Targeting neuropathic pain prevention: Modulating the neuroimmunology of peripheral nerve injury

以预防神经病理性疼痛为目标:调节周围神经损伤的神经免疫学

基本信息

  • 批准号:
    10062833
  • 负责人:
  • 金额:
    $ 34.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-12-01 至 2023-11-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Neuropathic pain occurs in epidemic proportions worldwide and none of the currently available therapeutics provides adequate pain relief and all have significant side effects. None are “disease modifying” as all are simply palliative in targeting symptoms, not cause. There must be a better approach to pain control. What we have discovered could potentially revolutionize the clinical treatment of trauma and surgical pa- tients, all of whom are at marked risk (~50-70%) for developing neuropathic pain. Our discovery is that 6 wk of moderate voluntary exercise that ceases at the time of nerve trauma appears to permanently suppress the lat- er development of neuropathic pain. Such an effect has never been previously reported. The core thesis of this proposal is that novel, superior pharmacological and/or herbalism treatment strate- gies will arise from understanding how non-pharmacological voluntary exercise produces dramatic prevention of chronic pain. The critical first step is to understand how VWR prevents chronic pain. This enlightens target- ed, evidence-based steps toward achieving the same dramatic prevention of pain via pharmacological and/or herbal medicine approaches. The mechanisms explored in the present proposal are unique from those of any currently available pain therapeutic. If we can understand and harness prevention of neuropathic pain, this should lead to early drug interventions of broad practical importance. How 6 wk voluntary wheel running (VWR) could profoundly influence the cascade of neuroimmunological and neuropathological events set into motion by later nerve injury has never been explored. This is critical to understand at a mechanistic level, as prior VWR appears to be the first “disease modifying” approach to con- trolling whether chronic pain develops. Understanding how this occurs will enable development of novel drug regimens to pharmacologically duplicate these effects without the necessity of exercise regimens that few peo- ple will follow. We predict that understanding how prior voluntary exercise (VWR) exerts such powerful, and seemingly permanent suppression of neuropathic pain is a tractable research goal, addressable by the multi-disciplinary approach proposed. This would first seek to understand the behavioral, immunological, neuroimmunological, and functional effects of: (a) VWR, (b) nerve injury (classic sciatic chronic constriction injury [CCI] model in male and female rats), and (c) their interaction on the aftermath of nerve injury. Based on these findings, mechanistic studies are proposed so to begin to explore how prior VWR could exert such a positive, pain- preventative effect on later nerve injury. Toward this goal, studies that seek to inhibit and to recapitulate the effects of VWR are both proposed. The long term aim is to capitalize on the understanding of how prior VWR creates such long-lasting suppression of neuropathic pain so to identify clinically relevant approaches to neu- ropathic pain prevention, thereby providing a far superior approach to pain control than currently available.
项目摘要 神经性疼痛在世界范围内流行,目前可用的治疗方法 提供足够的疼痛缓解,并且都有显著的副作用。没有一个是“疾病修饰”,因为所有都是 只是治标不治本必须有更好的方法来控制疼痛。 我们的发现可能会彻底改变创伤和外科手术的临床治疗, 所有这些人都有发生神经性疼痛的显著风险(约50-70%)。我们的发现是, 在神经创伤时停止的适度的自愿运动似乎永久地抑制了后者, 神经性疼痛的发展。这种影响以前从未报道过。 该提案的核心论点是,新的、上级药理学和/或草药治疗策略- gies将产生于理解非药物自愿运动如何产生戏剧性的预防 慢性疼痛。关键的第一步是了解VWR如何预防慢性疼痛。这启发了目标- 艾德,循证步骤,以实现相同的戏剧性预防疼痛,通过药理学和/或 草药的方法。本提案中探讨的机制与任何其他机制都不同, 目前可用的疼痛治疗剂。如果我们能够理解和利用预防神经性疼痛, 应导致具有广泛实际重要性的早期药物干预。 6周自愿轮跑(VWR)如何深刻影响神经免疫级联反应 以及后来神经损伤引发的神经病理事件从未被探索过。这对于 在机械水平上理解,因为先前的VWR似乎是第一个“疾病修饰”方法, 是否会出现慢性疼痛了解这是如何发生的,将有助于开发新药 方案,以避免重复这些影响,而不需要运动方案,很少有人- Ple将跟随。 我们预测,了解事先自愿运动(VWR)如何发挥如此强大的,似乎 永久性抑制神经性疼痛是一个易处理的研究目标,可由多学科 建议的方法。这将首先寻求了解行为,免疫,神经免疫, 和功能影响:(a)VWR,(B)神经损伤(经典坐骨神经慢性压迫性损伤[CCI]模型, 雄性和雌性大鼠),以及(c)它们在神经损伤后的相互作用。根据这些发现, 提出了机制研究,以便开始探索先前的VWR如何发挥这种积极的、痛苦的作用, 对以后的神经损伤有预防作用。为了实现这一目标,寻求抑制和概括 VWR的影响都提出了。长期目标是利用对先前VWR如何 产生这种持久的神经性疼痛抑制,以便确定临床相关的方法, 从而提供了比目前可用的更好的上级疼痛控制方法。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Suppression of active phase voluntary wheel running in male rats by unilateral chronic constriction injury: Enduring therapeutic effects of a brief treatment of morphine combined with TLR4 or P2X7 antagonists.
  • DOI:
    10.1002/jnr.24645
  • 发表时间:
    2022-01
  • 期刊:
  • 影响因子:
    4.2
  • 作者:
    Green-Fulgham SM;Ball JB;Maier SF;Rice KC;Watkins LR;Grace PM
  • 通讯作者:
    Grace PM
Preconditioning by voluntary wheel running attenuates later neuropathic pain via nuclear factor E2-related factor 2 antioxidant signaling in rats.
  • DOI:
    10.1097/j.pain.0000000000002589
  • 发表时间:
    2022-10-01
  • 期刊:
  • 影响因子:
    7.4
  • 作者:
  • 通讯作者:
T cell transgressions: Tales of T cell form and function in diverse disease states.
  • DOI:
    10.1080/08830185.2021.1921764
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    5
  • 作者:
    Harris KM;Clements MA;Kwilasz AJ;Watkins LR
  • 通讯作者:
    Watkins LR
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LINDA WATKINS其他文献

LINDA WATKINS的其他文献

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{{ truncateString('LINDA WATKINS', 18)}}的其他基金

Enduring enhancement of neuropathic pain by early post-trauma morphine
创伤后早期吗啡持久增强神经性疼痛
  • 批准号:
    9906887
  • 财政年份:
    2018
  • 资助金额:
    $ 34.65万
  • 项目类别:
Enduring enhancement of neuropathic pain by early post-trauma morphine
创伤后早期吗啡持久增强神经性疼痛
  • 批准号:
    10393512
  • 财政年份:
    2018
  • 资助金额:
    $ 34.65万
  • 项目类别:
Targeting toll like receptor 4 (TLR4) and TLR2 to resolve EAE-associated paralysis, pain and cognitive deficits: efficacy of a clinically-relevant blood brain barrier permeable TLR4/TLR2 antagonist
靶向 Toll 样受体 4 (TLR4) 和 TLR2 以解决 EAE 相关的麻痹、疼痛和认知缺陷:临床相关血脑屏障可渗透性 TLR4/TLR2 拮抗剂的功效
  • 批准号:
    9153350
  • 财政年份:
    2016
  • 资助金额:
    $ 34.65万
  • 项目类别:
Spinal adenosine modulator: enduring anti-inflammatory action in neuropathic pain
脊髓腺苷调节剂:对神经性疼痛具有持久的抗炎作用
  • 批准号:
    7805660
  • 财政年份:
    2009
  • 资助金额:
    $ 34.65万
  • 项目类别:
Spinal adenosine modulator: enduring anti-inflammatory action in neuropathic pain
脊髓腺苷调节剂:对神经性疼痛具有持久的抗炎作用
  • 批准号:
    7937819
  • 财政年份:
    2009
  • 资助金额:
    $ 34.65万
  • 项目类别:
Models and mechanisms for the transition of acute-to-chronic orofacial pain
急性至慢性口面部疼痛转变的模型和机制
  • 批准号:
    7936108
  • 财政年份:
    2009
  • 资助金额:
    $ 34.65万
  • 项目类别:
Models and mechanisms for the transition of acute-to-chronic orofacial pain
急性至慢性口面部疼痛转变的模型和机制
  • 批准号:
    7805658
  • 财政年份:
    2009
  • 资助金额:
    $ 34.65万
  • 项目类别:
Optoid Analgesics: Modulation of Trigeminal & Spinal Glial Activation
Optoid 镇痛药:三叉神经的调节
  • 批准号:
    7840785
  • 财政年份:
    2009
  • 资助金额:
    $ 34.65万
  • 项目类别:
Exploring the Potential of Glia for Regulating Clinically Relevant Opiod Actions
探索神经胶质细胞调节临床相关阿片类药物作用的潜力
  • 批准号:
    8267435
  • 财政年份:
    2008
  • 资助金额:
    $ 34.65万
  • 项目类别:
Immune and Gilia Regulation of Pain & Analgesic Actions
免疫和吉利亚疼痛调节
  • 批准号:
    8284453
  • 财政年份:
    2008
  • 资助金额:
    $ 34.65万
  • 项目类别:

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