Defining descending inhibitory pathway functionality in health and disease

定义健康和疾病中的下降抑制途径功能

• 批准号: MR/W004739/1
• 负责人: Kirsty Bannister
• 金额: $ 63.32万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW004739%2F1
• 关键词: Defining; descending; inhibitory; pathway; functionality

When we break an ankle, further damage is prevented through the protective sensation of pain; we avoid weight bearing. Unfortunately on occasion, after damaged body parts have healed, pain persists. This kind of pain, termed chronic pain, has no protective function. Current pain relieving drugs do not always work and as such chronic pain affects up to 20% of the adult population. This results in a significant economic strain on the healthcare system as well as a huge socioeconomic burden on the individual. To identify new drugs that make chronic pain patients feel less pain we must identify new therapeutic targets based on novel mechanistic insight. My research ultimately aims to provide such insight. The process of pain perception is highly complex. It involves many different nerve signals travelling from the brain to the spinal cord. These nerve signals comprise regulatory pathways that, in the normal situation, make us feel less pain. However, in chronic pain, the function of these regulatory pathways can go wrong leading us to feel more pain. This grant seeks to investigate the functionality of these pathways a) in health and b) in a rodent model of chronic pain. Chronic pain can manifest in patients suffering from cancer; the growth of secondary cancer tumours in the bone may lead to cancer induced bone pain (CIBP). Due to improvements in cancer treatments coupled with largely ineffective pain relieving options, the prevalence of CIBP is high. In my laboratory I have developed a rodent model of CIBP that encompasses early and late stages of the disease. I have collected preliminary data showing that regulatory pathways, from the brain to the spinal cord, do not function in the proper manner in these rodents in the early stage of disease. I wish to use NIRG MRC funding to prove whether or not the nerve signals that comprise the regulatory pathways have gone wrong in a manner that is specific to the stage of disease progression. My hypotheses are that multiple distinct regulatory pathways exist and that regulatory pathways are impacted negatively in a stage-specific way. I propose that this negative impact on regulatory pathways is an underlying cause of the pain associated with this disease, and if true it would mean that directed therapies, intended to relieve suffering in, for example, cancer pain patients, could be more easily formulated according to, for example, the stage of disease. To this end I will study the influencing factors and function of brain to spinal cord inhibitory pain pathways in health and in CIBP rats. Through comparison it will be possible to pinpoint where regulatory pain pathway connections have gone wrong. Ultimately, pain-relieving agents could be prescribed more effectively if we understand what regulatory pain pathway we should target for chronic pain relief.

当我们摔断脚踝时，通过疼痛的保护性感觉来防止进一步的伤害;我们避免负重。不幸的是，有时，在受损的身体部位愈合后，疼痛仍然存在。这种疼痛被称为慢性疼痛，没有保护功能。目前的止痛药物并不总是有效，因此慢性疼痛影响多达20%的成年人。这对医疗保健系统造成了巨大的经济压力，并对个人造成了巨大的社会经济负担。为了找到能让慢性疼痛患者感觉更少疼痛的新药，我们必须基于新的机制见解来确定新的治疗靶点。我的研究最终旨在提供这样的见解。疼痛感知的过程是非常复杂的。它涉及许多不同的神经信号从大脑传播到脊髓。这些神经信号包括调节通路，在正常情况下，使我们感觉不到疼痛。然而，在慢性疼痛中，这些调节通路的功能可能会出错，导致我们感到更多的疼痛。这项资助旨在研究这些途径a）在健康中的功能和B）在慢性疼痛的啮齿动物模型中的功能。慢性疼痛可以在患有癌症的患者中表现出来;继发性癌症肿瘤在骨中的生长可能导致癌症诱导的骨痛（CIBP）。由于癌症治疗的改进加上大部分无效的疼痛缓解选择，CIBP的患病率很高。在我的实验室里，我开发了一种CIBP的啮齿动物模型，包括疾病的早期和晚期。我收集的初步数据显示，从大脑到脊髓的调节通路在疾病的早期阶段不能以适当的方式在这些啮齿动物中发挥作用。我希望利用NIRG MRC的资金来证明构成调节通路的神经信号是否以特定于疾病进展阶段的方式出错。我的假设是，存在多个不同的调节途径，并且调节途径以特定于阶段的方式受到负面影响。我认为，这种对调节途径的负面影响是与这种疾病相关的疼痛的根本原因，如果这是真的，这将意味着定向治疗，旨在减轻痛苦，例如，癌症疼痛患者，可以更容易地根据疾病的阶段制定。为此，我将在健康和CIBP大鼠中研究大脑到脊髓抑制性疼痛通路的影响因素和功能。通过比较，可以查明疼痛调节通路连接在哪里出现了问题。最终，如果我们了解我们应该针对慢性疼痛缓解的调节疼痛通路，那么止痛剂可以更有效地处方。

项目成果

Distinct brainstem to spinal cord noradrenergic pathways inversely regulate spinal neuronal activity.

• DOI: 10.1093/brain/awac085
• 发表时间: 2022-07-29
• 期刊: Brain : a journal of neurology

The origin of diffuse noxious inhibitory controls

弥漫性有害抑制控制的起源

• DOI: 10.1101/2022.03.29.486214
• 发表时间: 2022
• 作者: Kucharczyk M

A back-translational study of descending interactions with central mechanisms of hyperalgesia induced by high frequency stimulation in rat and human

大鼠和人类高频刺激引起的痛觉过敏中枢机制的下降相互作用的反向翻译研究

• DOI: 10.1101/2022.11.25.517919
• 发表时间: 2022
• 作者: Patel R

One size does not fit all: towards optimising the therapeutic potential of endogenous pain modulatory systems.

• DOI: 10.1097/j.pain.0000000000002697
• 发表时间: 2023-01-01
• 期刊: Pain
• 影响因子: 7.4

A critical brainstem relay for mediation of diffuse noxious inhibitory controls.

• DOI: 10.1093/brain/awad002
• 发表时间: 2023-06-01
• 期刊: Brain : a journal of neurology