The activated caveolin-3/μ-opioid receptor complex drives morphine-induced rescue therapy in failing hearts

  • Br J Pharmacol. 2025 Feb;182(3):651-669. doi: 10.1111/bph.17326.
Chengxiao Guo  1  2 ,  Xinxin Pan  1  2 ,  Mengyun Dou  1  2 ,  Juan Wu  3 ,  Xinyu Chen  1  2 ,  Baoli Wang  1  2 ,  Rui Zhu  1  2 ,  Shijin Xu  1  2 ,  Wenyi Peng  1  2 ,  Chao Wu  1  2 ,  Shufang He  1  2 ,  Sihe Zhang  4 ,  Ye Zhang  1  2 ,  Shiyun Jin  1  2
Affiliations
  • 1. Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 2. Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China.
  • 3. Department of Clinical Pharmacology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 4. Department of Cell Biology, School of Medicine, Nankai University, Tianjin, China.
PMID: 39427683 DOI: 10.1111/bph.17326
Abstract

Background and purpose: Opioid analgesics can alleviate ischaemia/reperfusion (I/R) injury in chronic heart failure. However, the underlying mechanisms and targets remain unknown. Here, we investigate if caveolin-3 (Cav3) interacts with μ opioid receptors and if Cav3-μ receptor interactions play a role in morphine-induced cardioprotection in failing hearts.

Experimental approach: Cav3 and μ Receptor Proteins in human and rat heart tissue were determined by western blot, immunofluorescence and co-immunoprecipitation. Methyl-β-cyclodextrin (MβCD), a destroyer of caveolae, and AAV-Cav3 shRNA were used to reduce Cav3 expression in failing rat hearts. CTOP, a specific μ antagonist, was administrated before morphine preconditioning in perfused failing heart models of myocardial I/R injury.

Key results: Levels of Cav3 and μ Receptor Proteins were significantly higher in human and rat myocardial tissues with heart failure than in control tissues. Cav3 and μ receptor expression levels were positively correlated with disease severity. The signal of the cardiac Cav3 protein was colocalized with μ receptor in both the human and rat heart sections. Disruption of caveolae in the failing heart by either MβCD or AAV-Cav3 shRNA significantly inhibits morphine-induced phosphorylation of ERK1/2 and cardioprotection. Administration of CTOP substantially reduced Cav3 expression and morphine-induced cardioprotective effect in heart failure.

Conclusion and implications: Our data suggest that up-regulation of the Cav3/μ receptor complex is critical for morphine protection of the failing heart against I/R injury by regulating the ERK1/2 pathway. The activated Cav3/μ receptor complex is an understudied therapeutic target for opioid treatment of heart failure and ischaemic insult.

Keywords
caveolin‐3; chronic heart failure; ischaemia/reperfusion injury; morphine; μ‐opioid receptor.
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