Morphine Reduces Myocardial Infarct Size via Heat Shock Protein 90 in Rodents

Opioids reduce injury from myocardial ischemia-reperfusion in humans. In experimental models, this mechanism involves GSK3 beta inhibition. HSP90 regulates mitochondrial protein import, with GSK3 beta inhibition increasing HSP90 mitochondrial content. Therefore, we determined whether morphine-induced cardioprotection is mediated by HSP90 and if the protective effect is downstream of GSK3 beta inhibition. Male Sprague-Dawley rats, aged 8-10 weeks, were subjected to an in vivo myocardial ischemia-reperfusion injury protocol involving 30 minutes of ischemia followed by 2 hours of reperfusion. Hemodynamics were continually monitored and myocardial infarct size determined. Rats received morphine (0.3 mg/kg), the GSK3 beta inhibitor, SB216763(0.6mg/kg), or saline, 10 minutes prior to ischemia. Some rats received selective HSP90 inhibitors, radicicol (0.3mg/kg), or deoxyspergualin (DSG, 0.6mg/kg) alone or 5 minutes prior to morphine or SB216763. Morphine reduced myocardial infarct size when compared to control (42 +/- 2% versus 60 +/- 1%). This protection was abolished by prior treatment of radicicol or DSG (59 +/- 1%, 56 +/- 2%). GSK3 beta inhibition also reduced myocardial infarct size (41 +/- 2%) with HSP90 inhibition by radicicol or DSG partially inhibiting SB216763-induced infarct size reduction (54 +/- 3%, 47 +/- 1%, resp.). These data suggest that opioid-induced cardioprotection is mediated by HSP90. Part of this protection afforded by HSP90 is downstream of GSK3 beta, potentially via the HSP-TOM mitochondrial import pathway.