Susceptibility to Chronic Pain: role of Cerebellar - Periaqueductal Gray Communication

对慢性疼痛的易感性：小脑 - 导水管周围灰质通讯的作用

• 批准号: MR/T019484/1
• 负责人: Bridget Lumb
• 金额: $ 66.66万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT019484%2F1
• 关键词: Susceptibility; Chronic; Pain; role; Cerebellar

Acute pain is a necessary sensory function that signals tissue damaging stimuli such as the heat of a fire. It is short lasting and is essential for survival, as it drives simple protective measures such as removing the hand from the fire. Other protective measures triggered by acute pain, such as changes in fear and anxiety, are more complex and involve networks of neurons that encompass many brain regions; the so-called survival network. Acute pain ends following removal of the stimulus or upon repair of the injury. However, in a significant proportion of individuals pain persists beyond the period of tissue repair and can last for months or years; this is known as chronic pain and it is a massive problem. Current treatments are largely ineffective and so new lines of research are needed to identify novel targets for the development of treatments. It is clear that some people are more susceptible to the development of chronic pain than others. Susceptibility is also a feature of anxiety disorders (such as post-traumatic stress disorder) as a small population of people cannot 'forget' (extinguish) a fear response to a fearful event that has occurred in the past. Importantly, anxiety disorders and chronic pain often occur together, suggesting they share similar neuronal mechanisms. A major unanswered question is what makes some people susceptible to the transition from acute to chronic pain and what are the underlying mechanisms? Survival is promoted by alterations in pain perception. In some instances (such as escaping from danger) stopping pain is advantageous as it allows an animal to escape without distraction of the pain. By contrast, in other situations (such as during recovery from illness) increased awareness of pain becomes an advantage as it encourages resting behaviour. This is beneficial, as rest allows the individual to focus on recuperation from illness. Suppression or enhancement of pain is mediated by pathways that originate in the brain and travel down to the spinal cord to alter pain transmission (the so-called descending pain modulatory system or DPMS). Brain survival networks can suppress or enhance the pain signal by controlling activity in the DPMS. In acute pain, activity in these pathways alters the pain experience to promote survival in the ways described. However, in some vulnerable individuals the DPMS becomes abnormal and amplifies the pain signal leading to chronic pain.Similar to anxiety disorders, such as post-traumatic stress disorder, we propose that a failure of the brain to 'forget' the memory of a painful stimulus triggers changes in brain functioning; thus creating an illusion, which is interpreted by the brain as pain. We hypothesise that the development of chronic pain is due in part to a change in the ability of the survival network to correctly predict the appropriate pain response to injury based on past pain experience, and that this alters the DPMS causing amplification of the pain signal resulting in chronic pain. The cerebellum is a region of the brain that detects differences between predictable and unpredictable pain information (termed prediction error). The cerebellum has interactions with a brain structure called the periaqueductal gray (PAG), which is a source of DPMS. Both the cerebellum and the PAG are components of the survival network and their dual roles in pain processing and signalling prediction error make them strong candidates for driving the development of chronic pain. This project will test, in a rat model, whether susceptibility to chronic pain is dependent on changes in the interactions between the cerebellum and the PAG that results in abnormal activity in descending control of pain signalling and, as a consequence, amplifies the perception and the responsiveness to pain. A better understanding of these brain functions will open important new avenues for the development of therapies for chronic pain.

急性疼痛是一种必要的感觉功能，它发出组织损伤刺激的信号，如火的热量。它是短暂的，对生存至关重要，因为它驱动简单的保护措施，如将手从火中移开。由急性疼痛引发的其他保护措施，如恐惧和焦虑的变化，更为复杂，涉及包括许多大脑区域的神经元网络;所谓的生存网络。急性疼痛在刺激物去除或损伤修复后结束。然而，在很大一部分人中，疼痛持续超过组织修复期，可以持续数月或数年;这被称为慢性疼痛，这是一个巨大的问题。目前的治疗方法在很大程度上是无效的，因此需要新的研究路线来确定新的治疗目标。很明显，有些人比其他人更容易患上慢性疼痛。易感性也是焦虑症（如创伤后应激障碍）的一个特征，因为一小部分人不能“忘记”（消除）对过去发生的可怕事件的恐惧反应。重要的是，焦虑症和慢性疼痛经常一起发生，这表明它们具有相似的神经机制。一个主要的未回答的问题是什么使一些人容易从急性疼痛过渡到慢性疼痛，以及潜在的机制是什么？疼痛感知的改变促进了生存。在某些情况下（例如逃离危险），停止疼痛是有利的，因为它允许动物在不分散疼痛的情况下逃跑。相比之下，在其他情况下（如从疾病中恢复），增加对疼痛的认识成为一种优势，因为它鼓励休息行为。这是有益的，因为休息可以让个人专注于从疾病中恢复。疼痛的抑制或增强是由起源于大脑并向下行进到脊髓以改变疼痛传递的通路（所谓的下行疼痛调节系统或DPMS）介导的。大脑生存网络可以通过控制DPMS的活动来抑制或增强疼痛信号。在急性疼痛中，这些通路的活动改变了疼痛体验，以上述方式促进生存。然而，在一些脆弱的个体中，DPMS变得异常，并放大了疼痛信号，导致慢性疼痛。类似于焦虑症，如创伤后应激障碍，我们提出，大脑无法“忘记”痛苦刺激的记忆会触发大脑功能的变化;因此产生幻觉，大脑将其解释为疼痛。我们假设，慢性疼痛的发展部分是由于生存网络的能力发生变化，根据过去的疼痛经验正确预测对损伤的适当疼痛反应，这改变了DPMS，导致疼痛信号放大，导致慢性疼痛。小脑是大脑的一个区域，可以检测可预测和不可预测的疼痛信息之间的差异（称为预测误差）。小脑与称为导水管周围灰质（PAG）的大脑结构相互作用，这是DPMS的来源。小脑和PAG都是生存网络的组成部分，它们在疼痛处理和信号预测错误中的双重作用使它们成为驱动慢性疼痛发展的强有力的候选者。该项目将在大鼠模型中测试对慢性疼痛的易感性是否取决于小脑和PAG之间的相互作用的变化，这种变化导致疼痛信号的下行控制异常活动，从而放大对疼痛的感知和反应。更好地了解这些大脑功能将为慢性疼痛疗法的发展开辟重要的新途径。