li,1 Shoshana Eitan,2 Jiong Wu,1 Christopher J. Evans,2 Brigitte Kieffer,3 Xiaojian Sun,4 and Roberto D. Polakiewicz1*

Cell Signaling Technology, Inc., Beverly, Massachusetts,1 Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute, University of California, Los Angeles, Los Angeles, California,2 IGBMC UMR 7104, Parc d'Innovation, 67404 Illkirch Cedex, France,3 Endocrinology Division, University of Vermont College of Medicine, Burlington, Vermont4

Received 14 April 2003/ Returned for modification 21 May 2003/ Accepted 5 June 2003

Morphine analgesia is mediated principally by the µ-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.

* Corresponding author. Mailing address: Cell Signaling Technology, Inc., 166B Cummings Center, Beverly, MA 01915. Phone: (978) 867-2369. Fax: (978) 867-2402. E-mail: rpolakiewicz{at}cellsignal.com.

Molecular and Cellular Biology, September 2003, p. 6255-6266, Vol. 23, No. 17
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.17.6255-6266.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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