Morphine exacerbates myocardial ischemia/reperfusion injury by overactivation of NLRP3 inflammasome via suppression of p-TRPV1 in male rats

Abstract

The pathology of early MIRI (myocardial ischemia/reperfusion injury) is characterized by sterile inflammation. TRPV1 (transient receptor potential vanilloid 1) and NLRP3 inflammasome sense harmful stimulation and modulate inflammation in cardiomyocytes. We recently demonstrated morphine downregulated p-TRPV1 and exacerbated MIRI. In this study, we investigate the potential crosstalk of TRPV1 and NLRP3 inflammasome activities and a potential modulatory effect of morphine on the interaction in MIRI. In vivo and in vitro experiments were conducted. Coding RNA and pharmacological modulations were used in this study. We found MI/R (myocardial ischemia and reperfusion) upregulated p-TRPV1 without change in expression of NLRP3 inflammasome. Giving morphine during myocardial ischemia increased ventricular arrythmia, reduced heart rate and +dp/dt Max in reperfusion, and increased serum cTnI (cardiac troponin I) and infarct size. Suppression of p-TRPV1 but enhancement of NLRP3 inflammasome activity at the end of MI/R were detected. The alterations were reversed by an opioid μ-receptor antagonist or a NLRP3 inhibitor. Giving TRPV1 antagonist or knockdown of TRPV1 in cultured primary cardiomyocytes inhibited p-TRPV1 but increased NLRP3 inflammasome and the downstream cytokines and LDH (lactate dehydrogenase) in the supernatants. Conversely, treatment with capsaicin (a TRPV1 agonist) or upregulation of TRPV1 via transfection of Ad-TRPV1 elevated p-TRPV1 and reduced NLRP3 and LDH. The results indicated morphine treatment during myocardial ischemia aggravates MIRI by increasing the activity of NLRP3 inflammasome, via suppressing the inhibitory effect of p-TRPV1 on NLRP3 inflammasome. Targeting the signal chain of opioid μ-receptor agonist/TRPV1/NLRP3 inflammasome may find a novel way to improve MIRI.