Intrathecal morphine remotely preconditions the heart via a neural pathway.
Central opioid receptor activation triggers cardioprotection against ischemia reperfusion injury, independent of peripheral opioid receptor activity. Using a rodent model of myocardial ischemia reperfusion injury with infarct size as the primary outcome, we tested the hypothesis that spinal opioids confer this beneficial effect via a neural pathway. Intrathecal morphine reduced the infarct size compared with control (23% ± 7% vs. 58% ± 3%, respectively, P < 0.01). Prior antagonism of the autonomic pathway, and the receptors for bradykinin, calcitonin gene-related peptide, and the KATP channel, respectively, abolished this cardioprotection (54% ± 13%, 52% ± 10%, 56% ± 9%, and 49% ± 8%, respectively, P < 0.05). In a second set of experiments, we demonstrated that the increased expression of myocardial phosphorylated-Akt and endothelial nitric oxide synthase induced by intrathecal morphine was blocked by prior administration of hexamethonium. These findings support the notion that spinal opioid receptors stimulate a neural pathway that uses nonopioid neurotransmitters to confer cardioprotection from ischemia reperfusion injury. The use of intrathecal morphine for this purpose has potential clinical application, and it is already being used in the perioperative period to provide prolonged analgesia.
Department of Anaesthesiology, University of Hong Kong, Room 424, K Block, Queen Mary Hospital, Pokfulam Road, Hong Kong. gordon@hku.hk
Gordon Tin Chun
GT
Wong
Lu
L
Yao
Zhengyuan
Z
Xia
Michael G
MG
Irwin
D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects* / Q000294:innervation*; D060186:Infusions, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology
D000701:Analgesics, Opioid; D018377:Neurotransmitter Agents; D011957:Receptors, Opioid; D009020:Morphine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051057:Proto-Oncogene Proteins c-akt