Involvement of the δ‐opioid receptor in exercise‐induced cardioprotection

Abstract

What is the central question of this study? Does the δ-opioid receptor trigger exercise-induced cardioprotection against ischaemia-reperfusion injury? What is the main finding and its importance? In exercised hearts, the δ-opioid receptor appears to trigger cardioprotection against ischaemia-reperfusion-induced tissue necrosis but not apoptosis. Endogenous opioids mediate exercise-induced cardioprotection against ischaemia-reperfusion (IR) injury, although the opioid receptor subtype mediating this effect is unknown. We investigated whether the δ-opioid receptor mediates exercise-induced cardioprotection against IR injury. Endogenous opioids are produced in various tissues, including the heart and skeletal muscle; therefore, we also sought to identify the effect of exercise on circulating endogenous opioid as well as transcript, protein and receptor expression in heart and skeletal muscle. Male Sprague-Dawley rats (n=73) were assigned randomly to treadmill exercise or sedentary treatments. Cardiac tissue and serum were harvested 0, 20 and 120min following exercise and from sedentary animals (n=32) to quantify effects on proenkephalin and δ-opioid receptor mRNA and protein levels, as well as serum enkephalin. Skeletal muscle (soleus) was harvested at identical time points for determination of proenkephalin protein and mRNA. A separate group of rats (n=41) were randomly assigned to sham operation (Sham; surgical control), sedentary (Sed), exercise (Ex) or exercise+δ-opioid receptor antagonist (ExD; naltrindole, 5mgkg(-1) i.p.) and received IR by left anterior descending coronary artery ligationin vivo.After IR, tissues were harvested to quantify treatment effects on necrosis and apoptosis. Cardiac proenkephalin mRNA expression increased following exercise (0min, P=0.03; 120min, P=0.021), while soleus expression was unaffected. Exercise-induced changes in serum enkephalin were undetectable. After IR, tissue necrosis was elevated in Sed and ExD hearts (P<0.001 and P=0.003, respectively) compared with the Sham group, while the Ex group was partly protected. After IR, apoptosis was evident in Sed hearts (P=0.016), while Ex and ExD hearts were protected. Data suggest that cardioprotective opioids are produced by the heart, but not by the soleus. After IR, the δ-opioid receptor may mediate, in part, cardioprotection against necrosis but not apoptosis.