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.

与原发性和转移性骨肿瘤相关的疼痛通常很严重且难以控制阿片类药物。 严重癌症疼痛的一线治疗方法，但其副作用，包括耐受性、成瘾性和呼吸系统 抑郁症，限制其使用具有高镇痛功效和低不良反应的阿片类药物替代品。 效果取得了有限的成功，长期目标是找到新颖、有效和安全的替代品。 该项目的重点是 Resolvin D1 (RvD1)，它是 -3 的内源性衍生物。 多不饱和脂肪酸，作为一种可能的癌症疼痛治疗方法，使用骨癌小鼠模型。 初步数据表明，全身施用 RvD1 会引发癌症引起的痛觉过敏， 伤害感受器和伤害性背角神经元的敏化减弱，下行神经元减少 促进，同时增加对头侧腹内侧痛觉传递的下行抑制 髓质 (RVM) 不会损害运动功能，也不会产生位置偏好，表明它不是。 该提案的总体目标是确定外围和中枢的潜在机制。 RvD1 发挥镇痛作用的核心假设是全身施用 RvD1 会抑制酶。 参与促痛性前列腺素 (PG) 的生物合成和镇痛性前列腺素的水解 内源性大麻素（eCB）可降低伤害性神经元的敏感性并抑制下行促进。 初步数据表明，DRG、脊髓和 RVM 中 PG 增加，eCB 减少 由于 RvD1 增加了 eCB，因此在癌症期间有助于神经元敏化和疼痛。 RvD1 中大麻素受体的类型产生的反作用将得到阐明。 在三个具体目标上进行测试 1) 确定外周 RvD1 反感的分子机制。 和中枢神经系统；2) 确定 RvD1 对伤害性初级传入神经和脊髓的功能影响 癌症引起的骨痛期间的神经元；3) 确定 RvD1 对下行神经元的功能影响 第一个目标是使用生化和分子方法来促进和抑制 RVM。 确定癌痛发展过程中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 第二个目标是研究 Resolvin D1 对敏化的影响。 使用体内电生理学和体外 [Ca2+]i 成像观察伤害感受器和背角神经元 第三个目标将评估 RvD1 对下行促进和抑制的影响。 确定 RvD 是否会降低 RVM 中 ON 细胞的活性并增加 OFF 细胞的活性，以及​​它如何发挥作用 影响脊髓背角神经元的伤害性传递。这项研究具有创新性，因为它。 将揭示 RvD1 减轻癌症疼痛的新机制 该项目意义重大，因为它将 为 RvD1 作为治疗癌症疼痛的安全有效方法提供了基于机制的理由。