Trigger and mediation phase of chronic opioid preconditioning are mediated via divergent pathways

Abstract

Chronic opioid preconditioning confers a pronounced and prolonged cardioprotective phenotype, existing at least 24 hours beyond opioid drug withdrawal. This study aims to delineate both the trigger and mediation phase of this cardioprotective state. To this end, we employed an isolated, perfused murine heart model of ischemia reperfusion. Following 25 min ischemia and 45 min reperfusion, placebo-treated hearts exhibited a pronounced degree of contractile dysfunction (EDP, 32 ± 3 mmHg; RPP, 40 ± 4% baseline). In stark contrast, chronic morphine-treated (CMP) hearts (75 mg pellet, 5 days) displayed a significant recovery of RPP (83 ± 3%) and an almost complete return of EDP. As expected, co-administration of opioid antagonist, naloxone, via osmotic minipump for 5 days prevented the initiation (“trigger” phase), and thus, protection of CMP (RPP, 46 ± 2%). Moreover, 5 day infusion of the primary morphine metabolites, morphine-3-glucuronide and morphine-6-glucuronide, failed to induced any form of cardioprotection, suggesting that neither the mu-opioid receptor nor metabolites are involved. Concurrent infusion of the PKA inhibitor, PKI, during the activation phase failed to abolish the CMP-mediated protection (69 ± 5% RPP). Interestingly, naloxone, administered pre-and post-ischemia (the “mediation” phase), following 5 days of morphine exposure, failed to modify the CMP-induced phenotype, while PKI completely abolished CMP protection, with no effect on placebo-treated hearts.

These data offer an insight into the genesis of CMP in the murine heart, whereby the trigger phase is opioid receptor-dependent and PKA-independent, whereas the mediation phase is independent of opioid receptor activation and is PKA-dependent.