Morphine cardioprotection

On the other hand, a number of studies have shown that morphine and opioid peptides could have cardioprotective effects toward ischemic processes and may be able to reduce the size of infarct [72,73]. These effects seem to involve the activation of delta opioid receptors, the localization of which remains unknown. In addition, enkephalin-degrading enzyme inhibitors, such as acetorphan and, particularly, RB 101, have also been demonstrated to decrease the susceptibility to the arrhythmogenic action of epinephrine. Thus RB 101 completely prevented the ventricular tachycardia, fibrillation, and repetitive ventricular extrasystoles induced by epinephrine (Maslov et al., unpublished data). These effects were reversed by the selective delta antagonist ICI 174,864. 

Interestingly, morphine is primarily considered to have selective effects on the mu opioid receptor for its analgesic effects however, there is also evidence that it possesses effects on delta or kappa opioid receptors and that crosstalk can occur between mu and delta opioid receptors [44]. To test the hypothesis that the cardioprotective effects of IPC and morphine were acting via a delta opioid receptor, Schultz et al. [45] administered the selective delta receptor antagonist naltrindole to rats prior to IPC or morphine infusion. In both instances, the cardioprotective effects of morphine and IPC were completely abolished at a dose of naltrindole that had no effect by itself on infarct size in nonpreconditioned rat hearts. These data clearly suggest that both IPC and morphine are exerting their cardioprotective effects via the delta opioid receptor in the intact rat heart. 

To further address the signaling pathways involved in opioid-induced cardioprotection, Schultz et al. [55] determined the involvement of a Gi/o protein in mediating delta -induced cardioprotection produced by the selective nonpeptide delta opioid agonist, TAN-67. Pretreatment with pertussis toxin for 48 h prior to TAN-67 administration completely blocked its cardioprotective elfect as well as that to IPC, suggesting that a Gi/o protein is intimately involved in the cardioprotection produced by these two interventions. Subsequently, Miki et al. [56] found that morphine produced a cardioprotective elfect in isolated rabbit hearts which was blocked by pretreatment with chelerythrine, a protein kinase C (PKC) inhibitor at a concentration that had no elfect on infarct size in the absence of morphine. More recently, Fryer et al. [57] extended these findings to the intact rat heart and showed that the protective elfect of TAN-67 to reduce infarct size was blocked by chelerythrine and GF 109203X, two selective PKC inhibitors with different binding sites, and that TAN-67 produced a selective translocation of the PKC-delta isoform to the mitochondria. 

Endogenous opioid peptides are increased in myocardial ischemia. Their effect is mediated through presynaptic and postsynaptic mechanisms. Opioids limit the release of stimulating catecholamines by its presynaptic action while opioid receptor agonists act via Gi -linked pathways postsynaptically and alter myocardial channel activity and intracellular activities of protein kinases. Table 1. Figure 10. Blockade of 5 and x-opioid receptors reduced the tolerance of the isolated rabbit heart to ischemia and reperfusion.105 Furthermore, blockade of 8-opioid receptor abrogated the ischemic preconditioning mediated cardioprotective effect while activation of 8-opioid receptor by morphine decreased infarct size and apoptosis in a rabbit model of coronary occlusion and reperfusion.106... 

J. N. Peart, G. J. Gross, Morphine-tolerant mice exhibit a profound and persistant cardioprotective phenotype, Circulation 109, 1219-22 (2004). 

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