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

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.

Chronic pain is associated with enhanced excitability within both the peripheral and central sensory nervous system; our understanding of the pathophysiological mechanisms underlying this sensitisation is still incomplete but is critically important for the development of new analgesic therapies. We will focus on a novel molecular pathway involving the protein CASPR2 (contactin associated protein 2). This is a member of the neurexin superfamily and recently two groups have independently shown that autoantibodies directed against this protein are associated with a high incidence of neuropathic pain in patients. The mechanism of this effect is however completely unknown. In our initial studies of mice lacking CASPR2 animals show behavioural hypersensitivity to noxious stimuli and dorsal root ganglia neurons derived from these animals show an enhanced response to chemical algogens. We will further define the behavioural phenotype of these animals and investigate the mechanism of this hypersensitivity using anatomical outcomes, electrophysiology, calcium imaging and assessment of voltage gated potassium channel trafficking (ion channels with which CASPR2 is known to complex). We will establish a new pain model induced by passive immunisation of rodents with CASPR2 autoantibodies in order to understand pathophysiological mechanisms and to test treatment outcomes. We have recently found that levels of CASPR2 significantly fall following traumatic nerve injury and we will therefore investigate the hypothesis that reduced CASPR2 expression contributes to acquired neuropathic pain syndromes. Finally we will establish if normalising CASPR2 levels can reverse pain-related hypersensitivity.

The research proposed in this application has a number of potential beneficiaries. In the short term this will include academics from outside the field of pain and patients suffering chronic pain due to the presence of CASPR2 autoantibodies. In the longer term potential beneficiaries include Pharmaceutical companies, the healthcare system and chronic pain patients.
CASPR2 is known to have a role in neuronal development leading to a range autism spectrum disorders particularly those associated with epilepsy. It is also thought to contribute to symptoms other than pain in Morvan's syndrome and Neuromyotonia, both neurological autoantibody mediated conditions. In the work outlined in this proposal we aim to understand the pathophysiological mechanisms underlying CASPR2's role in disease. Therefore a better understanding of these mechanisms would benefit researchers looking at the effects of CASPR2 in other important areas of neuroscience. We have found that purified IgG from patients with high levels of CASPR2 autoantibodies can cause pain in mice. We aim to establish this as an animal model of autoimmune pain and will trial immunotherapies as well as current analgesics, such as gabapentin, in order to assess their efficacy in reducing pain-related behaviours. These findings will be immediately beneficial to clinicians and inform them of the best options available for the treatment of pain in these patients. This will of course also be beneficial to the patient who will receive better targeted therapies to manage their pain, leading to an enhanced quality of life and well being.
CASPR2 is a novel pain target and by demonstrating that normalising CASPR2 levels in animal models of chronic pain can alleviate symptoms we will highlight its therapeutic potential. It would therefore be of great interest to pharmaceutical companies involved in development programmes for analgesic treatments. We also hope to define the mechanism by which CASPR2 regulates excitability, for instance through the trafficking of potassium channels. By creating a viable strategy of targeting this pathway huge financial gains could be obtained for the commercial industry and this would also speed the development of analgesic treatments for patients. Current drugs for the relief of pain are not always effective (1 in 5 adults sufferer chronic pain) and cause numerous adverse reactions. Treatment efforts are costly to the healthcare system and some sufferers can become incapacitated, resulting in further economic loss due to time spent off work. The development of a new analgesic therapy would have major benefits to the healthcare system and economy. There would also be significant benefits to the individual chronic pain sufferer. From better treatments, a patient's quality of life will be increased due to more adequate pain relief and monetary gains due to returning to work.