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This dissertation, Opioid Cardioprotection in the Perioperative Period by Tin-chun, Gordon, Wong, 黃田鎮, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Many factors present during the perioperative period render patients susceptible in developing myocardial ischaemia reperfusion injury. Various mode of conditioning the heart against this type of injury has been discovered in animal models and involve powerful innate pathways that enhance cellular survival. These may be harnessed by applying a trigger either immediately before (preconditioning) or after (postconditioning) the lethal ischaemic injury, by physical or pharmacological means. Morphine was the first clinically used opioid shown to be cardioprotective but the intravenous dose required limited its use clinically. Remifentanil, an ultra-short acting opioid, was later also shown to be cardioprotective. A better understanding of how these opioids can protect the heart may enable the rational design of clinical regimens that best protect patients. The purpose of this thesis is to demonstrate and elucidate how these two agents provide cardiac protection. I first demonstrated the clinical efficacy of remifentanil preconditioning in reducing the release CKMB, cardiac troponin I, heart type fatty acid binding protein and ischaemia modified albumin following cardiopulmonary bypass. As opioids cannot be omitted completely from patients undergoing cardiac surgery due to ethical considerations, I then used a well-established animal model of ischaemia reperfusion injury to complete the remainder of the studies. I demonstrated that remifentanil postconditioning was also effective in reducing myocardial infarct size, an effect mediated through the activation of kappa and delta opioid receptor subtypes, and in part triggered at the level of the myocardium. I then confirmed previous findings showing the efficacy of intrathecal morphine preconditioning using clinically relevant doses. In addition, I demonstrated that all three opioid receptor subtypes were involved. This effect was comparable to that achievable by classical ischaemic or intravenous morphine preconditioning and is mediated by central but not peripheral opioid receptor activation. Intrathecal morphine reduces the degree of myocardial apoptosis, alters the phosphorylation of Akt and the expression of endothelial nitric oxide synthatase and opens the potassium ATP channels. It also involves spinal adenosine receptors, similar to spinal morphine mediated analgesia. Intrathecal morphine preconditioning can be abolished by the interruption of autonomic nervous system function and blockade of calcitonin gene related peptide (CGRP) and bradykinin receptors. Intrathecal morphine postconditioning also has an infarct sparing effect. It also involves the activation of central opioid receptors and peripheral adenosine and CGRP receptors. Finally I demonstrated a pivotal role of central opioid receptor in remote preconditioning by showing that selective blockade of these receptors abolished the protective effects of remote but not classical ischaemic preconditioning. Cumulatively, these results demonstrated the versatility of opioid mediated cardioprotection using morphine or remifentanil and the pivotal role of central opioid receptors in cardioprotection and revealed some of the mechanisms underlying these benefits. Not only does intrathecal morphine provide analgesia, it also generates signals that are transmitted through the autonomic nervous system resulting in changes in cellular function in the heart. This point to the pos

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