Inflammatory signalling in the pain pathway: age-dependent differences in the response of neuronal ensembles to pain promoting molecules

疼痛通路中的炎症信号传导：神经元群对疼痛促进分子的反应存在年龄依赖性差异

• 批准号: 2747583
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 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=studentship-2747583
• 关键词: Inflammatory; signalling; pain; pathway; age

The dorsal horn (DH) of the spinal cord, as part of the central nervous system, is a complex network of neurons whose purpose is to respond and process afferent sensory information conveyed to it from the peripheral nervous system. The DH is a layered (laminated) structure, much like the cerebral cortex, with each lamina receiving different sensory inputs. Neurons in each lamina are also highly heterogenous, some are interneurons conveying information to the brain, others are interneurons relaying information from site to site within the DH. Recently we have shown that the systemic immune system responds differently to inflammatory stimuli in early life compared to adulthood. It has been shown, by us and others, that pain in early life is detected and processed differently by children and neonates. This is due to normal maturational changes which take place throughout the body including the brain and spinal cord. More recently other groups have shown that inflammation is able to leave a lasting "memory" in parts of the brain which can be reactivated later in life to drive further inflammation even when the initial challenge has resolved. We have also shown that the immune cells of the CNS, microglia, also respond to damage and infection differently in early life and that the molecules they secrete, the so called "inflammatory soup", in response to these challenges is different. This project will use our world-leading expertise in pain neurobiology and our unique technological tools to assess how pain processing is effected by specific inflammatory signalling at different points in the life-course. We will use a combination of in vivo and ex-vivo approaches to see how spinal networks respond to specific components of the inflammatory soup when they are applied to the spinal cord or parts of the brain which process and respond to pain. We will see how early life events can impact on the response of these brain centres to inflammation and by identifying differences in these processes in different ages identify targets for age appropriate therapies to treat and manage pain.Pain is a neurological phenomenon that affects the lives of people of all ages and regardless of sex or ethnicity. It blights the lives of people leading to social withdrawal, anxiety and depression. Central to the experience of pain is the DH and this project will break new ground in understanding how these complex networks function and ultimately lead to behavioural responses and the experienced of pain, with the long-term aim of identifying populations of neurons or signalling pathways that can be manipulated to relieve pain in people and animals.

脊髓背角（dorsal horn，DH）是中枢神经系统的一部分，是一个复杂的神经元网络，其目的是响应和处理从外周神经系统传递给它的传入感觉信息。DH是一个分层（层压）结构，很像大脑皮层，每个层接受不同的感觉输入。每个层中的神经元也是高度异质的，一些是向大脑传递信息的中间神经元，另一些是在DH内从一个位点到另一个位点传递信息的中间神经元。 最近，我们已经表明，与成年期相比，早期生命中的全身免疫系统对炎症刺激的反应不同。我们和其他人已经表明，儿童和新生儿在早期生活中对疼痛的检测和处理方式不同。这是由于正常的成熟变化发生在整个身体，包括大脑和脊髓。最近，其他研究小组表明，炎症能够在大脑的某些部分留下持久的“记忆”，即使最初的挑战已经解决，这些记忆也可以在以后的生活中重新激活，以驱动进一步的炎症。我们还表明，中枢神经系统的免疫细胞，小胶质细胞，在生命早期也对损伤和感染有不同的反应，并且它们分泌的分子，即所谓的“炎症汤”，响应这些挑战是不同的。该项目将利用我们在疼痛神经生物学方面的世界领先的专业知识和我们独特的技术工具来评估疼痛处理如何受到生命过程中不同点的特定炎症信号的影响。我们将使用体内和体外方法的组合来观察脊髓网络如何响应炎症汤的特定成分，当它们被应用于脊髓或大脑的处理和响应疼痛的部分时。我们将看到早期生活事件如何影响这些大脑中心对炎症的反应，并通过确定不同年龄的这些过程的差异，确定适合年龄的治疗和管理疼痛的目标。疼痛是一种神经学现象，影响所有年龄段的人的生活，无论性别或种族。它破坏了人们的生活，导致社会退缩，焦虑和抑郁。疼痛体验的核心是DH，该项目将在理解这些复杂网络如何发挥作用并最终导致行为反应和疼痛体验方面开辟新天地，其长期目标是确定可以操纵以缓解人类和动物疼痛的神经元或信号通路的群体。