enkephalin--ala(2)-mephe(4)-gly(5)- and Heart-Failure

The therapeutic potential of cardiac μ-opioid receptors in ischaemia-reperfusion (I/R) injury during opioid-modulating diseases, such as heart failure, is unknown. We aimed to explore the changes of cardiac μ-opioid receptor expression during heart failure, and its role in opioid-induced cardioprotection.. Cardiac μ-opioid receptor mRNA concentrations were 3.2 times elevated in DOX-treated rats compared with NS rats, while cardiac μ-opioid receptor protein concentrations showed 6.1- and 3.5-fold increases in DOX-treated and post-infarcted rats, respectively. DAMGO reduced I/R-caused infarct size, expressed as the ratio of area at risk, from 0.50 (0.04) to 0.25 (0.03) in failing rat hearts, but had no effect on infarct size in control hearts. DAMGO promoted phosphorylation of ERK and glycogen synthase kinase (GSK)-3β only in failing hearts. DAMGO-mediated cardioprotection was blocked by an ERK inhibitor. The μ-opioid receptor antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) prevented morphine- and remifentanil-induced cardioprotection and phosphorylation of ERK and GSK-3β in failing hearts. In contrast, δ- and κ-opioid receptor selective antagonists were less potent than CTOP in the failing hearts.. Cardiac μ-opioid receptors were substantially up-regulated during heart failure, which increased DAMGO-induced cardioprotection against I/R injury.

Topics: Analgesics, Opioid; Animals; Antibiotics, Antineoplastic; Cardiotonic Agents; Chronic Disease; Coronary Vessels; Doxorubicin; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Glycogen Synthase Kinase 3; Heart; Heart Failure; Ligation; Male; MAP Kinase Signaling System; Morphine; Myocardial Infarction; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Remifentanil