The Role of Delta-Opioid Receptor in Mediating the Cardioprotective Effects of Morphine Preconditioning via the JAK2/STAT3 Pathway in a Failing Heart.

Background: Failing heart is more likely to suffer from myocardial ischemia/reperfusion (I/R) injury. This poses a great challenge for anesthesiologists in managing patients with heart failure during major surgery. Evidence from animal studies suggests that the delta-opioid receptor (DOR) contributes to alleviating acute myocardial injuries. However, little is known regarding the cardioprotective effects of cardiac DOR in patients with chronic heart failure. This study aimed to examine DOR expression in failing hearts and explore how DOR regulates the Janus kinase signal transducer and activator of the transcription-3 (JAK/STAT3) pathway to mediate morphine-induced cardio protection in heart failure.

Methods: We measured the DOR protein levels in human and rat heart tissues with chronic heart failure. To investigate the cardioprotective role of DOR, we administered the DOR-specific antagonist, naltrindole (NTD), and JAK2 inhibitor, AG490, before morphine preconditioning (MPC) in an isolated perfusion model of myocardial I/R injury in postinfarcted failing rat heart. We examined the infarct size, cardiac enzymes, cardiac function, cardiomyocyte apoptosis, apoptosis-related proteins, and STAT3 phosphorylation in the heart.

Results: The protein levels of DOR were significantly elevated in the myocardial tissues of humans and rats with chronic heart failure, by 1.4-fold (mean difference 0.41; 95% confidence interval [CI], 0.04-0.78; P = .032) and 2.3-fold (mean difference 1.26; 95% CI, 0.25-2.28; P = .009), respectively, compared to control tissues. Disease severity positively correlated with DOR expression (human: R2 = 0.316, P = .004; rat: R2 = 0.871, P = .021). Blocking DOR substantially reversed the cardioprotective effects of MPC in postinfarcted rat hearts, increasing the mean (standard deviation) percentage of infarct size from 15.0 (3.9)% to 30.8 (7.7)% (P < .001). Similarly, AG490 inhibited MPC restoration of cardiomyocyte apoptosis (33.3 [4.2]% vs 16.6 [3.4]%; P < .001). Both NTD and AG490 markedly suppressed STAT3 phosphorylation by 60.1% (mean difference 0.60; 95% CI, 0.27-0.93; P = .002) and 44.1% (mean difference 0.44; 95% CI, 0.06-0.83; P = .027), respectively, and also lowered the Bcl-2/Bax ratio by 85.5% (mean difference 0.86; 95% CI, 0.28-1.43; P = .006) and 68.2% (mean difference 0.68; 95% CI, 0.51-0.85; P < .001) respectively in heart tissues at the end of reperfusion.

Conclusions: DOR protein levels increased in failing hearts of both humans and rats. Blocking cardiac DOR selectively reduced morphine-induced cardio protection by inhibiting the JAK2/STAT3 pathway. These findings indicate that cardiac DOR is a potential therapeutic target for protecting against heart failure due to I/R injury.