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:
- 金额:$ 43.32万
- 依托单位:
- 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:
- 关键词:Absence of pain sensationAdverse effectsAffectAnabolismAnalgesicsAttenuatedBehavioralBiochemicalBiophysicsBone PainBone neoplasmsBrainBrain StemCNR1 geneCancer ModelCancer Pain ManagementCellsCentral Nervous SystemClinicalDataDerivation procedureDevelopmentDisseminated Malignant NeoplasmElectrophysiology (science)EndocannabinoidsEnzyme InhibitionGoalsHydrolysisHyperalgesiaIn VitroInflammatoryKnowledgeLifeMalignant Bone NeoplasmMalignant NeoplasmsMediatingMembraneMetastatic Neoplasm to the BoneMolecularNervous SystemNeuronsNociceptionNociceptorsOmega-3 Fatty AcidsOpioidOutcomePainPain managementPathway interactionsPatientsPeripheralPeripheral Nervous SystemPolyunsaturated Fatty AcidsPosterior Horn CellsPropertyProstaglandin InhibitionProstaglandinsResearchRoleSpinalSpinal CordTechniquesTestingTherapeuticTissuesVentilatory DepressionVertebral columnaddictionantinociceptionbonecancer paincancer therapycannabinoid receptorcarcinogenesiseffectiveness evaluationendocannabinoid signalingevidence baseexperienceimaging approachin vivoinnovationinterdisciplinary approachlipid mediatormotor impairmentmouse modelnon-opioid analgesicnovelpreferencereceptorresponseside effectsuccesstransmission processtreatment 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RvD 1外周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。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Tryptophan Prevents the Development of Non-Alcoholic Fatty Liver Disease.
- DOI:10.2147/dmso.s444278
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Exosome-associated lysophosphatidic acid signaling contributes to cancer pain.
- DOI:10.1097/j.pain.0000000000002967
- 发表时间:2023-12-01
- 期刊:
- 影响因子:7.4
- 作者:
- 通讯作者:
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Sergey G Khasabov其他文献
Sergey G Khasabov的其他文献
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{{ truncateString('Sergey G Khasabov', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 43.32万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 43.32万 - 项目类别:
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