Time-Dependent Changes in Protein Composition of Medial Prefrontal Cortex in Rats with Neuropathic Pain

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.

Label-free quantitative proteomics analysis models in vivo and in vitro reveal key proteins and potential roles in sciatic nerve injury

“…Analysis of the differences in translational and posttranslational modifications in the nervous system that occur after injury by SNI can help identify key biological markers of SNI that can be used as major molecular targets for drug therapy and improve the efficacy of SNI treatment (Niederberger and Geisslinger, 2008). A number of studies have been conducted using different animal models to simulate the onset of SNI and for the triggers of SNI (e.g., viruses (Wang et al, 2022c)), therapeutic agents (Chen et al, 2022b;Xiong et al, 2022), temporal changes (Ujcikova et al, 2022;Vergara et al, 2018). In contrast, the current study constructed ex vivo models of SNI using compressive injury and OGD induction and explored DEPs in SNI that suffered an injury based on label-free quantitative proteomics extraction and identification of proteins.…”

Proteomic and metabolomic approaches elucidate the molecular mechanism of emodin against neuropathic pain through modulating the gamma‐aminobutyric acid (GABA)‐ergic pathway and PI3K/AKT/NF‐κB pathway

“…The perception and transmission of pain is a complex phenomenon that depends on an extended network of different cortical brain regions, including the primary somatosensory cortex, prefrontal cortex, anterior cingulate cortex, insular cortex, and so on (Kuner & Kuner, 2021; Mouraux & Iannetti, 2018). Numerous studies have confirmed that the structural changes and functional changes in the above brain regions are closely associated with the presence of NeP (Kim, Kim, & Nabekura, 2017; Selvarajah et al, 2019; Ujcikova et al, 2022; Wang, Zhang, Wang, & Luo, 2021; Zhao et al, 2018). These changes mainly include the calcium activity of neurons, excitatory postsynaptic current (EPSC) frequency and amplitude, synaptic strength, intrinsic excitability, the turnover rate or density of dendritic spines, and brain oscillations, which can be recognized as biomarkers for NeP (Bak, Park, & Kim, 2021; Zhuo, 2020).…”

“…The perception and transmission of pain is a complex phenomenon that depends on an extended network of different cortical brain regions, including the primary somatosensory cortex, prefrontal cortex, anterior cingulate cortex, insular cortex, and so on Mouraux & Iannetti, 2018). Numerous studies have confirmed that the structural changes and functional changes in the above brain regions are closely associated with the presence of NeP (Kim, Kim, & Nabekura, 2017;Selvarajah et al, 2019;Ujcikova et al, 2022;Wang, Zhang, Wang, & Luo, 2021;Zhao et al, 2018).…”

Alterations of endogenous pain-modulatory system of the cerebral cortex in the neuropathic pain

“…It critically modulates the pain experience and a large number of comorbidities of painful disease are evoked by PFC changes, structural reorganization of neurons and glia, signal transduction, and cellular metabolism. 11 , 12 …”