Morphine induces physiological, structural, and molecular benefits in the diabetic myocardium

The obesity epidemic has increased type II diabetes mellitus (T2DM) across devel- oped countries. Cardiac T2DM risks include ischemic heart disease, heart failure with preserved ejection fraction, intolerance to ischemia- reperfusion (I- R) injury, and re- fractoriness to cardioprotection. While opioids are cardioprotective, T2DM causes opioid receptor signaling dysfunction. We tested the hypothesis that sustained opi- oid receptor stimulus may overcome diabetes mellitus- induced cardiac dysfunction via membrane/mitochondrial- dependent protection. In a murine T2DM model, we investigated effects of morphine on cardiac function, I- R tolerance, ultrastructure, subcellular cholesterol expression, mitochondrial protein abundance, and mitochon- drial function. T2DM induced 25% weight gain, hyperglycemia, glucose intoler- ance, cardiac hypertrophy, moderate cardiac depression, exaggerated postischemic myocardial dysfunction, abnormalities in mitochondrial respiration, ultrastructure and Ca2+- induced swelling, and cell death were all evident. Morphine administra- tion for 5 days: (1) improved glucose homeostasis; (2) reversed cardiac depression; (3) enhanced I- R tolerance; (4) restored mitochondrial ultrastructure; (5) improved mitochondrial function; (6) upregulated Stat3 protein; and (7) preserved membrane cholesterol homeostasis. These data show that morphine treatment restores contrac- tile function, ischemic tolerance, mitochondrial structure and function, and membrane dynamics in type II diabetic hearts. These findings suggest potential translational value for short- term, but high- dose morphine administration in diabetic patients un- dergoing or recovering from acute ischemic cardiovascular events.