Sustained ligand-activated preconditioning via δ-opioid receptors. J Pharmacol Exp Ther 2011 Jan;336(1):274-81
Date
10/16/2010Pubmed ID
20947639Pubmed Central ID
PMC3014309DOI
10.1124/jpet.110.172593Scopus ID
2-s2.0-78650777210 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
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.
Author List
Peart JN, Hoe LE, Gross GJ, Headrick JPMESH terms used to index this publication - Major topics in bold
AnimalsDelayed-Action Preparations
Ischemic Preconditioning, Myocardial
Ligands
Male
Mice
Mice, Inbred C57BL
Morphine
Myocardial Contraction
Receptors, Opioid, delta
Time Factors
