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Abstract: Aims: This study aims to investigate the role of peripheral δ2 opioid receptors in cardiac tolerance to ischemia/reperfusion injury and to examine the contribution of PKC, TK, KATP channels and the autonomic nervous system in δ2 cardioprotection. Main methods: Deltorphin II and various inhibitors were administered in vivo prior to coronary artery occlusion and reperfusion in a rat model. The animals were monitored for the development of arrhythmias, infarct development and the effects of selected inhibitors. Key findings: Pretreatment with peripheral and δ2 specific opioid receptor (OR) antagonists completely abolished the cardioprotective effects of deltorphin II. In contrast, the selective δ1 OR antagonist 7-benzylidenenaltrexone (BNTX) had no effect. The protein kinase C (PKC) inhibitor chelerythrine and the NO-synthase inhibitor L-NAME (N-nitro-l-arginine methyl ester) also reversed both deltorphin II effects. The nonselective ATP-sensitive K+ (KATP) channel inhibitor glibenclamide and the selective mitochondrial KATP channel inhibitor 5-hydroxydecanoic acid only abolished the infarct-sparing effect of deltorphin II. Inhibition of tyrosine kinase (TK) with genistein, the ganglion blocker hexamethonium and the depletion of endogenous catecholamine storage with guanethidine reversed the antiarrhythmic action of deltorphin II but did not change its infarct-sparing action. Significance: The cardioprotective mechanism of deltorphin II is mediated via stimulation of peripheral δ2 opioid receptors. PKC and NOS are involved in both its infarct-sparing and antiarrhythmic effects. Infarct-sparing is dependent upon mitochondrial KATP channel activation while the antiarrhythmic effect is dependent upon TK activation. Endogenous catecholamine depletion reduced antiarrhythmic effects but did not alter the infarct-sparing effect of deltorphin II. [Copyright &y& Elsevier]