Abstract
Chronic pain is associated with time-dependent structural and functional reorganization of the prefrontal cortex that may reflect adaptive pain compensatory and/or maladaptive pain-promoting mechanisms. However, the molecular underpinnings of these changes and whether there are time-dependent relationships to pain progression are not well characterized. In this study, we analyzed protein composition in the medial prefrontal cortex (mPFC) of rats at two timepoints after spinal nerve ligation (SNL) using two-dimensional gel electrophoresis (2D-ELFO) and liquid chromatography with tandem mass spectrometry (LC–MS/MS). SNL, but not sham-operated, rats developed persistent tactile allodynia and thermal hyperalgesia, confirming the presence of experimental neuropathic pain. Two weeks after SNL (early timepoint), we identified 11 proteins involved in signal transduction, protein transport, cell homeostasis, metabolism, and apoptosis, as well as heat-shock proteins and chaperones that were upregulated by more than 1.5-fold compared to the sham-operated rats. Interestingly, there were only four significantly altered proteins identified at 8 weeks after SNL (late timepoint). These findings demonstrate extensive time-dependent modifications of protein expression in the rat mPFC under a chronic neuropathic pain state that might underlie the evolution of chronic pain characterized by early pain-compensatory and later aberrant mechanisms.
Highlights
Chronic pain patients often suffer from negative emotional, affective, and cognitive consequences that cause a substantial burden on their lives
A neuroimaging study in rats demonstrated time-dependent alterations in the ACC and medial prefrontal cortex (mPFC) regions in animals with persistent neuropathic pain [30], confirming that key mechanisms of acute and chronic pain processing in the brain are conserved in rats despite significant cortical differences across species
At 2 weeks following spinal nerve ligation (SNL) or sham surgery, SNL rats showed significantly lower paw withdrawal thresholds and latencies compared to the baseline, demonstrating the development of tactile allodynia (Figure 1a) and thermal hyperalgesia (Figure 1b), respectively
Summary
Chronic pain patients often suffer from negative emotional, affective, and cognitive consequences that cause a substantial burden on their lives. A neuroimaging study in rats demonstrated time-dependent alterations in the ACC and mPFC regions in animals with persistent neuropathic pain [30], confirming that key mechanisms of acute and chronic pain processing in the brain are conserved in rats despite significant cortical differences across species. Both human and preclinical findings in animals suggest that mPFC brain circuits undergo remodeling that might underlie a hypothesized transition to a chronic maladaptive pain state. Neuropathic pain state was confirmed over time by measuring tactile allodynia and thermal hyperalgesia
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