Direct Transduction and Regulation of Pathological Pain by Neuronal TRPM2 Channels

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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.