Treatment of cancer pain by lipid mediator Resolvin D1: role of Prostaglandin and Endocannabinoid signaling

脂质介质 Resolvin D1 治疗癌痛：前列腺素和内源性大麻素信号传导的作用

• 批准号: 10462717
• 负责人: Sergey G Khasabov
• 金额: $ 46.05万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-05 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462717
• 关键词: Absence of pain sensation; Adverse effects; Affect; Anabolism; Analgesics; Attenuated; Behavioral; Biochemical; Biophysics; Bone Pain; Bone neoplasms; Brain; Brain Stem; CNR1 gene; Cancer Model; Cancer Pain Management; Cannabinoids; Cells; Clinical; Data; Development; Disseminated Malignant Neoplasm; Electrophysiology (science); Endocannabinoids; Enzymes; Goals; Hydrolysis; Hyperalgesia; In Vitro; Inflammatory; Knowledge; Life; Malignant Bone Neoplasm; Malignant Neoplasms; Mediating; Membrane; Metastatic Neoplasm to the Bone; Molecular; Nervous system structure; Neuraxis; Neurons; Nociception; Nociceptors; Omega-3 Fatty Acids; Opioid; Outcome; Pain; Pain management; Pathway interactions; Patients; Peripheral; Polyunsaturated Fatty Acids; Posterior Horn Cells; Property; Prostaglandin Inhibition; Prostaglandins; Research; Role; Spinal; Spinal Cord; Techniques; Testing; Therapeutic; Tissues; Ventilatory Depression; addiction; base; bone; cancer pain; cancer therapy; cannabinoid receptor; effectiveness evaluation; endocannabinoid signaling; evidence base; experience; imaging approach; in vivo; innovation; interdisciplinary approach; lipid mediator; motor impairment; mouse model; non-opioid analgesic; novel; pain inhibition; preference; receptor; response; side effect; success; transmission process; treatment strategy

Pain associated with primary and metastatic bone tumors is often severe and difficult to manage. Opioids are first-line treatment for severe cancer pain, but their side effects, including tolerance, addiction and respiratory depression, limit their use. The search for opioid alternatives with high analgesic efficacy and low adverse effects has yielded limited success. Long-term goal is to identify novel, effective, and safe alternatives to opioids for pain treatment. This project is focused on Resolvin D1 (RvD1), an endogenous derivative of -3 polyunsaturated fatty acids, as a possible therapeutic for cancer pain. Using a mouse model of bone cancer pain. Preliminary data show that systemic administration of RvD1 decreased cancer-evoked hyperalgesia, attenuated sensitization of nociceptors and nociceptive dorsal horn neurons, and reduced descending facilitation while increasing descending inhibition of nociceptive transmission from the rostral ventromedial medulla (RVM). RvD1 did not impair motor function and did not produce place preference, suggesting it is not addictive. The overall objective in this proposal is to determine peripheral and central underlying mechanisms of RvD1 exerts analgesia. The central hypothesis is that systemic administration of RvD1 inhibits enzymes involved in the biosynthesis of pronociceptive prostaglandins (PGs) and the hydrolysis of antinociceptive endocannabinoids (eCBs) that reduce sensitization of nociceptive neurons and inhibit descending facilitation. Preliminary data suggest that increased PGs and decreased eCBs in the DRG, spinal cord and RVM contribute to neuronal sensitization and pain during cancer. Because RvD1 increased eCBs, role of different types of cannabinoid receptors in RvD1 produced antinociception will be elucidated. The central hypothesis will be tested in three specific aims. 1) Identify molecular mechanisms of RvD1 antinociception in the peripheral and central nervous system; 2) Determine functional effects of RvD1 on nociceptive primary afferent and spinal neurons during cancer-induced bone pain; and 3) Determine functional effects of RvD1 on descending facilitation and inhibition from the RVM. For the first aim biochemical and molecular approaches will be used to determine changes in prostaglandin and endocannabinoid signaling during the development of cancer- pain and the effects of Resolvin D1. The second aim will investigate the effects of Resolvin D1 on sensitization of nociceptors and dorsal horn neurons using in vivo electrophysiological and in vitro [Ca2+]i-imaging approaches. The third aim will evaluate the effects of RvD1 on descending facilitation and inhibition by determining if RvD1 reduces activity of ON cells and increases activity of OFF cells in the RVM and how it affect nociceptive transmission in spinal dorsal horn neurons. The proposed research is innovative because it will uncover novel mechanisms by which RvD1 reduces cancer pain. This project is significant because it will provide a mechanistic-based justification for RvD1 as a safe and effective approach to manage cancer pain.

与原发骨肿瘤和转移性骨肿瘤相关的疼痛通常是严重的和难以处理的。阿片类药物 严重癌症疼痛的一线治疗，但其副作用，包括耐受性、成瘾和呼吸 抑郁症，限制其使用。寻找高效低毒的阿片类药物替代品 Effects取得的成功有限。长期目标是确定新的、有效的和安全的替代方案 治疗疼痛的阿片类药物。本项目的重点是-3的内源性衍生物Resolvin D1(Rvd1) 多不饱和脂肪酸，可能是一种治疗癌症疼痛的药物。用小鼠骨癌模型 疼痛。初步数据显示，全身应用Rvd1可减少癌症引起的痛觉过敏， 减弱伤害性感受器和伤害性背角神经元的敏感化，并减少下行 易化的同时增加对头端腹内侧部伤害性信息传递的下行抑制 延髓(RVm)。Rvd1没有损害运动功能，也没有产生位置偏爱，这表明它不是 让人上瘾。本提案的总体目标是确定外围和中央基础机制 Rvd1具有镇痛作用。中心假说是全身给药Rvd1抑制酶 参与伤害感受性前列腺素(PGs)的生物合成和抗伤害感受性物质的水解 内源性大麻素(ECB)，减少伤害性神经元的敏感化，抑制下行促进。 初步数据显示，DRG、脊髓和RVM中的PG增加，ECB减少 有助于神经敏感化和癌症期间的疼痛。由于Rvd1增加了ECB，因此作用不同 Rvd1中产生抗伤害感受的大麻素受体的类型将被阐明。中心假说将 在三个具体目标上进行测试。1)确定RvD1在外周的抗伤害作用的分子机制 2)测定Rvd1对伤害性初级传入和脊髓的功能影响 癌症骨痛中的神经元；3)确定Rvd1对下行的功能影响 来自RVM的促进和抑制。对于第一个目标，将使用生化和分子方法来 确定前列腺素和内源性大麻素信号在癌痛发生过程中的变化 以及Resolvin D1的作用。第二个目的是研究Resolvin D1对小鼠胸腺细胞增敏的影响。 伤害性感受器和背角神经元在体电生理和体外[Ca~(2+)]i成像的研究 接近了。第三个目标将评估Rvd1对下行促进和抑制的作用，通过 确定RvD1是否降低了RVM中ON细胞的活性，增加了OFF细胞的活性，以及它是如何 影响脊髓背角神经元的伤害性传递。这项拟议的研究具有创新性，因为它 将揭示RvD1减轻癌症疼痛的新机制。这个项目意义重大，因为它将 为RvD1作为一种安全有效的癌症疼痛管理方法提供了一个基于机制的理由。