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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

基本信息

批准号：
10684674
负责人：
Sergey G Khasabov
金额：
$ 43.32万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
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/10684674
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 Cells Central Nervous System Clinical Data Derivation procedure Development Disseminated Malignant Neoplasm Electrophysiology (science)Endocannabinoids Enzyme Inhibition Goals Hydrolysis Hyperalgesia In Vitro Inflammatory Knowledge Life Malignant Bone Neoplasm Malignant Neoplasms Mediating Membrane Metastatic Neoplasm to the Bone Molecular Nervous System Neurons Nociception Nociceptors Omega-3 Fatty Acids Opioid Outcome Pain Pain management Pathway interactions Patients Peripheral Peripheral Nervous System Polyunsaturated Fatty Acids Posterior Horn Cells Property Prostaglandin Inhibition Prostaglandins Research Role Spinal Spinal Cord Techniques Testing Therapeutic Tissues Ventilatory Depression Vertebral column addiction antinociception bone cancer pain cancer therapy cannabinoid receptor carcinogenesis effectiveness evaluation endocannabinoid signaling evidence base experience imaging approach in vivo innovation interdisciplinary approach lipid mediator motor impairment mouse model non-opioid analgesic novel preference receptor response side effect success transmission process treatment strategy

项目摘要

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，难以控制。阿片类药物是严重癌症疼痛的一线治疗，但其副作用，包括耐受性，成瘾性和呼吸抑郁症，限制其使用。寻找具有高镇痛效果和低不良反应的阿片替代品效果有限。长期目标是确定新的、有效的和安全的替代品，阿片类药物治疗疼痛该项目的重点是Resolvin D1（RvD 1），这是一种内源性的β-3衍生物多不饱和脂肪酸，作为癌症疼痛的可能治疗剂。使用骨癌小鼠模型痛苦初步数据显示，RvD 1的全身给药降低了癌症诱发的痛觉过敏，减弱伤害感受器和伤害感受背角神经元的敏感性，易化，同时增加从头端腹内侧的伤害性传递的下行抑制髓质（RVM）。RvD 1没有损害运动功能，也没有产生位置偏好，这表明它不是上瘾。本建议的总体目标是确定外围和中心的基本机制的RvD 1发挥镇痛作用。中心假设是RvD 1的全身给药抑制酶参与原伤害感受性前列腺素（PGs）的生物合成和抗伤害感受性前列腺素的水解，内源性大麻素（eCB），其降低伤害感受神经元的敏化并抑制下行易化。初步数据表明，背根节、脊髓和右心室中PG增加，eCB减少导致癌症期间的神经元敏化和疼痛。由于RvD 1增加了eCB，不同的作用将阐明RvD 1产生的抗伤害感受中的大麻素受体类型。核心假设将在三个具体目标中进行测试。1)确定外周中RvD 1抗伤害感受的分子机制 2）确定RvD 1对伤害性初级传入和脊髓神经元的功能作用; 3）确定RvD 1对癌症引起的骨痛中神经元的功能影响; RVM的促进和抑制作用。对于第一个目标，生物化学和分子方法将用于确定癌症疼痛发展过程中前列腺素和内源性大麻素信号的变化以及Resolvin D1的影响。第二个目的是研究Resolvin D1对致敏性的影响。伤害感受器和背角神经元的体内电生理和体外[Ca 2 +] i成像接近。第三个目标是通过以下方法评估RvD 1对下行易化和抑制的影响：确定RvD 1是否降低RVM中ON小区的活动和增加OFF小区的活动，以及RvD 1如何影响脊髓背角神经元的伤害性传递。这项研究是创新的，因为它将揭示RvD 1减少癌症疼痛的新机制。这个项目意义重大，因为它将为RvD 1作为一种安全有效的癌症疼痛管理方法提供了基于机制的依据。