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

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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.