Cardioprotection heart opioid receptors

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. 

A final series of experiments were performed in our laboratory to determine the role of the sarcolemmal KATP (sarcKATP) channel and the mitoKATP channel in TAN-67-induced cardioprotection in the intact rat heart [60]. Administration of the selective sarcKATP inhibitor HMR 1098 prior to TAN-67 did not significantly block the cardioprotection produced by TAN-67. Elowever, pretreatment with 5HD, the selective mitoKATP channel blocker, completely abolished TAN-67-induced cardioprotection. These data clearly suggest that delta, opioid receptor-induced infarct size reduction is mediated by the mito KATP channel in rats. A summary of the major signaling components involved in acute opioid-induced preconditioning is schematically depicted in Figure 2. 

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... 

Opioid receptors play an important role in the cardioprotective effect of ischaemic preconditioning in the rat heart (Schultz et al. 1998). 

The NEP and APN levels are moderate on heart [74,75] while the concentration of both peptidases is higher in vascular endothelium or vagus nerve terminals [76-78]. However, the mechanisms and site of action (central or peripheral) involved in the cardioprotective effects of the endogenous opioid peptides remain unknown. Nevertheless, owing to their lack of narcotic effects, inhibition of endogenous enkephalin catabolism and subsequent stimulation of delta receptor could have interesting clinical applications in the cardiovascular domain. 

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