Abstract
Neuropathic pain is common neurological disorder affecting between 5-10% of the general population and
predicted to become more common in the future because of the aging population. Although analgesics are
available, this type of pain is particularly resistant to our current treatment strategies leaving patients with few
options. In addition, these drugs cause severe side effects. This is of course hugely debilitating for individuals,
negatively affecting their quality of life. Furthermore, it has significant economic ramifications (treatment costs,
time spent off work) and is a burden on healthcare services that needs to be addressed. As a result, there is a
pressing need to develop new better-targeted therapies for the treatment of neuropathic pain. One obstacle has
been the lack of translation from basic science findings into the clinic. Here, we aim to address this by using
patient samples to enhance the relevance of our basic research. It is now well accepted that neuroimmune
interactions contribute to abnormal pain states and one relatively under studied aspect of is through the action
of human autoantibodies. The anti-CV2 autoantibodies target a protein called collapsin response mediator
protein 5 (CRMP5) and are associated with neuropathic pain in patients. CRMP5 is an understudied onconeural
protein highly expressed in the developing brain. In adults, CRMP5 expression is absent from the brain but
retained in sensory neurons, nerves and synapses present in the spinal cord. In neuropathic pain, CRMP5
expression is decreased at post-synaptic sites in the spinal cord, while the levels of GluN2B, a subunit of the
NMDA receptor, and a novel CRMP5 binding protein, is increased. Using patients' autoantibodies and a rat
model of neuropathic pain, we will test the hypothesis that disruption of CRMP5 functions underlies allodynia in
anti-CV2 autoimmune neuropathy and in neuropathic pain. Aim 1 will investigate the alterations of sensory
neurotransmission elicited by anti-CV2 autoantibodies. This will include a functional profiling of sensory neurons
using whole cell and slice electrophysiology. With this we will decipher the site of action of anti-CV2
autoantibodies produce to allodynia. Aim 2 will focus on elucidating the pre- and post-synaptic function of CRMP5
in spinal neurotransmission and neuropathic pain. We will explore the novel idea that loss of CRMP5 regulation
of GluN2B underlies allodynia in neuropathic pain. This proposal uses a combination of novel biochemical and
functional methods to reverse-translate the clinical findings of CRMP5 (anti-CV2) auto-immunity causing
allodynia to interrogate how CRMP5 can contribute to neuropathic pain. The identification of a novel therapeutic
target for chronic pain is an exciting outcome with far reaching applications for future therapeutic development.