Acute methadone treatment reduces myocardial infarct size via the delta-opioid receptor in rats during reperfusion.
BACKGROUND
Methadone is an opioid agonist often given to manage acute and chronic pain. We sought to determine whether methadone compared with morphine dose dependently reduces myocardial infarct size (IS) and whether the mechanism is delta-opioid receptor mediated. Furthermore, we examined whether myocardial IS reduction varies with the timing of methadone administration or duration of induced ischemia.


METHODS
After surgical instrumentation, we divided male Sprague-Dawley rats into 3 sets. The first set was divided into groups, which received methadone (0.03-3 mg/kg), morphine (0.03-3 mg/kg), or water (placebo) 30 min before ischemia. Some animals of the first set also received the delta-opioid antagonist naltrindole (5 mg/kg) before methadone (0.3 mg/kg), morphine (0.3 mg/kg), or placebo administration. The second set of animals was divided into groups that received methadone (0.3 mg/kg) 5 min before reperfusion or 10 s after reperfusion. These 2 sets of animals were subjected to 30 min of myocardial ischemia by left anterior descending coronary artery occlusion and then 2 h of reperfusion. The third set of animals received placebo, methadone (0.3 mg/kg), or morphine (0.3 mg/kg) 5 min before reperfusion and were subjected to 45 min of ischemia by left anterior descending coronary artery occlusion with 2 h of reperfusion. Myocardial IS was assessed by staining myocardial tissue with triphenyltetrazolium chloride and expressed as a percentage of the area at risk (mean +/- sem).


RESULTS
Methadone or morphine administered before ischemia reduced myocardial IS. The greatest effect was achieved at a dose of 0.3 mg/kg (methadone, 46% +/- 1%, P < 0.001 and morphine, 47% +/- 1%, P < 0.001 versus placebo, 61% +/- 1%, respectively). Naltrindole (5 mg/kg) blocked methadone-induced (0.3 mg/kg) and morphine-induced (0.3 mg/kg) cardioprotection (naltrindole + methadone, 58% +/- 1%, P < 0.001 versus methadone; and naltrindole + morphine, 58 +/- 1%, P < 0.001 versus morphine). Methadone (0.3 mg/kg) reduced myocardial IS when given 5 min before reperfusion (46% +/- 1%, P < 0.001 versus placebo) but not 10 s after reperfusion (60% +/- 1%, P = 0.675 versus placebo). No significant myocardial IS differences were seen for placebo when comparing the 45-min ischemia group (64% +/- 1%) with the 30-min ischemia group (60% +/- 1%, P = 0.069). The longer ischemia time of 45 min abrogated methadone-induced IS reduction (64% +/- 2%, P = 0.867 versus 45-min ischemia placebo group) and morphine-induced IS reduction (65% +/- 1%, P = 0.836 versus 45-min ischemia placebo group).


CONCLUSIONS
These findings demonstrate that methadone and morphine produce similar myocardial IS-sparing effects that are delta-opioid receptor mediated and that are dependent on the duration of myocardial ischemia.
Department of Anesthesiology, Stanford University, Stanford, California, USA.
Eric R
ER
Gross
Anna K
AK
Hsu
Garrett J
GJ
Gross
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008297:Male; D008691:Methadone / Q000008:administration & dosage / Q000494:pharmacology*; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D013997:Time Factors
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D009271:Naltrexone; D009020:Morphine; C055382:naltrindole; D008691:Methadone