Trigger and mediation phase of chronic opioid preconditioning are mediated via divergent pathways

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Title Trigger and mediation phase of chronic opioid preconditioning are mediated via divergent pathways
Author Peart, Jason Nigel John; Headrick, John Patrick; Gross, Garrett J.
Journal Name Journal of Molecular and Cellular Cardiology
Editor Dr. R. A. Walsh (Editor-in-Chief)
Year Published 2006
Place of publication United Kingdom
Publisher Academic Press
Abstract Chronic opioid preconditioning confers a pronounced and prolonged cardioprotective phenotype, existing at least 24 hours beyond opioid drug withdrawal. This study aims to delineate both the trigger and mediation phase of this cardioprotective state. To this end, we employed an isolated, perfused murine heart model of ischemia reperfusion. Following 25 min ischemia and 45 min reperfusion, placebo-treated hearts exhibited a pronounced degree of contractile dysfunction (EDP, 32 ± 3 mmHg; RPP, 40 ± 4% baseline). In stark contrast, chronic morphine-treated (CMP) hearts (75 mg pellet, 5 days) displayed a significant recovery of RPP (83 ± 3%) and an almost complete return of EDP. As expected, co-administration of opioid antagonist, naloxone, via osmotic minipump for 5 days prevented the initiation (“trigger” phase), and thus, protection of CMP (RPP, 46 ± 2%). Moreover, 5 day infusion of the primary morphine metabolites, morphine-3-glucuronide and morphine-6-glucuronide, failed to induced any form of cardioprotection, suggesting that neither the mu-opioid receptor nor metabolites are involved. Concurrent infusion of the PKA inhibitor, PKI, during the activation phase failed to abolish the CMP-mediated protection (69 ± 5% RPP). Interestingly, naloxone, administered pre-and post-ischemia (the “mediation” phase), following 5 days of morphine exposure, failed to modify the CMP-induced phenotype, while PKI completely abolished CMP protection, with no effect on placebo-treated hearts. These data offer an insight into the genesis of CMP in the murine heart, whereby the trigger phase is opioid receptor-dependent and PKA-independent, whereas the mediation phase is independent of opioid receptor activation and is PKA-dependent.
Peer Reviewed No
Published Yes
Publisher URI
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Volume 41
Issue Number 4
Page from 743
Page to 744
ISSN 0022-2828
Date Accessioned 2009-04-06
Language en_AU
Research Centre Menzies Health Institute Qld; Heart Foundation Research Centre
Faculty Griffith Health Faculty
Subject Cardiology (incl Cardiovascular Diseases)
Publication Type Letter or Note
Publication Type Code c3

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