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

疼痛是我们在日常生活中都会经历的事情。它是一种警告和生存信息，告诉我们身体有威胁。即使是最原始的生物，如蛞蝓、蜗牛和苍蝇，在它们微小的神经系统中也有一些机制，使它们能够逃避有害的刺激。我们大多数人都有短暂的疼痛，但想象一下，头痛、扭伤脚踝或经期疼痛只是持续不断，持续数月或数年。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有严重疼痛的人。这种持续的疼痛对生活质量产生了重大影响，扰乱了社交生活、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发生了什么，通过电子和化学事件，这些信息是基于我们的神经系统到达大脑的。如果我们的视觉系统受损，我们就失去了正常看东西的能力，我们可能会失明。令人惊讶的是，我们的感觉神经，即发出疼痛和触觉信号的神经，经常会受到损伤。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会导致神经损伤，这是很常见的。大多数神经受损的病人失去了正常的感觉，有麻木的区域。值得注意的是，许多患者即使失去了正常的神经功能，也会感到严重而奇怪的疼痛。一个例子是幻肢，即使身体的一部分被截肢了，这个人仍然“感觉到”来自缺失肢体的疼痛。高达25%的患者在神经损伤后会出现严重和异常的疼痛，在英国有近100万人患有这种疾病。神经损伤引起的疼痛包括持续疼痛、异常性疼痛(一种非常痛苦的状态，仅仅是触摸或刷牙就会感到疼痛（患者经常无法承受衣服或被褥的压力，无法梳头）或痛觉过敏（疼痛刺激比正常情况严重许多倍）。这表明神经系统因神经损伤而发生了改变。我们想找出神经、脊髓和大脑中发生了什么导致了这些不正常的疼痛。不出所料，患有这些疼痛的患者通常会感到抑郁、焦虑和睡不好觉。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。这些神经通路是如何相互沟通的，为什么当神经受损时它们会发生变化。加巴喷丁（gabapentin， GBP）是治疗神经损伤疼痛的主要药物，但它只对三分之一的患者有效，对普通疼痛没有效果。我们想找出为什么会这样，并理解它是如何只改变异常活动的，比如由神经损伤引起的活动。大脑中有一种叫做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（如疼痛）改变，以及药物如何以及为什么起作用。了解是什么决定了这一点，应该可以让更多的病人从这种痛苦的疼痛状态中得到缓解。它应该使我们能够理解我们的神经、脊髓和大脑如何有能力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方式。

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.