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

慢性疼痛是一个巨大的健康问题。它给患者及其照顾者带来身心痛苦，并给卫生保健系统带来巨大压力。尤其是因为许多类型的慢性疼痛特别难以治疗，大多数传统的止痛药要么无效，要么有严重的副作用。许多慢性疼痛病症的常见主要原因之一是特定外周神经的不受控制的活动，所述特定外周神经通常是沉默的并且仅响应于潜在的破坏性刺激而变得活跃。损伤感知神经的这种病理活动（外周敏化）可能持续数月或数年（例如在关节炎或神经性疼痛中），导致无限制的疼痛。不幸的是，尽管付出了很多努力，外周敏化的机制仍然知之甚少。最近的工作在实验室的申请人已经导致了积累？临界质量？有足够的证据来发现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，神经损伤触发长激光下调特定组的基因编码的蛋白质家族称为？M型钾通道？控制周围神经的活动。重要的是，我们发现了另一种蛋白质，叫做？休息？其能够特异性地与M型钾通道基因相互作用并调节其表达。我们的假设（由我们最近发表但尚未发表的数据支持）是神经损伤或炎症触发REST的表达，这反过来又抑制了外周感觉神经中M型钾通道的表达，从而增加了它们的自发活动。该提案的目的是对这种新机制进行全面而严格的调查。我们将使用已知的神经病理性疼痛的动物模型，结合一系列尖端的遗传学、分子学、生物化学和电生理学方法，以充分证实神经损伤诱导的M型钾通道基因表达模式的变化。我们将进一步探索负责控制感觉神经中M通道表达和功能的机制，特别关注REST的新发现的作用。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来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 Our hypothesis (supported by our recently published and yet unpublished data) is that nerve injury or inflammation triggers the expression of REST which, in turn, suppresses the expression of M-type potassium channels in peripheral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.