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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.

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