The upregulation of nociceptive ion channels expressed in dorsal root ganglia (DRG) contributes to the development and retaining of diabetic pain symptoms. The flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone) is a component extracted from various fruits and vegetables and exerts anti-inflammatory, analgesic, anticarcinogenic, antiulcer, and antihypertensive effects. However, the exact mechanism underlying quercetin's analgesic action remains poorly understood. The aim of this study was to investigate the effects of quercetin on diabetic neuropathic pain related to the P2X receptor in the DRG of type 2 diabetic rat model. Our data showed that both mechanical withdrawal threshold and thermal withdrawal latency in diabetic rats treated with quercetin were higher compared with those in untreated diabetic rats. The expression levels of P2X messenger RNA and protein in the DRG of diabetic rats were increased compared with the control rats, while quercetin treatment significantly inhibited such enhanced P2X expression in diabetic rats. The satellite glial cells (SGCs) enwrap the neuronal soma in the DRG. Quercetin treatment also lowered the elevated coexpression of P2X and glial fibrillary acidic protein (a marker of SGCs) and decreased the upregulation of phosphorylated p38 mitogen-activated protein kinase (p38MAPK) in the DRG of diabetic rats. Quercetin significantly reduced the P2X agonist adenosine triphosphate-activated currents in HEK293 cells transfected with P2X receptors. Thus, our data demonstrate that quercetin may decrease the upregulation of the P2X receptor in DRG SGCs, and consequently inhibit P2X receptor-mediated p38MAPK activation to relieve the mechanical and thermal hyperalgesia in diabetic rats.
The hippocampus is an important region
for the interaction between
depression and pain. Studies show that the P2X4 receptor plays key
role in neuropathic pain. This work investigated the potential implication
of the P2X4 receptor in the hippocampus in comorbidity of chronic
pain and depression. The rat model induced by chronic constriction
injury (CCI) plus unpredictable chronic mild stress (UCMS) was used
in this study. Our data showed that CCI plus UCMS treatment resulted
in abnormal changes in pain and depressive-like behaviors in the rat,
accompanied by the upregulated expression of P2X4, NLRP3 (NOD-like
receptor protein 3) inflammasome, and interleukin-1β and the
activation of p38 MAPK in the hippocampus. The P2X4 antagonist 5-BDBD
reversed these abnormal changes in the hippocampus, relieved hippocampal
neuronal damage, and alleviated the abnormal pain and depressive-like
behaviors in the CCI plus UCMS treated rats. These findings suggest
that the P2X4 receptor in the hippocampus may mediate and significantly
contribute to the pathological processes of comorbid pain and depression.
Neuropathic pain is a complex disease with high incidence. Adenosine triphosphate (ATP) and its activated P2X7 receptor are involved in the signal transmission of neuropathic pain. Gallic acid (3,4,5-trihydroxybenzoic acid) is a traditional Chinese medicine obtained from natural plants that exhibit anti-inflammatory, analgesic, and antitumor effects. However, the underlying mechanism for gallic acid in analgesia remains unknown. This study aims to reveal how gallic acid alleviates neuropathic pain behaviors in a rat model with chronic constriction injury (CCI). Real-time PCR, western blotting, double-label immunofluorescence, molecular docking, and whole-cell patch clamp technology were used to explore the therapeutic action of gallic acid on neuropathic pain. The results showed that after CCI rats were treated with gallic acid for 1 week, the mechanical withdrawal threshold and thermal withdrawal latency were increased, accompanied by inhibition of the upregulated expression of P2X7 and TNF-α at both mRNA and protein levels, and reduced NF-κB and phosphorylated-STAT3 in the dorsal root ganglia. At the same time, gallic acid significantly decreased the coexpression of P2X7 and glial fibrillary acidic protein in the dorsal root ganglia. In addition, gallic acid could suppress ATP-activated current in human embryonic kidney 293 (HEK293) cells transfected with the plasmid expressing P2X7 but had no effect on ATP activation current of P2X7-mutant plasmid (with the point mutation sequence of the key site where gallic acid binds to the P2X7 receptor). Therefore, our work suggests that gallic acid may alleviate neuropathic pain in CCI rats by inhibiting the P2X7 receptor and subsequent activation of the TNF-α/STAT3 signaling pathway.
Activation of satellite
glial cells (SGCs) in the dorsal root ganglia (DRG) is involved in
mechanical and thermal hyperalgesia. The upregulated P2Y12 receptor expressed in SGCs of the DRG participates in the nociceptive
transmission of neuropathic pain. Guanfu base A (GFA) has been reported
to exhibit antiarrhythmic and anti-inflammatory effects. In this study,
we explored the effects of GFA on P2Y12 receptor-mediated
mechanical and thermal hyperalgesia in chronic constriction injury
(CCI) rats. Sprague–Dawley rats were randomly divided into
sham operation group (Sham), CCI operation group (CCI), CCI rats treated
with guanfu base A group (CCI + GFA) and control rats treated with
GFA group (Ctrl + GFA). Mechanical withdrawal threshold and thermal
withdrawal latency were measured. P2Y12 expression in L4–L6
dorsal root ganglion (DRG) was detected by quantitative real-time
PCR and Western blot. After CCI treatment, mechanical and thermal
hyperalgesia and the expression values of P2Y12 receptor
mRNA and protein in DRG were increased. Dual-labeling immunofluorescence
showed that the coexpression of P2Y12 receptor and glial
fibrillary acidic protein (GFAP) in the DRG of CCI rats was increased
compared to sham rats. GFA relieved mechanical and thermal hyperalgesia
in the CCI rats, decreased the expression of P2Y12 mRNA
and protein and phosphorylation of p38 MAPK in the DRG, and increased
the ADP-downregulated cAMP concentrations in HEK293 cells transfected
with P2Y12 plasmid. After CCI rats were treated with GFA,
the coexpression of P2Y12 receptor and GFAP in the DRG
was significantly decreased compared to the untreated CCI group. Thus,
downregulating the P2Y12 receptor relieved mechanical and
thermal hyperalgesia in the CCI rats.
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