Investigating Circadian Rhythmicity in Pain Sensitivity Using a Neural Circuit Model for Spinal Cord Processing of Pain

Primary processing of painful stimulation occurs in the dorsal horn of the spinal cord. In this article, we introduce mathematical models of the neural circuitry in the dorsal horn responsible for processing nerve fiber inputs from noxious stimulation of peripheral tissues and generating the resultant pain signal. The differential equation models describe the average firing rates of excitatory and inhibitory interneuron populations, as well as the wide dynamic range (WDR) neurons whose output correlates with the pain signal. The temporal profile of inputs on the different afferent nerve fibers that signal noxious and innocuous stimulation and the excitability properties of the included neuronal populations are constrained by experimental results. We consider models for the spinal cord circuit in isolation and when top-down inputs from higher brain areas that modulate pain processing are included. We validate the models by replicating experimentally observed phenomena of A fiber inhibition of pain and wind-up. We then use the models to investigate mechanisms for the observed phase shift in circadian rhythmicity of pain that occurs with neuropathic pain conditions. Our results suggest that changes in neuropathic pain rhythmicity can occur through dysregulation of inhibition within the dorsal horn circuit.