Regulation of M-type K+ channel expression in sensory neurones as a novel mechanism contributing to chronic pain states

慢性疼痛是一个严重的健康问题。它给患者和他们的照顾者带来了身体和心理上的痛苦，并给卫生保健系统带来了巨大的压力。这一点尤其正确，因为许多类型的慢性疼痛特别难以治疗，大多数传统止痛药要么无效，要么有严重的副作用。许多慢性疼痛的主要原因之一是特定周围神经的不受控制的活动，这些神经通常是沉默的，只有在对潜在的破坏性刺激作出反应时才变得活跃。这种损伤感知神经的病理活动（外周致敏）可能持续数月或数年（例如关节炎或神经性疼痛），导致无法抑制的疼痛。不幸的是，尽管付出了很多努力，但人们对外周致敏的机制知之甚少。申请人实验室最近的工作导致了一个？临界质量?有证据表明可能成为导致慢性疼痛的关键分子机制之一。我们的研究结果表明，神经损伤会触发一组特定基因的长时间下调，这些基因编码的蛋白质家族被称为？m型钾通道？控制周围神经的活动。重要的是，我们发现了另一种叫做？休息吗?该基因能够特异性地与m型钾通道基因相互作用并调节其表达。我们的假设（由我们最近发表的和尚未发表的数据支持）是神经损伤或炎症触发REST的表达，而REST反过来又抑制周围感觉神经中m型钾通道的表达，从而增加其自发活动。本提案的目的是对这一新机制进行全面而严格的研究。我们将使用已知的神经性疼痛动物模型，结合一系列尖端的遗传、分子、生化和电生理学方法，全面表征神经损伤诱导的m型钾通道基因表达模式的变化。我们将进一步探讨控制感觉神经中m通道表达和功能的机制，特别关注REST新发现的作用。我们的工作有可能确定新的目标和策略，可用于开发更好的药物治疗和管理慢性疼痛。

Chronic pain constitutes an enormous health problem. It brings physical and psychological distress to the sufferers and their carers and puts significant pressure on the health care system. It is especially true because many types of chronic pains are particularly difficult to treat, most of the conventional analgesics are either ineffective or have serious side-effects. One of the common primary causes of many chronic pain conditions is an uncontrolled activity of specific peripheral nerves which normally are silent and only become active in response to potentially damaging stimulation. This pathological activity of damage-sensing nerves (peripheral sensitisation) may last for months or years (e.g. in arthritis or neuropathic pain) causing unrestrained pain. Unfortunately, despite of much effort, the mechanisms underlying peripheral sensitisation are poorly understood. Recent work in the laboratories of the applicants has lead up to the accumulation of a ?critical mass? of evidence towards the discovery of what may become one of the key molecular mechanism contributing to the chronic pain. Our findings revealed that nerve injury triggers long-lasing down-regulation of specific group of genes that encode family of proteins called ?M-type potassium channels? that control activity of peripheral nerves. Importantly, we identified another protein called ?REST?, which is able to specifically interact with and regulate expression of the M-type potassium channel genes. Our hypothesis (supported by our recently published and yet unpublished data) is that nerve injury or inflammation triggers the expression of REST which, in turn, suppresses the expression of M-type potassium channels in peripheral sensory nerves thus increasing their spontaneous activity. The aim of this proposal is to perform comprehensive and rigorous investigation of this novel mechanism. We will use known animal models for neuropathic pain in combination with an array of cutting edge genetic, molecular, biochemical and electrophysiological approaches to fully characterise the changes in the expression patterns of the M-type potassium channel genes induced by nerve injury. We will further probe the mechanism responsible for control of M-channel expression and function in sensory nerves with particular attention to the newly discovered role of REST. Our work has the potential to identify new targets and strategies that may be used to develop better medicines for the treatment and management of chronic pain.