Hyperexcitability in Pain Processing Neurons: Pathological and Compensatory Mechanisms

Neuropathic pain is associated with hyperexcitability in primary afferent neurons (PANs) and the spinal dorsal horn network. Hyperexcitability develops despite compensatory changes that can offset the effects of pathological changes, implying that compensation ultimately fails. I hypothesized that compensatory changes, despite robustly maintaining certain aspects of excitability, fail to maintain others. To test my hypothesis in PANs, I used an existing computer model to show that distinct ion channel combinations that yield equivalent rheobase fail to yield equivalent outcomes for other factors such as energy used per spike. To test my hypothesis in spinal dorsal horn neurons whose synaptic inhibition can be compromised in distinct ways, I developed a new computer model. Consistent with my hypothesis, simulations revealed that distinct forms of disinhibition differ in their effects on dynamic range and receptive field size. These results demonstrate the limits of compensation and may help explain how hyperexcitability develops despite compensation.M.Sc