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

痛苦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，告诉我们身体受到了威胁。即使是最原始的生物，如鼻涕虫、蜗牛和苍蝇，它们微小的神经系统中也有机制让它们能够逃避破坏性的刺激。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，并持续数月甚至数年。这是慢性疼痛。这种慢性疼痛可以由癌症、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严重疼痛的人。这种持续的疼痛对生活质量有重大影响，扰乱了社会生活、工作和爱好，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，这些信息通过电子和化学事件通过我们的神经系统传递到大脑。如果我们的视觉系统受到损害，我们的正常视力就会丧失，我们可能会失明。令人惊讶的是，我们的感觉神经--传递疼痛和触摸信号的神经--经常会受到损伤。例如，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。大多数神经受损的患者会失去正常的感觉，并有麻木的区域。值得注意的是，许多患者即使失去了正常的神经功能，也会有剧烈而奇怪的疼痛。一个例子是幻肢，即使通过截肢切除了身体的一部分，患者仍然感受到缺失的肢体的疼痛。多达25%的患者在神经损伤后出现严重和异常的疼痛，导致英国近100万人死亡。神经损伤带来的疼痛包括持续性疼痛、超常疼痛，这是一种非常令人痛苦的状态，仅仅触摸或刷牙就会疼痛(患者通常无法承受衣服或床上用品的压力，也不能刷头)或痛觉过敏(疼痛刺激比正常情况严重许多倍)。这些迹象表明，神经损伤已经改变了神经系统。我们想找出神经、脊髓和大脑中发生了什么，才会产生这些异常的疼痛。这些疼痛的患者并不出人意料，往往情绪低落、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。当神经受损时，这些神经通路是如何相互交流的？为什么它们会发生变化？一种名为加巴喷丁(GBP)的药物是治疗神经损伤疼痛的主要药物，但它只在三分之一的患者中有效，对普通疼痛无效。我们想找出为什么会这样，并了解它如何只改变不正常的活动，比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，它可能是加巴喷丁减轻损伤相关疼痛作用的关键。因此，这项申请将把3名申请者聚集在一起，使用广泛的现代技术来了解我们的神经系统是如何因外部事件(如疼痛)而改变的，以及药物如何起作用以及为什么起作用。知道是什么决定了这一点，应该会让更多的患者从这种令人痛苦的疼痛状态中获得缓解。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、内部想法和疾病状态的反应和互动方式。

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.