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: 10275766
• 负责人: Sergey G Khasabov
• 金额: $ 45.77万
• 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/10275766
• 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; 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.

与原发性和转移性骨肿瘤相关的疼痛通常严重且难以管理。阿片类药物是 一线治疗严重的癌症疼痛，但它们的副作用，包括耐受性，成瘾和呼吸道 抑郁，限制其使用。寻找具有高镇痛效率和低逆境的阿片类药物替代品 效果取得了有限的成功。长期目标是确定新颖，有效和安全的选择 用于疼痛治疗的o虫类药物。该项目的重点是Resolvin D1（RVD1），这是一个内源性衍生物。 多不饱和脂肪酸，作为癌症疼痛的可能治疗方法。使用骨癌的小鼠模型 疼痛。初步数据表明，RVD1的系统给药降低了癌症诱发的痛觉过敏， 伤害感受器和伤害性背角神经元的敏感性减弱，并降低 促进，同时增加了从腹膜上的降低伤害感受传播的抑制作用 髓质（RVM）。 RVD1不会损害运动功能，也不会产生位置偏好，这表明不是 上瘾。该提案的总体目的是确定外围和中央基础机制 RVD1出口镇痛。中心假设是全身施用RVD1抑制酶 参与proactative Prostaglandins（PGS）的生物合成和抗伤害感受的水解 内源性大麻素（ECB）降低伤害性神经元的敏感性并抑制降级设施。 初步数据表明，DRG，脊髓和RVM中PG的增加和ECB增加 癌症期间神经元敏感性和疼痛的贡献。因为RVD1增加了ECB，所以不同的作用 RVD1中产生的抗伤害感受的大麻素受体的类型将被阐明。中心假设将 以三个特定目标进行测试。 1）确定周围RVD1抗伤害感受的分子机制 和中枢神经系统； 2）确定RVD1对伤害性初级传入和脊柱的功能效应 癌症引起的骨痛期间的神经元； 3）确定RVD1对下降的功能效应 RVM的促进和抑制作用。对于第一个目标，生化和分子方法将用于 确定前列腺素和内源性大麻素信号传导的变化 以及Resolvin D1的影响。第二个目标将研究Resolvin D1对敏感性的影响 使用体内电生理学和体外[Ca2+] I-Imaging的伤害感受器和背角神经元 方法。第三个目标将评估RVD1对下降设施的影响和抑制 确定RVD1是否会降低细胞的活性并增加RVM中OFF细胞的活性以及如何增加 影响脊髓背角神经元的伤害性传播。拟议的研究具有创新性，因为它 将发现RVD1减轻癌症疼痛的新型机制。这个项目很重要，因为它将 为RVD1提供基于机械的理由，作为管理癌症疼痛的安全有效方法。