Upregulation of the cAMP pathway as a mechanism of opiate tolerance and dependence. Opiates acutely inhibit the functional activity of the cAMP pathway.

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Upregulation of the cAMP pathway as a mechanism of opiate tolerance and dependence. Opiates acutely inhibit the functional activity of the cAMP pathway (eg, as indicated by cellular levels of cAMP or cAMP-dependent protein phosphorylation). With continued opiate exposure, functional activity of the cAMP pathway gradually recovers and increases far above control levels on removal of the opiate (eg, by administration of the opioid receptor antagonist, naloxone). These changes in the functional state of the cAMP pathway are mediated via the induction of adenylyl cyclase and protein kinase A (PKA) in response to chronic opiate administration. Induction of these enzymes accounts for the gradual recovery in the functional activity of the cAMP pathway seen during chronic opiate exposure (tolerance and dependence) and for the activation of the cAMP pathway seen on removal of the opiate (withdrawal). (Reproduced with permission from Nestler EJ. Historical review: Molecular and cellular mechanisms of opiate and cocaine addiction. Trends Pharmacol Sci. 2004;25(4):210–218.) Source: Reinforcement and Addictive Disorders, Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3e Citation: Nestler EJ, Hyman SE, Holtzman DM, Malenka RC. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3e; 2015 Available at: https://neurology.mhmedical.com/DownloadImage.aspx?image=/data/books/1204/nes003_fig_16-05.png&sec=72650574&BookID=1204&ChapterSecID=72650484&imagename= Accessed: October 20, 2017 Copyright © 2017 McGraw-Hill Education. All rights reserved