Jiang Lingling, Hu Jun, He Shufang, Zhang Li, Zhang Ye
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.).
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.)
J Pharmacol Exp Ther. 2016 Sep;358(3):450-6. doi: 10.1124/jpet.116.234021. Epub 2016 Jun 29.
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.
几十年来，吗啡一直被广泛用作人类心脏病发作和心力衰竭的抢救治疗药物。关于脊髓阿片受体在吗啡心脏保护中的作用，人们所知相对较少。最近的研究表明，鞘内注射吗啡可以减轻大鼠缺血（I）/再灌注（R）引起的心脏损伤。然而，鞘内吗啡心脏保护的分子和细胞机制尚未确定。在此，我们报告鞘内吗啡后处理（IMPOC）可挽救平均动脉压（MAP）并减轻I/R中的心肌损伤。通过鞘内给药，用选择性μ-阿片受体拮抗剂纳洛酮（NAL）或一氧化氮合酶（NOS）抑制剂进行预处理可完全消除IMPOC的心脏保护作用，这表明脊髓μ-阿片受体及其下游NOS信号通路参与了吗啡诱导效应的机制。与此一致，IMPOC在相似的时间进程中显著增强了脊髓神经NOS磷酸化、一氧化氮和cGMP含量。鞘内应用鸟苷酸环化酶的特异性抑制剂1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮可完全消除IMPOC诱导的心脏保护增强和脊髓cGMP含量增加。IMPOC对MAP和缺血损伤的挽救与IMPOC对NOS信号的增强相关。总的来说，这些发现强化了脊髓μ-阿片受体作为介导吗啡诱导心脏保护的治疗靶点的概念。我们还提供了证据表明脊髓NOS信号的激活对吗啡心脏保护至关重要。
