Molecular and functional studies of mechanisms that determine the efficacy of anti-hyperalgesic agents in persistent pain models.

决定抗痛觉过敏药物在持续性疼痛模型中疗效的机制的分子和功能研究。

• 批准号: BB/D018250/1
• 负责人: Anthony Dickenson
• 金额: $ 85.71万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD018250%2F1
• 关键词: Molecular; functional; studies; mechanisms; determine

Pain is something we all experience in everyday life. It serves as a warning and survival message telling us of a threat to our body. Even the most primitive organisms such as slugs, snails and flies have mechanisms in their tiny nervous systems that allow them to escape damaging stimuli. Most of us have short-lasting pains but imagine that a headache, sprained ankle or period pain just went on and on and lasted for months and years on end. This is chronic pain. This chronic pain can arise from cancer, surgery, diseases such as rheumatism and arthritis and most people have a relation or know someone who has severe pain. This ongoing pain has a major impact on quality of life, disrupting social life, work, hobbies and furthermore, treatment can often be difficult. Nerves tell us what is happening in our bodies and in the outside world and by electrical and chemical events these messages are based on through our nervous system to the brain. If damage occurs to our visual system , our ability to see properly is lost and we may go blind. It is surprising how often our sensory nerves, nerves that signal pain and touch can be damaged. Examples could be an injury or even quite simple surgery. It is common that diseases such as diabetes, HIV and other viruses can lead to nerve damage. Most patients with damaged nerves have a loss of normal feeling and have numb areas. Remarkably, many patients also have severe and strange pains even though they have lost normal nerve function. One example would be phantom limbs where even through a part of the body has been removed by amputation, the person still 'feels' pain from the missing limb. Up to 25% of patients have severe and abnormal pains after nerve injury, leading to almost a million people in the UK. Pains from nerve injury include ongoing pain, allodynia, a very distressing state where mere touch or brushing is painful (patients often cannot bear the pressure of clothes or bedding, can't brush their hair) or hyperalgesia, (where a painful stimulus is many times worse than normal). These suggest the nervous system has been changed by the nerve injury. We want to find out what has happened in the nerves, spinal cord and brain to produce these abnormal pains. Patients with these pains not unexpectedly, often are depressed, anxious and can't sleep well. We have shown that the parts of the brain that deal with these emotions also change pain signals. How do these nervous pathways talk to each other and why do they change when nerves are damaged. A drug, gabapentin, (GBP) is the main treatment for nerve injury pain but it only works well in 1 in 3 patients and has no effect on ordinary pains. We want to find out why this is the case and understand how it only changes abnormal activity such as that caused by nerve injury. A chemical messenger in the brain called 5HT, important in mood and sleep, may be a key to the injury-linked pain reducing actions of gabapentin. Therefore this application will bring together 3 applicants using a wide range of modern techniques to understand how our nervous system is changed by external events such as pain and how and why drugs work. Knowledge of what determines this should allow greater numbers of patients to gain relief from this distressing pain state. It should enable us to understand how our nerves, spinal cord and brain have the ability to change the way they respond and interact in response to external stimuli, internal thoughts and disease states.

疼痛是我们在日常生活中都会经历的事情。它充当警告和生存信息，告诉我们身体受到威胁。即使是最原始的生物体，如蛞蝓、蜗牛和苍蝇，其微小的神经系统中也有机制，使它们能够逃避有害的刺激。我们大多数人都会经历短暂的疼痛，但想象一下头痛、扭伤脚踝或经期疼痛会持续数月甚至数年。这是慢性疼痛。这种慢性疼痛可能由癌症、手术、风湿病和关节炎等疾病引起，大多数人都有亲戚或认识患有剧烈疼痛的人。这种持续的疼痛对生活质量产生重大影响，扰乱社交生活、工作、爱好，而且治疗往往很困难。神经告诉我们身体和外部世界正在发生什么，并通过电和化学事件告诉我们这些信息是通过我们的神经系统传递到大脑的。如果我们的视觉系统受损，我们就会丧失正常视力，甚至可能失明。令人惊讶的是，我们的感觉神经、发出疼痛和触觉信号的神经经常受到损害。例子可能是受伤，甚至是非常简单的手术。糖尿病、艾滋病毒和其他病毒等疾病通常会导致神经损伤。大多数神经受损的患者会失去正常感觉并出现麻木的情况。值得注意的是，许多患者即使失去了正常的神经功能，也会出现剧烈且奇怪的疼痛。一个例子是幻肢，即使身体的一部分被截肢去除，人们仍然会“感觉到”缺失肢体的疼痛。高达 25% 的患者在神经损伤后出现严重且异常的疼痛，导致英国近百万人患病。神经损伤引起的疼痛包括持续性疼痛、异常性疼痛、一种非常痛苦的状态，其中仅仅触摸或刷牙就会感到疼痛（患者通常无法承受衣服或床上用品的压力，无法梳理头发）或痛觉过敏（其中疼痛刺激比正常情况严重许多倍）。这些表明神经系统已因神经损伤而发生改变。我们想找出神经、脊髓和大脑中发生了什么导致这些异常疼痛的原因。患有这些疼痛的患者不出所料，往往会感到抑郁、焦虑，睡不好觉。我们已经证明，大脑中处理这些情绪的部分也会改变疼痛信号。这些神经通路如何相互交流以及为什么当神经受损时它们会发生变化。加巴喷丁 (GBP) 是治疗神经损伤疼痛的主要药物，但仅对三分之一的患者有效，并且对普通疼痛没有效果。我们想找出为什么会出现这种情况，并了解它如何改变异常活动，例如由神经损伤引起的活动。大脑中一种名为 5HT 的化学信使对情绪和睡眠很重要，可能是加巴喷丁减轻损伤相关疼痛作用的关键。因此，该申请将汇集 3 名申请人，使用广泛的现代技术来了解我们的神经系统如何被外部事件（例如疼痛）改变，以及药物如何以及为何发挥作用。了解造成这种情况的原因应该可以让更多的患者从这种令人痛苦的疼痛状态中得到缓解。它应该使我们能够了解我们的神经、脊髓和大脑如何能够改变它们对外部刺激、内部思想和疾病状态的反应和相互作用的方式。