Peart, Jason N., and Garrett J. Gross. Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors. Am J Physiol Heart Circ Physiol 285: H81-H89, 2003. First published March 13, 2003 10.1152/ajpheart.00985.2002The relative roles of free-radical production, mitochondrial ATP-sensitive K ϩ (mitoKATP) channels and possible receptor cross-talk in both opioid and adenosine A 1 receptor (A1AR) mediated protection were assessed in a rat model of myocardial infarction. Sprague-Dawley rats were subjected to 30 min of occlusion and 90 min of reperfusion. The untreated rats exhibited an infarct of 58.8 Ϯ 2.9% [infarct size (IS)/area at risk (AAR), %] at the end of reperfusion. Pretreatment with either the nonselective opioid receptor agonist morphine or the selective A1AR agonist 2-chloro-cyclopentyladenosine (CCPA) dramatically reduced IS/AAR to 41.1 Ϯ 2.2% and 37.9 Ϯ 5.5%, respectively (P Ͻ 0.05). Protection afforded by either morphine or CCPA was abolished by the reactive oxygen species scavenger N-(2-mercaptopropionyl)glycine or the mitoKATP channel blocker 5-hydroxydecanoate. Both morphine-and CCPA-mediated protection were attenuated by the selective A1AR antagonist 1,3-dipropyl-8-cyclopentylxanthine and the selective ␦ 1-opioid receptor (DOR) antagonist 7-benzylidenealtrexone. Simultaneous administration of morphine and CCPA failed to enhance the infarct-sparing effect of either agonist alone. These data suggest that both DOR and A 1AR-mediated cardioprotection are mitoK ATP and reactive oxygen species dependent. Furthermore, these data suggest that there are converging pathways and/or receptor cross-talk between A 1AR-and DOR-mediated cardioprotection.reactive oxygen species; ATP-sensitive potassium channel ADENOSINE AND ADENOSINE RECEPTOR agonists have been shown to protect the myocardium from ischemia-reperfusion injury (48-50). Earlier research focused on the role of the A 1 adenosine receptor (A 1 AR); however, recent evidence suggests that the A 3 adenosine receptor (A 3 AR) may also afford cardioprotection (29,48,50,63). Both A 1 AR and A 3 AR activation may be important triggers of both early preconditioning (EPC) and delayed preconditioning (DPC) (4, 58, 67); however, separate signaling pathways may be involved (38). Activation of opioid receptors has also been demonstrated to trigger EPC and DPC, primarily through the ␦-opioid receptor (DOR) (45,47,54). Indeed, blockade of the DOR abrogates the infarct-sparing effect of ischemic preconditioning (55).The signal-transduction pathways responsible for both DOR and A 1 /A 3 AR-mediated cardioprotection appear to be similar. A 1 ARs and A 3 ARs activate phospholipase C and phospholipase D, respectively (44). Activation of the DOR has also been reported to activate phospholipase C (33, 41). Activation of phospholipase C or phospholipase D results in translocation of specific isoforms of protein kinase C (PKC) (59, 61). Translocation of PKC may then lead to opening of a mitochondrial ATP-sensitive K ϩ (K ATP ) chan...