The role of CASPR2 in regulating sensory neuronal excitability and chronic pain

疼痛提醒身体注意实际或潜在的组织损伤，从而有助于防止任何初始或进一步的损伤。在组织受损的情况下，疼痛的感觉会增强，以努力保护受伤的区域并加快恢复过程。因此，疼痛是一种有用的感觉，尽管是一种令人不快的感觉。然而，疼痛可能会变得不适应，持续超过它的作用，使患者变得虚弱。这种疼痛持续数月，有时甚至数年，称为慢性疼痛，每5个成年人中就有1人受到影响。尽管目前仍在使用止痛药，但由于治疗费用和下班时间的原因，它会产生重大的经济影响。目前的镇痛药除了缺乏疗效外，还会产生严重的副作用。我们有新的数据表明，接触素相关蛋白2(CASPR2)是一种在感觉神经系统中表达的蛋白质，可以调节疼痛敏感性。这种蛋白的自身抗体最近被认为与患者的神经病理性疼痛有关。该项目的主要目的将是确定CASPR2在急性和慢性疼痛状态中的作用。我们将开发一个动物模型，以了解CASPR2自身抗体是如何导致慢性疼痛的。此外，在神经损伤后，CASPR2水平会下降。我们将通过它与钾通道的已知相互作用来确定这是否与神经病理性疼痛有关，钾通道在调节神经元兴奋性方面具有重要作用。我们的目标是确定CASPR2如何改变感觉神经系统内的功能，以更好地针对该蛋白自身抗体患者的当前治疗方法，同时也潜在地开发治疗神经病理性疼痛的新疗法。

Pain alerts the body to actual or potential tissue damage and thereby helps to prevent any initial or further injury. In the case where tissue is damaged the sensation of pain is enhanced in an effort to protect the injured area and speed the recovery process. Therefore pain is a useful sensation albeit an unpleasant one. However pain can become maladaptive, persisting beyond its usefulness and becoming debilitating for the sufferer. This type of pain, which persists for months and in some cases years, is termed chronic pain and affects 1 in 5 adults. It has major economic repercussions due to treatment costs and time spent off work and this is in spite of current analgesic use. In addition to a lack of efficacy current analgesics also cause severe side-effects. We have new data to suggest that contactin associated protein 2 (CASPR2), a protein expressed within the sensory nervous system, can regulate pain sensibility. Autoantibodies to this protein have recently been associated with neuropathic pain in patients. The main aim of this project will be to determine the role of CASPR2 in both acute and chronic pain states. We will develop an animal model in order to understand how CASPR2 autoantibodies cause chronic pain. Furthermore levels of CASPR2 fall after nerve injury. We will determine if this contributes to neuropathic pain through its known interactions with potassium channels which have an important role in regulating neuronal excitability. Our aim is to define how CASPR2 alters function within the sensory nervous system to better target current therapeutics in patients with autoantibodies to this protein but also to potentially develop novel therapeutics for the treatment of neuropathic pain.