Authors: Pan X. et al.
Anesthesia & Analgesia, October 2025. DOI: 10.1213/ANE.0000000000007290
This translational study investigated the role of delta-opioid receptor (DOR) signaling in myocardial protection during ischemia/reperfusion (I/R) injury in the setting of chronic heart failure. Patients with heart failure are highly susceptible to perioperative myocardial damage, and evidence from animal models has implicated DOR activation in cardioprotection, but its molecular mechanisms and clinical relevance remain unclear.
The researchers measured DOR protein expression in myocardial tissue from both humans and rats with chronic heart failure, finding significant upregulation compared with normal hearts—1.4-fold higher in human samples and 2.3-fold higher in rat models. Moreover, DOR expression correlated with heart failure severity in both species. To evaluate function, the investigators used an isolated postinfarction rat heart model, performing morphine preconditioning (MPC) before inducing I/R injury. Some rats received the DOR antagonist naltrindole (NTD) or the JAK2 inhibitor AG490 to block pathway activation.
Morphine preconditioning markedly reduced infarct size, improved cardiac function, and decreased apoptosis in failing rat hearts. However, when DOR or JAK2 was inhibited, these protective effects were abolished. Specifically, NTD increased infarct size from 15% to 31% and nearly doubled cardiomyocyte apoptosis. Both NTD and AG490 significantly reduced phosphorylation of STAT3—a downstream effector of JAK2—and decreased the anti-apoptotic Bcl-2/Bax ratio, indicating suppression of the protective JAK2/STAT3 signaling cascade.
The findings demonstrate that DOR is upregulated in failing hearts and plays a crucial role in mediating morphine-induced cardioprotection through the JAK2/STAT3 pathway. These results suggest that enhancing DOR signaling may represent a therapeutic strategy to reduce ischemic injury during surgery in patients with chronic heart failure.
What You Should Know
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DOR expression is increased in both human and rat hearts with chronic heart failure.
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DOR activation by morphine preconditioning protects failing hearts from ischemia/reperfusion injury.
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Blocking DOR or JAK2/STAT3 signaling eliminates morphine’s cardioprotective effects.
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The DOR–JAK2/STAT3 axis may be a future therapeutic target to protect vulnerable hearts during surgery.
Thank you to Anesthesia & Analgesia for publishing this study revealing a mechanistic link between delta-opioid receptor signaling and cardioprotection in chronic heart failure.