Role of ceramide in morphine hyperalgesia and tolerance

神经酰胺在吗啡痛觉过敏和耐受中的作用

• 批准号: 7528339
• 负责人: DANIELA SALVEMINI
• 金额: $ 21.18万
• 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: 2008-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7528339
• 关键词: Acute; Address; Adverse effects; Anabolism; Analgesics; Apoptosis; Apoptotic; Attenuated; Behavioral; Biochemical; Biochemical Pathway; Cell Death; Ceramides; Chronic; Clinical; Development; Dose; Electrospray Ionization; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Etiology; Event; Figs - dietary; Foundations; Fumonisin B1; Genetic; Goals; Hydrolysis; Hyperalgesia; Hypersensitivity; Inflammatory; Inhibition of Apoptosis; Interleukins; Link; Mass Spectrum Analysis; Measures; Modeling; Molecular; Morphine; Morphine Sulfate; Mus; Narcotic Analgesics; Necrosis; Neuroglia; Neurons; Nuclear; Opiates; Opioid; Oxidative Stress; Pain; Pain management; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Poly(ADP-ribose) Polymerases; Property; Public Health; Quality of life; Relative (related person); Role; Serine; Signaling Molecule; Sphingolipids; Sphingomyelinase; Sphingomyelins; Spinal; Spinal Cord; Spinal cord posterior horn; Stimulus; Stress; Testing; Time; Tissues; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Validation; attenuation; base; caspase-3; chronic pain; clinically relevant; cytokine; dihydroceramide desaturase; dorsal horn; expectation; frontier; human TNF protein; inhibitor/antagonist; novel; oxidative DNA damage; research study; serine palmitoyltransferase; socioeconomics; sphingomyelin synthase; thermozymocidin; xanthate D609

DESCRIPTION (provided by applicant): Opiate/narcotic analgesics, typified by morphine sulfate, are the most effective analgesics for treating acute and chronic severe pain, but their clinical utility is often hampered by the development of analgesic tolerance and painful hypersensitivity to both innocuous and noxious stimuli. The mechanisms by which chronic opiate exposure induce hyperalgesia and antinociceptive tolerance are unclear but neuroimmune activation, cellular apoptosis and oxidative/nitrative stress in the spinal cord have been proposed, Ceramide is a sphingolipid signaling molecule with powerful proapoptotic and proinflammatory properties and may also contribute to oxidative/nitrative stress. Ceramide is generated from de novo synthesis coordinated by serine palmitosyltransferase and ceramide synthase and/or by enzymatic hydrolysis of sphingomyelin by sphingomyelinases (SMases). Using a well established murine model, our preliminary experiments revealed that repeated administration of morphine increased the levels of ceramide in the dorsal horn of the lumbar segment of the spinal cord and that its inhibition by fumonisin B1, an inhibitor of ceramide synthase, attenuated the development of antinociceptive tolerance. These events were associated with inhibition of apoptosis and oxidative/nitrative stress in dorsal horn tissues. Furthermore, inhibition of ceramide synthesis by D609 and myriocin, inhibitors of SMAse/sphingomyelin synthase and serine palmitoyltransferase respectively blocked antinociceptive tolerance. Together, these findings support the central thesis of this exploratory proposal: increased formation of ceramide in the spinal cord is an important pathway in the development of morphine-induced hyperalgesia and antinociceptive tolerance. To address this novel hypothesis, we propose a comprehensive experimental strategy employing molecular, bio-analytical, biochemical, pharmacological and genetic approaches. Two Specific Aims will test our hypothesis. In Specific Aim 1, we will demonstrate by pharmacologic and genetic approaches that inhibition of the increased formation of ceramide blocks the development of morphine- induced hyperalgesia and antinociceptive tolerance thus identifying the predominant enzymatic pathway responsible for its biosynthesis. In Specific Aim 2, we will elucidate the molecular and biochemical mechanisms whereby ceramide modulates hyperalgesia and antinociceptive tolerance. Specifically, we will determine ceramide's effects on three biochemical pathways within spinal tissue: (a) neuroimmune activation, (b) oxidative/nitrative stress and (c) apoptosis. Successful validation of our hypothesis will define for the first time the important role of ceramide in morphine-induced hyperalgesia and antinociceptive tolerance providing the scientific foundation towards the development of inhibitors of ceramide biosynthesis as adjunct to opiates for the management of chronic pain, in particular for those patients who require long-term opioid treatment for pain relief. PUBLIC HEALTH RELEVANCE Opioid drugs such as morphine are the most effective analgesics for treating severe chronic pain, but their 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 inhibition of ceramide biosynthesis, with novel agents, restores the pain-relieving action of morphine. The broader implications of our findings may open a new frontier in chronic pain management thus alleviating the socioeconomic consequences it causes.

描述（由申请人提供）：以硫酸吗啡的含量为代表的阿片类/麻醉镇痛药是治疗急性和慢性剧烈疼痛的最有效的镇痛药，但它们的临床效用通常会因镇痛耐受性和对无害和有害性刺激的高敏性而受到阻碍。已经提出了脊髓中的慢性鸦片暴露诱导痛觉过敏和抗伤害感受耐受性的机制尚不清楚，但神经免疫性激活，细胞凋亡和氧化/硝化应激在脊髓中提出，Ceramide是Ceramide，Ceramide是一种鞘脂信号传导分子，具有强大的促蛋白质和良好的氧气和促进性/可能的特性。神经酰胺是由丝氨酸棕榈糖基转移酶和神经酰胺合酶和/或通过鞘磷脂酶（SMASE）对鞘磷脂的酶水解产生的。使用良好的鼠模型，我们的初步实验表明，重复给药吗啡增加了脊髓腰部腰部背角中神经酰胺的水平，并且富莫尼酶B1抑制神经酰胺抑制剂，陶瓷酶合酶的抑制剂减弱了抗心动耐药性耐受性的发育。这些事件与背角组织中凋亡和氧化/硝化应激的抑制有关。此外，D609和Myriocin对神经酰胺合成的抑制作用，Smase/鞘磷脂合酶和丝氨酸棕榈酰转移酶的抑制剂分别阻断了抗伤害感受耐受性的抑制剂。这些发现共同支持了此探索性建议的中心论点：脊髓中神经酰胺的形成增加是吗啡诱导的痛觉过敏和抗伤害感受耐受性的重要途径。为了解决这一新的假设，我们提出了一种采用分子，生物分析，生化，药理学和遗传学方法的全面实验策略。两个具体的目标将检验我们的假设。在特定的目标1中，我们将通过药物和遗传学方法证明，抑制神经酰胺的形成的增加会阻止吗啡诱导的痛觉过敏和抗伤害感受耐受性的发展，从而鉴定出负责其生物合成的主要酶途径。在特定的目标2中，我们将阐明神经酰胺调节痛觉过敏和抗伤害感受的分子和生化机制。具体而言，我们将确定神经酰胺对脊柱组织内三种生化途径的影响：（a）神经免疫性激活，（b）氧化/硝化应激和（c）凋亡。成功验证我们的假设将首次定义神经酰胺在吗啡诱导的痛觉过敏和抗伤害感受耐受性中的重要作用，从而为神经酰胺生物合成抑制剂的发展提供了科学基础，这是对慢性疼痛治疗的患者的治疗，以治疗长期治疗疼痛的患者。公共卫生相关性阿片类药物（例如吗啡）是治疗严重慢性疼痛的最有效的镇痛药，但是在长期给药期间，它们的缓解疼痛作用通常会减少，因此需要降低剂量，从而降低患者的生活质量。我们的研究将首次确定抑制神经酰胺生物合成的新药物可以恢复吗啡的缓解疼痛作用。我们发现的更广泛的含义可能打开了慢性疼痛管理方面的新领域，从而减轻了其造成的社会经济后果。