Sustained ligand-activated preconditioning via δ-opioid receptors

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Title Sustained ligand-activated preconditioning via δ-opioid receptors
Author Peart, Jason Nigel John; See Hoe, Louise Elizabeth; Gross, Garrett J.; Headrick, John Patrick
Journal Name Journal of Pharmacology and Experimental Therapeutics
Year Published 2011
Place of publication United States
Publisher American Society for Pharmacology and Experimental Therapeutics
Abstract We have previously described novel cardioprotection in response to sustained morphine exposure, efficacious in young to aged myocardium and mechanistically distinct from conventional opioid or preconditioning (PC) responses. We further investigate opioid-dependent sustained ligand-activated preconditioning (SLP), assessing duration of protection, opioid receptor involvement, additivity with conventional responses, and signaling underlying preischemic induction of the phenotype. Male C57BL/6 mice were treated with morphine (75-mg subcutaneous pellet) for 5 days followed by morphine-free periods (0, 3, 5, or 7 days) before ex vivo assessment of myocardial tolerance to 25-min ischemia/45-min reperfusion. SLP substantially reduced infarction (by ∼50%) and postischemic contractile dysfunction (eliminating contracture, doubling force development). Cardioprotection persisted for 5 to 7 days after treatment. SLP was induced specifically by δ-receptor and not κ- or μ-opioid receptor agonism, was eliminated by δ-receptor and nonselective antagonism, and was additive with adenosinergic but not acute morphine- or PC-triggered protection. Cotreatment during preischemic morphine exposure with the phosphoinositide-3 kinase (PI3K) inhibitor wortmannin, but not the protein kinase A (PKA) inhibitor myristoylated PKI-(14-22)-amide, prevented induction of SLP. This was consistent with shifts in total and phospho-Akt during the induction period. In summary, data reveal that SLP triggers sustained protection from ischemia for up to 7 days after stimulus, is δ-opioid receptor mediated, is induced in a PI3K-dependent/PKA-independent manner, and augments adenosinergic protection. Mechanisms underlying SLP may be useful targets for manipulation of ischemic tolerance in young or aged myocardium.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1124/jpet.110.172593
Copyright Statement Self-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the author[s] for more information.
Volume 336
Issue Number 1
Page from 274
Page to 281
ISSN 0022-3565
Date Accessioned 2011-04-29
Language en_AU
Research Centre Griffith Health Institute; Heart Foundation Research Centre
Faculty Griffith Health Faculty
Subject Basic Pharmacology; Cardiology (incl Cardiovascular Diseases)
URI http://hdl.handle.net/10072/40168
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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