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: 7691359
• 负责人: DANIELA SALVEMINI
• 金额: $ 18.06万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7691359
• 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; 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; inhibitor/antagonist; novel; oxidative DNA damage; public health relevance; 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（申请人提供）：以硫酸吗啡为代表的阿片类/麻醉性镇痛药是治疗急性和慢性剧烈疼痛最有效的镇痛药，但其临床应用常常因镇痛耐受性的发展以及对无害和有害刺激的疼痛过敏而受到阻碍。慢性阿片类药物暴露引起痛觉过敏和抗伤害耐受的机制尚不清楚，但已提出神经免疫激活、细胞凋亡和脊髓氧化/硝化应激。神经酰胺是一种鞘脂信号分子，具有强大的促凋亡和促炎特性，也可能导致氧化/硝化应激。神经酰胺是由丝氨酸棕榈糖基转移酶和神经酰胺合酶协调的从头合成和/或鞘磷脂酶 (SMase) 酶促水解鞘磷脂产生的。使用完善的小鼠模型，我们的初步实验表明，重复施用吗啡会增加脊髓腰段背角的神经酰胺水平，并且神经酰胺合酶抑制剂伏马菌素 B1 的抑制作用会减弱镇痛耐受的发展。这些事件与背角组织中细胞凋亡和氧化/硝化应激的抑制有关。此外，D609 和多球菌素对神经酰胺合成的抑制、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镇痛耐受。总之，这些发现支持了这一探索性提议的中心论点：脊髓中神经酰胺形成的增加是吗啡引起的痛觉过敏和镇痛耐受发生的重要途径。为了解决这一新假设，我们提出了一种采用分子、生物分析、生物化学、药理学和遗传学方法的综合实验策略。两个具体目标将检验我们的假设。在具体目标 1 中，我们将通过药理学和遗传学方法证明，抑制神经酰胺形成的增加可以阻止吗啡诱导的痛觉过敏和镇痛耐受的发展，从而确定负责其生物合成的主要酶途径。在具体目标 2 中，我们将阐明神经酰胺调节痛觉过敏和镇痛耐受的分子和生化机制。具体来说，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）神经免疫激活，（b）氧化/硝化应激和（c）细胞凋亡。我们的假设的成功验证将首次明确神经酰胺在吗啡引起的痛觉过敏和抗伤害耐受中的重要作用，为开发神经酰胺生物合成抑制剂作为阿片类药物的辅助治疗慢性疼痛提供科学基础，特别是对于那些需要长期阿片类药物治疗缓解疼痛的患者。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，但在长期给药过程中，其止痛作用往往会减弱，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，用新型药物抑制神经酰胺生物合成可以恢复吗啡的止痛作用。我们的研究结果具有更广泛的影响，可能会开辟慢性疼痛管理的新领域，从而减轻其造成的社会经济后果。

项目成果

Peroxynitrite and opiate antinociceptive tolerance: a painful reality.

• DOI: 10.1016/j.abb.2008.11.005
• 发表时间: 2009-04-15
• 期刊: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
• 影响因子: 3.9
• 作者: Salvemini, Daniela

Spinal NADPH oxidase is a source of superoxide in the development of morphine-induced hyperalgesia and antinociceptive tolerance.

脊髓 NADPH 氧化酶是吗啡引起的痛觉过敏和镇痛耐受中超氧化物的来源。

• DOI: 10.1016/j.neulet.2010.07.013
• 发表时间: 2010-10-11
• 期刊: NEUROSCIENCE LETTERS
• 影响因子: 2.5
• 作者: Doyle, Tim;Bryant, Leesa;Muscoli, Carolina;Cuzzocrea, Salvatore;Esposito, Emanuela;Chen, Zhoumou;Salvemini, Daniela
• 通讯作者: Salvemini, Daniela

Counter-regulation of opioid analgesia by glial-derived bioactive sphingolipids.

• DOI: 10.1523/jneurosci.2391-10.2010
• 发表时间: 2010-11-17
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Muscoli C;Doyle T;Dagostino C;Bryant L;Chen Z;Watkins LR;Ryerse J;Bieberich E;Neumman W;Salvemini D
• 通讯作者: Salvemini D

Targeting peroxynitrite driven nitroxidative stress with synzymes: A novel therapeutic approach in chronic pain management.

用合酶靶向过氧亚硝酸盐驱动的硝基氧化应激：慢性疼痛管理的一种新治疗方法。

• DOI: 10.1016/j.lfs.2009.06.011
• 发表时间: 2010
• 期刊: Life sciences
• 影响因子: 6.1
• 作者: Salvemini,Daniela;Neumann,William
• 通讯作者: Neumann,William

NMDA-receptor activation and nitroxidative regulation of the glutamatergic pathway during nociceptive processing.

• DOI: 10.1016/j.pain.2010.01.015
• 发表时间: 2010-04
• 期刊: Pain
• 影响因子: 7.4
• 作者: Chen Z;Muscoli C;Doyle T;Bryant L;Cuzzocrea S;Mollace V;Mastroianni R;Masini E;Salvemini D
• 通讯作者: Salvemini D