Intrathecal morphine preconditioning induces cardioprotection via activation of delta, kappa, and mu opioid receptors in rats.
BACKGROUND
Small doses of intrathecal morphine provide cardioprotection similar to that conferred by IV morphine. However, the extent of intrathecal morphine preconditioning (IT-MPC) relative to that resulting from ischemic preconditioning (IPC) is unknown. Further, it is uncertain whether IT-MPC is mediated by opioid receptor dependent pathways. In this study, we compared the extent of cardioprotection conferred by IT-MPC with IPC and investigated the role of opioid receptors in this effect.


METHODS
Eighty anesthetized, open-chest, male Sprague-Dawley rats were assigned to 1 of 13 groups (n = 6-7) after successful intrathecal catheter placement. Rats in the IPC group were subjected to three 5-min cycles of myocardial ischemia (induced by occlusion of the left main coronary artery) interspersed with 5 min of reperfusion. After IPC, myocardial ischemia and reperfusion injury was induced by 30 min of left main coronary artery occlusion followed by 2 h of reperfusion. In the IT-MPC groups, the rats were given 3 consecutive 5 min intrathecal morphine infusions (0.03, 0.3, 3.0, or 30.0 microg/kg, respectively) interspersed with 5 min infusion-free periods, before myocardial ischemia reperfusion injury. In 2 other groups either 300microg/kg of IV morphine or 10 microL of intrathecal normal saline were given. The selective delta, kappa, and mu opioid receptor antagonists naltrindole, nor-binaltorphimine, and D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), respectively, were given to groups of animals receiving IT-MPC to evaluate the relative role of the specific opioid receptor subtypes in IT-MPC preconditioning. Myocardial infarct size (IS), as a percentage of the area at risk (AAR), was determined by 2,3,5-triphenyltetrazolium staining.


RESULTS
Intrathecal morphine 0.3 to 30 microg/kg reduced myocardial IS compared with intrathecal normal saline control animals. The IS/AAR were 33% +/- 10% (0.3 microg/kg), 29% +/- 10% (3 microg/kg) and 29% +/- 16% (30 mug/kg), versus 53% +/- 8% for the control group (P < 0.01). The reduction in IS/AAR with IT-MPC was similar to that produced by IV morphine (33% +/- 6%, P = 0.84) and IPC (22% +/- 4%, P = 0.41). Myocardial preconditioning due to IT-MPC was attenuated by co-administration of any one of the opioid receptor antagonists (IT-MPC + naltrindole 50% +/- 9%, IT-MPC + nor binaltorphimine 43% +/- 6%, IT-MPC + CTOP 53% +/- 9%, P = 0.14).


CONCLUSIONS
IT-MPC produced comparable cardioprotection to myocardial IPC and IV morphine. Myocardial preconditioning from intrathecal morphine seems to involve delta, kappa, and mu opioid receptors.
Li
Rui
R
Department of Anesthesiology, University of Hong Kong, Hong Kong.
Wong
Gordon T C
GT
Wong
Tak Ming
TM
Zhang
Ye
Y
Xia
Zhengyuan
Z
Irwin
Michael G
MG
D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D007263:Infusions, Parenteral; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists
D000701:Analgesics, Opioid; D002317:Cardiovascular Agents; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009020:Morphine