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Abstract
Neuropathic pain affects multiple brain functions, including motivational processing.
However, little is known about the structural and functional brain changes involved
in the transition from an acute to a chronic pain state. Here we combined behavioral
phenotyping of pain thresholds with multimodal neuroimaging to longitudinally monitor
changes in brain metabolism, structure and connectivity using the spared nerve injury
(SNI) mouse model of chronic neuropathic pain. We investigated stimulus-evoked pain
responses prior to SNI surgery, and one and twelve weeks following surgery. A progressive
development and potentiation of stimulus-evoked pain responses (cold and mechanical
allodynia) were detected during the course of pain chronification. Voxel-based morphometry
demonstrated striking decreases in volume following pain induction in all brain sites
assessed - an effect that reversed over time. Similarly, all global and local network
changes that occurred following pain induction disappeared over time, with two notable
exceptions: the nucleus accumbens, which played a more dominant role in the global
network in a chronic pain state and the prefrontal cortex and hippocampus, which showed
lower connectivity. These changes in connectivity were accompanied by enhanced glutamate
levels in the hippocampus, but not in the prefrontal cortex. We suggest that hippocampal
hyperexcitability may contribute to alterations in synaptic plasticity within the
nucleus accumbens, and to pain chronification.