Nerve Injury-Induced Neuronal PAP-I Maintains Neuropathic Pain by Activating Spinal Microglia

Abstract

Pancreatitis-associated proteins (PAPs) display multiple functions in visceral diseases. Previous studies showed that the expression level of PAP-I was low in the DRG of naive rats but was de novo expressed after peripheral nerve injury. However, its role in neuropathic pain remains unknown. We found that PAP-I expression was continuously upregulated in the DRG neurons from rat spared nerve injury models, and transported toward the spinal dorsal horn to act as a proinflammatory factor. Intrathecal delivery of PAP-I enhanced sensory hyperalgesia, whereas PAP-I deficiency by either gene knockout or antibody application alleviated tactile allodynia at the maintenance phase after spared nerve injury. Furthermore, PAP-I functioned by activating the spinal microglia via CC chemokine receptor Type 2 that participated in neuropathic pain. Inhibition of either microglial activation or CC chemokine receptor Type 2 abolished the PAP-Iinduced hyperalgesia. Thus, PAP-I mediates the neuron-microglial crosstalk after peripheral nerve injury and contributes to the maintenance of neuropathic pain.

Intravenous lidocaine alleviates postherpetic neuralgia in rats via regulation of neuroinflammation of microglia and astrocytes

“…It also inhibited the neuroinflammation in the spinal dorsal horn. Spinal cord plays a critical role in the occurrence and development of neuropathic pain, and in recent years, more and more studies have confirmed that neuropathic pain results by the activation of glial cells in the spinal dorsal horn (Chen et al, 2019;Echeverry et al, 2017;Li et al, 2020). The activation of glial cells is mainly manifested by the increase in the number and the enlargement of the cell body (Davis et al, 2017;Wang et al, 2017).…”

“…Microglia and astrocytes are the pivotal cells that result in the development of acute and chronic pain after peripheral and central nerve injuries (Hains and Waxman, 2006;Ji et al, 2019). Multiple studies have shown the close relationship between neuropathic pain and the activation of glial cells in the spinal dorsal horn (Chen et al, 2019;Li et al, 2020), prefrontal cortex (PFC) (Fiore and Austin, 2019), anterior cingulate cortex (ACC) (Tsuda et al, 2017), and hippocampus (Barcelon et al, 2019;Liu et al, 2017). Furthermore, Ji et al consider that neuropathic pain is related to central sensitization in the spinal cord, ACC, hippocampus, and other regions (Ji et al, 2018;Zhuo, 2007).…”

Neuronal GRK2 regulates microglial activation and contributes to electroacupuncture analgesia on inflammatory pain in mice

“…Microglia has been implicated in the acquisition and/or the development of most neurological disorders [ 39 ], including Alzheimer’s disease [ 41 ], Parkinson’s disease [ 42 , 43 ], stroke [ 44 ], and some chronic pain conditions [ 27 , 45 ]. There is mounting evidence indicating that the therapeutic strategies for those neurological diseases may induce reduction of neuroinflammation [ 27 , 46 ].…”

Analysis of Potential Hub Genes for Neuropathic Pain Based on Differential Expression in Rat Models

“…In the present work, three gene expression datasets (GSE24982, GSE30691, and GSE63442) were integrated for RRA analysis to screen out DEGs. RRA analysis is a widely utilized tool for the integration of genome-wide gene expression data from different datasets and the identification of the key genes that are most likely to be implicated in the development of the disease under investigation [ 22 ].The DEGs identified comprise REG3B [ 23 ] and ATF3 [ 19 , 24 ], which have been reported to assume a major role in the etiology of NP. After RRA analysis, enrichment analyses were conducted on 736 DEGs, which elucidated that they were mainly enriched in ion transmembrane transport [ 25 ], membrane potential regulation [ 26 ], sensory perception of pain [ 27 ], response to axon injury [ 28 ], and potassium ion transport [ 29 ].…”