Role of peroxynitrite in morphine hyperalgesia and tolerance

过氧亚硝酸盐在吗啡痛觉过敏和耐受中的作用

• 批准号: 8078936
• 负责人: DANIELA SALVEMINI
• 金额: $ 32.74万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078936
• 关键词: 3-nitrotyrosine; Acute; Adverse effects; Affect; American; Analgesics; Apoptosis; Apoptotic; Appearance; Attenuated; Behavioral; Biochemical; Biochemical Pathway; Chronic; Data; Development; Dose; Etiology; Event; Excision; Genetic; Glutamate Transporter; Glutamate-Ammonia Ligase; Goals; Health; Hyperalgesia; Hypersensitivity; Inflammation; Inflammatory; Infusion procedures; Knockout Mice; Link; Medical; Methods; Molecular; Morphine; Morphine Sulfate; Mus; N-Methyl-D-Aspartate Receptors; NADPH Oxidase; Necrosis; Neuroglia; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitrogen; Nuclear; Opiates; Opioid; Pain; Pain management; Pathway interactions; Patients; Peroxonitrite; Pharmaceutical Preparations; Poly(ADP-ribose) Polymerases; Production; Productivity; Quality of life; Rattus; Reactive Nitrogen Species; Relative (related person); Role; Signal Transduction; Source; Spinal; Spinal Cord; Spinal cord posterior horn; Stimulus; Superoxides; Testing; Time; Tissues; Work; acetovanillone; attenuation; catalyst; chronic pain; cost; cytokine; dorsal horn; frontier; improved; inhibitor/antagonist; nitration; novel; oxidative DNA damage; prevent; socioeconomics

DESCRIPTION (provided by applicant): Opiates like morphine sulfate are the most effective analgesics for treating acute and chronic severe pain, but their use is limited by development of tolerance and hypersensitivity to innocuous and noxious stimuli. The mechanisms of such opiate-induced hyperalgesia and antinociceptive tolerance are unclear. Peroxynitrite (ONOO-) produced from superoxide (O2.-) and nitric oxide (.NO), is a potent pro-inflammatory and pro- apoptotic reactive nitrogen species now implicated in hyperalgesia. Our central HYPOTHESIS is that endogenous ONOO- is the proximal molecule in a cascade of signaling events leading to morphine-induced hyperalgesia and antinociceptive tolerance. In mice we showed that repeated morphine administration leads to nitrotyrosine (NT, a marker of ONOO-) formation. The role of ONOO- was proven by showing that co- administering morphine with inhibitors of .NO synthase, scavengers of O2.- or novel ONOO- decomposition catalysts attenuated NT formation and prevented antinociceptive tolerance. These associative and causal links involving ONOO- and antinociceptive tolerance coincided with: 1) post-translational nitration of MnSOD, a glutamate transporter (GLT-1), and glutamine synthase (GS); 2) increased formation of pro-inflammatory cytokines; and 3) oxidative DNA damage and activation of the nuclear factor poly(ADP-ribose) polymerase. Inhibiting ONOO- attenuated these changes. Finally, results with systemic administration of ONOO- decomposition catalysts were confirmed by intrathechal dosing, thus supporting its role at the level of the spinal cord. Three Specific Aims will test our hypothesis. Specific Aim 1 will define the associative and causal link between spinal ONOO- and the development of morphine-induced hypersensitivity and antinociceptive tolerance. Specific Aim 2 will identify, using pharmacological and genetic approaches, the contribution of the NADPH oxidase as source of O2.- and thus, de novo ONOO- formation during the development of morphine hypersensitivity and antinociceptive tolerance. Specific Aim 3 will elucidate the molecular and biochemical mechanisms whereby ONOO- modulates hyperalgesia and antinociceptive tolerance. Results from these studies will define the important role of ONOO- in the development of antinociceptive tolerance providing the rationale towards the development of ONOO- decomposition catalysts as adjuncts to opiates for the management of chronic pain. Project Narrative: Chronic pain affects approximately 86 million Americans and cost at least $100 billion annually in medical expenses and reduced work productivity. PUBLIC HEALTH RELEVANCE Opioid drugs such as morphine are the most effective analgesics for treating severe chronic pain, but its pain-relieving action is often diminished during chronic administration, necessitating dose escalation that reduces quality of life for the patient. Our studies will determine for the first time that removal of peroxynitrite with novel agents, restores the pain-relieving action of morphine opening a new frontier in chronic pain management thereby improving the associated socioeconomic consequences.

描述（由申请人提供）：硫酸吗啡等阿片类药物是治疗急性和慢性剧烈疼痛最有效的镇痛药，但它们的使用因对无害和有害刺激产生耐受性和过敏而受到限制。这种阿片类药物引起的痛觉过敏和抗伤害耐受的机制尚不清楚。由超氧化物 (O2.-) 和一氧化氮 (.NO) 产生的过氧亚硝酸盐 (ONOO-) 是一种有效的促炎和促凋亡活性氮物质，目前与痛觉过敏有关。我们的中心假设是内源性 ONOO- 是导致吗啡诱导的痛觉过敏和镇痛耐受的一系列信号传导事件中的近端分子。在小鼠中，我们发现重复给予吗啡会导致硝基酪氨酸（NT，ONOO-的标记物）的形成。 ONOO-的作用通过以下证明得到证实：将吗啡与NO合酶抑制剂、O2-清除剂或新型ONOO-分解催化剂共同给药可减弱NT形成并防止镇痛耐受。这些涉及 ONOO 和抗伤害耐受性的关联和因果关系与：1) MnSOD、谷氨酸转运蛋白 (GLT-1) 和谷氨酰胺合酶 (GS) 的翻译后硝化作用相一致； 2）促炎细胞因子的形成增加； 3) 氧化性 DNA 损伤和核因子聚 (ADP-核糖) 聚合酶的激活。抑制 ONOO- 可减弱这些变化。最后，鞘内给药证实了ONOO分解催化剂全身给药的结果，从而支持了其在脊髓水平的作用。三个具体目标将检验我们的假设。具体目标 1 将定义脊髓 ONOO- 与吗啡引起的超敏反应和镇痛耐受之间的关联和因果关系。具体目标 2 将使用药理学和遗传学方法确定 NADPH 氧化酶作为 O2.- 来源的贡献，从而确定吗啡过敏和抗伤害耐受性发展过程中从头 ONOO- 的形成。具体目标 3 将阐明 ONOO 调节痛觉过敏和抗伤害耐受的分子和生化机制。这些研究的结果将明确 ONOO- 在抗伤害耐受性发展中的重要作用，为开发 ONOO- 分解催化剂作为阿片类药物的辅助剂来治疗慢性疼痛提供依据。项目叙述：慢性疼痛影响着大约 8600 万美国人，每年至少花费 1000 亿美元的医疗费用和工作效率下降。 公共卫生相关性 吗啡等阿片类药物是治疗严重慢性疼痛最有效的镇痛药，但其镇痛作用在长期给药过程中往往会减弱，需要增加剂量，从而降低患者的生活质量。我们的研究将首次确定用新型药物去除过氧亚硝酸盐可以恢复吗啡的止痛作用，从而开辟慢性疼痛治疗的新领域，从而改善相关的社会经济后果。