title: Spinal Neuronal NOS Signaling Contributes to Morphine Cardioprotection in Ischemia Reperfusion Injury in Rats.
abstract: Morphine has been widely used as rescue treatment for heart attack and failure in humans for many decades. Relatively little has been known about the role of spinal opioid receptors in morphine cardioprotection. Recent studies have shown that intrathecal injection of morphine can reduce the heart injury caused by ischemia (I)/reperfusion (R) in rats. However, the molecular and cellular mechanisms underlying intrathecal morphine cardioprotection has not been determined. Here, we report that intrathecal morphine postconditioning (IMPOC) rescued mean artery pressure (MAP) and reduced myocardial injury in I/R. Pretreatment with either naloxone (NAL), a selective mu-opioid receptor antagonist, or nitric oxide synthase (NOS) inhibitors via intrathecal delivery completely abolished IMPOC cardioprotection, suggesting that the spinal mu-opioid receptor and its downstream NOS signaling pathway are involved in the mechanism of the morphine-induced effect. Consistent with this, IMPOC significantly enhanced spinal neural NOS phosphorylation, nitric oxide, and cGMP content in a similar time course. Intrathecal application of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a specific inhibitor of guanylate cyclase, completely ablated IMPOC-induced enhancement of cardioprotection and spinal cGMP content. IMPOC rescue of MAP and ischemic injury is correlated with IMPOC enhancement of NOS signaling. Collectively, these findings strengthen the concept of spinal mu-opioid receptors as a therapeutic target that mediates morphine-induced cardioprotection. We also provide evidence suggesting that the activation of spinal NOS signaling is essential for morphine cardioprotection.
authors.affiliation: Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China (L.J., J.H., S.H., and Y. Z.); Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (L.J. and L.Z.).
authors.forename: Lingling
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China (L.J., J.H., S.H., and Y. Z.); Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (L.J. and L.Z.).
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China (L.J., J.H., S.H., and Y. Z.); Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (L.J. and L.Z.).
authors.forename: Shufang
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China (L.J., J.H., S.H., and Y. Z.); Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (L.J. and L.Z.).
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China (L.J., J.H., S.H., and Y. Z.); Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (L.J. and L.Z.) zhangye_hassan@sina.com.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D057775:Ischemic Postconditioning; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology
chemical_list: D002316:Cardiotonic Agents; D017450:Receptors, Opioid, mu; D009569:Nitric Oxide; D009020:Morphine; D052248:Nitric Oxide Synthase Type I; D006152:Cyclic GMP