Direct Transduction and Regulation of Pathological Pain by Neuronal TRPM2 Channels

病理性疼痛仍然是一个主要的未满足的临床问题，占医生就诊的80%。慢性关节炎疼痛尤其使人衰弱，并可能持续一生。它影响着英国数百万人，是导致发病和残疾的主要原因之一，因此给患者、医疗保健系统和英国经济带来了巨大的负担。然而，目前可用的治疗慢性疼痛的方法要么缺乏疗效，要么产生难以忍受的副作用。因此，有相当大的需要开发下一代疼痛疗法，以有效治疗慢性关节炎疼痛。因此，准确了解关节炎疼痛是如何转导并发展为慢性疾病是至关重要的，以便为治疗干预确定新的药物靶点。组织炎症是组织和神经损伤时疼痛的主要触发和放大因素。它是由免疫细胞和炎性细胞聚集到损伤部位产生的炎性因子引起的。然后，这些炎症因子作用于感觉神经末梢，导致疼痛加剧。免疫细胞和炎症细胞上的一种名为TRPM2的蛋白质对这些炎症因子的产生至关重要，因此，它与不同类型的疼痛（如炎症性和神经性疼痛）有关。因此，TRPM2对疼痛的影响被认为是一种间接作用。有趣的是，TRPM2不仅存在于免疫细胞和炎症细胞中。免疫TRPM2)，但也大量存在于感觉神经细胞(简称。神经TRPM2)负责疼痛的传递。虽然免疫TRPM2在病理性疼痛中起间接作用是明确的，但神经TRPM2的功能尚不清楚。有趣的是，我们已经发现证据支持神经TRPM2直接转导急性和慢性关节炎疼痛独立于组织炎症。在本研究中，我们旨在探讨神经TRPM2在急性和慢性关节炎疼痛的直接转导和调节中的具体作用，并了解其工作原理。对于急性关节炎疼痛，我们将确定神经TRPM2是否对关节炎关节中各种引起疼痛的药物诱导的感觉神经细胞的快速激活和放电是必要的。对于慢性关节炎疼痛，我们将了解TRPM2如何控制神经细胞中的基因程序，导致关节炎疼痛进展到慢性阶段。最后，我们将选择性地去除神经TRPM2，同时保留免疫TRPM2完整，然后确定神经TRPM2的损失对急慢性关节炎疼痛的影响。综上所述，本研究将揭示神经TRPM2在急性和慢性疼痛传递和调节中的新作用，并确定慢性疼痛的关键分子细节。这些发现无疑将促进我们对慢性疼痛的理解。此外，本研究将证明TRPM2化学抑制剂在缓解慢性疼痛方面的治疗益处。因此，TRPM2具有巨大的潜力，可以成为治疗许多慢性疼痛患者的有吸引力的药物靶点，这些患者目前的疼痛疗法治疗不足。

Pathological pain remains a major unmet clinical problem accounting for up to 80% of physician visits. Chronic arthritis pain is particularly debilitating and can last for a lifetime. It affects millions of people in the UK and is one of the leading causes of morbidity and disability, therefore posing an enormous burden on patients, the health care system and the UK economy. However, currently available treatments for chronic pain either lack efficacy or produce intolerable side effects. Thus, there is considerable need to develop the next-generation of pain therapies for the effective treatment of chronic arthritis pain. For this reason, it is essential to understand precisely how arthritis pain is transduced and progressed to a chronic condition in order to identify novel drug targets for therapeutic interventions.Tissue inflammation is the major trigger and amplifier of pain during tissue and nerve injury. It is caused by inflammatory agents produced in the immune and inflammatory cells recruited to the injury site. These inflammatory agents then act on sensory nerve endings resulting in enhanced pain. A protein called TRPM2 on the immune and inflammatory cells is critical to the production of these inflammatory agents, and therefore, has been implicated in different types of pain such as inflammatory and neuropathic pain. The effect of TRPM2 on pain is thus thought to be an indirect action. Interestingly, TRPM2 is not only present in immune and inflammatory cells (abbrev. immune TRPM2), but also found abundantly in sensory nerve cells (abbrev. nerve TRPM2) responsible for the transmission of pain. Although it is clear that immune TRPM2 plays an indirect role in pathological pain, the function of nerve TRPM2 is less understood. Intriguingly, we have found evidence supporting that nerve TRPM2 directly transduces acute and chronic arthritis pain independently of tissue inflammation. In this research, we aim to investigate the specific role of nerve TRPM2 in the direct transduction and regulation of acute and chronic arthritis pain and understand how it works. For acute arthritis pain, we will determine whether nerve TRPM2 is necessary for the rapid activation and firing of sensory nerve cells induced by various pain-eliciting agents in the joints of arthritis. For chronic arthritis pain, we will understand how TRPM2 controls gene programmes in nerve cells leading to progression to the chronic stage of arthritis pain. Finally, we will selectively remove nerve TRPM2, while leaving immune TRPM2 intact and then determine the effect of loss of nerve TRPM2 on acute and chronic arthritis pain. Taken together, this research will reveal the novel roles of nerve TRPM2 in the transmission and regulation of acute and chronic pain, and define the molecular details critical to chronic pain. These findings will in no doubt advance our understanding of chronic pain. Furthermore, this research will demonstrate therapeutic benefits of chemical inhibitors for TRPM2 in the alleviation of chronic pain. TRPM2 thus has huge potential to be an appealing drug target for the treatment of many patients with chronic pain, who are under-treated by the current pain therapies.