Inflammation-associated regulation of RGS in astrocytes and putative implication in neuropathic pain

Abstract

BackgroundRegulators of G-protein signaling (RGS) are major physiological modulators of G-protein-coupled receptors (GPCR) signaling. Several GPCRs expressed in both neurons and astrocytes participate in the central control of pain processing, and the reduced efficacy of analgesics in neuropathic pain conditions may rely on alterations in RGS function. The expression and the regulation of RGS in astrocytes is poorly documented, and we herein hypothesized that neuroinflammation which is commonly observed in neuropathic pain could influence RGS expression in astrocytes.MethodsIn a validated model of neuropathic pain, the spared nerve injury (SNI), the regulation of RGS2, RGS3, RGS4, and RGS7 messenger RNA (mRNA) was examined up to 3 weeks after the lesion. Changes in the expression of the same RGS were also studied in cultured astrocytes exposed to defined activation protocols or to inflammatory cytokines.ResultsWe evidenced a differential regulation of these RGS in the lumbar spinal cord of animals undergoing SNI. In particular, RGS3 appeared upregulated at early stages after the lesion whereas expression of RGS2 and RGS4 was decreased at later stages. Decrease in RGS7 expression was already observed after 3 days and outlasted until 21 days after the lesion. In cultured astrocytes, we observed that changes in the culture conditions distinctly influenced the constitutive expression of these RGS. Also, brief exposures (4 to 8 h) to either interleukin-1β, interleukin-6, or tumor necrosis factor α caused rapid changes in the mRNA levels of the RGS, which however did not strictly recapitulate the regulations observed in the spinal cord of lesioned animals. Longer exposure (48 h) to inflammatory cytokines barely influenced RGS expression, confirming the rapid but transient regulation of these cell signaling modulators.ConclusionChanges in the environment of astrocytes mimicking the inflammation observed in the model of neuropathic pain can affect RGS expression. Considering the role of astrocytes in the onset and progression of neuropathic pain, we propose that the inflammation-mediated modulation of RGS in astrocytes constitutes an adaptive mechanism in a context of neuroinflammation and may participate in the regulation of nociception.

Corydalis decumbens Can Exert Analgesic Effects in a Mouse Neuropathic Pain Model by Modulating MAPK Signaling

“…More recently, the critical importance of glial cells in the initiation and maintenance of neuropathic pain has become apparent [ 27 , 40 ]. Activated spinal cord glia have been observed in neuropathic pain models, including in the presence of inflammation, nerve injury, and cancer [ 22 , 41 , 42 ]. There is evidence that astrocytes and microglia are activated in the etiopathogenesis of RTX-induced neuropathic pain.…”

“…Computational and Mathematical Methods in Medicine neuropathic pain models, including in the presence of inflammation, nerve injury, and cancer [22,41,42]. There is evidence that astrocytes and microglia are activated in the etiopathogenesis of RTX-induced neuropathic pain.…”

Identification of biological processes and signaling pathways for the knockout of REV-ERB in mouse brain

“…Interestingly, we also found that the knockout of REV-ERB can affect GPCR signaling pathways. GPCR and RGS signaling pathways play key roles in mediating the physiological and pathological processes such as metabolism 33,34 , inflammation [35][36][37][38][39] , and tumorigenesis 40,41 . It was found that REV-ERB forms complexes with NR2E3 to further regulate the expression of Guanine nucleotide-binding protein 1 (Gnat1) 42 .…”

Amelioration of Neuropathic Pain and Attenuation of Neuroinflammation Responses by Tetrahydropalmatine Through the p38MAPK/NF-κB/iNOS Signaling Pathways in Animal and Cellular Models

“…Previous studies demonstrated that there are numerous mRNAs that are related to the regulation of neuropathic pain [ 24 ]. In this study, we used an mRNA microarray to analyze the remarkable differentially expressed mRNAs between the SNI and experimental groups.…”