Ischemic Preconditioning and Morphine-induced Cardioprotection Involve the Delta (δ)-opioid Receptor in the Intact Rat Heart

doi:10.1006/jmcc.1997.0454

Journal of Molecular and Cellular Cardiology

Volume 29, Issue 8, August 1997, Pages 2187-2195

https://doi.org/10.1006/jmcc.1997.0454 Get rights and content

Abstract

Several investigators have demonstrated that the opioid pathway is involved in tissue preservation during hypoxia or ischemia and that this protection is mediated via the delta (δ)-opioid receptor. Subsequently, we have shown that opioid receptors are involved in ischemic preconditioning (PC) in the rat heart and that morphine produces a cardioprotective effect; however, the class of opioid receptors involved in mediating these effects is still unknown. Therefore, the purpose of the present study was to test the hypothesis that ischemia- and morphine-induced cardioprotection are mediated via stimulation of theδ-opioid receptor in the rat heart. Anesthetized, open-chest Wistar rats were subjected to one of six protocols. The control group was subjected to 30 min of occlusion and 2 h of reperfusion. Ischemic PC was elicited by three 5 min occlusion periods interspersed with 5 min of reperfusion. Morphine-induced cardioprotection was produced by three 5 min morphine infusions (100μg/kg/infusion, i.v.) interspersed with a 5-min drug-free period. To determine if theδ-opioid receptor has a role in ischemic PC and morphine-induced cardioprotection, naltrindole (NTI), a selectiveδ-opioid receptor antagonist, was utilized. NTI (5 mg/kg, i.v.) was given 10 min prior to ischemic PC (NTI+PC) or morphine infusion (NTI+MOR). Also, NTI (5 mg/kg, i.v.) was given 10 min before the 30 min occlusion period in untreated rats. Infarct size (IS) as a percent of the area at risk (AAR) was determined by 2,3,5-triphenyltetrazolium chloride staining. Ischemic PC and morphine infusions resulted in similar reductions in IS/AAR from 51±4 to 11±3 and 15±4% (*P<0.05), respectively. NTI completely abolished the cardioprotective effect induced by ischemia and morphine. The results of the present study suggests a role ofδ;-opioid receptors in ischemic PC or morphine-induced myocardial protection in the rat.

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Citation Excerpt :
Opioids have been shown to help the myocardium recovering from the fatal insults of acute myocardial ischemia and reperfusion since late 1980's (Dvortsin and Shatalov, 1989). Laboratory experiments and clinical reports present that giving morphine or other opioids led to cardio-protection in the intact experimental animals (Schultz et al., 1995, 1997a, 1997b; Zhang et al., 2004), in isolated perfused heart of laboratory animals (Karck et al., 1998; Kevelaitis et al., 1999; Bolling et al., 2001; Gross et al., 2004, 2009; Chun et al., 2011) and in patients or human cardiomyocytes (Xu et al., 2009; Wong et al., 2010; Greco et al., 2012; Eitel et al., 2020; Lewinska et al., 2020). In the same time, clinical studies have been showing that the patients given morphine in the treatment for non–ST-elevation acute coronary syndromes (NSTE-ACS), non-ST-elevation acute myocardial infarction (NSTEMI) and ST-elevation acute myocardial infarction (STEMI), presented more adverse cardiovascular events and higher mortality (Meine et al., 2005; de Waha et al., 2015; Bellandi et al., 2016; McCarthy et al., 2018).
Morphine is generally used in clinical treatment for the patients who have not been effectively alleviated for chest pain after the treatment with nitrites or who contraindicate nitrite drugs. However, it was reported that the treatment with morphine in acute myocardial infarction or acute coronary artery syndromes induced increase in myocardial injury even increase of the mortality of the patients. After comparing the reported laboratory studies showing the cardioprotective effects and the clinical observations presenting the harmful consequences, we query whether the timing of the morphine treatment makes the difference in the prognosis of the ischemic/infarct myocardium. We found that intravenous injections of morphine (0.3 mg/kg) at 15 min before the acute myocardial ischemia, at 5 min and 20 min or 60 min after ligation of the coronary artery in separate groups of rats scheduled for acute myocardial ischemia, for 30 min or 90 min followed by reperfusion for 120 min, induced different results, reduction in the size of infarction, no effect and increases of the infarct sizes, respectively. The opioid μ- and kappa-receptors mediated the detrimental effect of morphine on the myocardial injury. The findings of this study suggest that administration of morphine may cause different consequences when used at different time in the pathology of acute myocardial ischemia and reperfusion. The underlying mechanisms in the pathology of acute myocardial ischemia warrant further study.
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When combined with morphine, nalbuphine not only does not affect the analgesic effect but also prevents opioid-induced side effects. The authors investigated whether nalbuphine interferes with morphine-induced cardioprotection in rats.
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Nalbuphine had no protective effect against the infarct area compared with the control treatment (NAL, 52.5 ± 5% versus CON, 52.6 ± 4%; *P < 0.01), and the infarct size-sparing effects of morphine were not affected by nalbuphine (NAL + MOR, 42.6 ± 7% versus MOR, 40.4 ± 3%; P > 0.05). The nalbuphine group did not show a change the levels of serum CK-MB compared with the control group, and nalbuphine did not affect the levels of serum CK-MB in the MOR group.
Nalbuphine does not interfere with the cardioprotective effect of morphine in vivo. Therefore, nalbuphine could be safely used or combined with morphine in patients with acute myocardial infarction.
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Heart failure is the leading cause of morbidity and mortality worldwide. Several lines of evidence suggest that physical activity and exercise can pre-condition the heart to improve the response to acute cardiac injury such as myocardial infarction or ischemia/reperfusion injury, preventing the progression to heart failure. It is becoming more apparent that cardioprotection is a concerted effort between multiple cell types and converging signaling pathways. However, the molecular mechanisms of cardioprotection are not completely understood. What is clear is that the mechanisms underlying this protection involve acute activation of transcriptional activators and their corresponding gene expression programs. Here, we review the known stress-dependent transcriptional programs that are activated in cardiomyocytes and cardiac fibroblasts to preserve function in the adult heart after injury. Focus is given to prominent transcriptional pathways such as mechanical stress or reactive oxygen species (ROS)-dependent activation of myocardin-related transcription factors (MRTFs) and transforming growth factor beta (TGFβ), and gene expression that positively regulates protective PI3K/Akt signaling. Together, these pathways modulate both beneficial and pathological responses to cardiac injury in a cell-specific manner.
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^☆: Please address all correspondence to: Garrett J. Gross, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

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Regular ArticleIschemic Preconditioning and Morphine-induced Cardioprotection Involve the Delta (δ)-opioid Receptor in the Intact Rat Heart☆

Abstract

Regular Article
Ischemic Preconditioning and Morphine-induced Cardioprotection Involve the Delta (δ)-opioid Receptor in the Intact Rat Heart☆