Glucocorticoid Receptor Regulation Of Sodium Channel Nav1.7 In Neuropathic Pain

Neuropathic pain(Neuropathic Pain, N P P) is pain caused by primary damage or dysfunction in nervous system. The incidence rate is more than 30% among various types of chronic pain diseases. However, the pathogenesis of NPP is still unclear, therefore, clinical therapeutic effect is poor. It has been reported that voltage-gated sodium channels in sensory neurons play an important role in neuropathic pain, such as sodium channels, potassium channels, and calcium ion channels and so on. In addition, the significant role of voltage-gated sodium channels in generation and maintenance of cell excitability is has received widespread attention. Voltage-gated sodium ion channels normally divided into 10subtypes(Nav1.1-1.9 and Nax), and Nav1.7 is encoded by SCN9 A gene. Mutations in SCN9 A gene can lead to congenital absence of pain, primary paroxysmal pain or erythema limb pain disorders. Glucocorticoids(GC) is a kind of steroid hormone secreted by adrenal cortex zona fasciculata, regulated by adrenocorticotropic hormone and it participated in a series of biochemical processes, such as proliferation, differentiation and apoptosis, by binding to the glucocorticoid receptor(GR). Researchers have found that nuclear transcription factor p-NF-?B involved in the regulation of Nav1.7 expression in diabetic neuropathic pain, administration of p-NF-?B inhibitors leads to decreased expression of Nav1.7, and relieve pain. The activated glucocorticoid receptor can inhibit NF-?B expression or activation, thereby blocking the regulation of its downstream gene transcription. Therefore, we hypotheses that GR may regulate Nav1.7 through NF-?B in neuropathic pain.To verify the relevance among GR、Nav1.7 and NF-?B in neuropathic pain, we used rat spared nerve injury(SNI) model, detected expression of GR, p-NF-?B andNav1.7 in dorsal root ganglion(DRG) by immunofluorescence and western blot.Then, we intrathecally administrated dexamethasone(DEX) and detected expression of p-NF-?B and Nav1.7, thus verifying the effect on Nav1.7 caused by GR in nerve damage induced neuropathic pain, in order to provide experimental basis for therapeutic targets of neuropathic pain.Method:60 adult male SD rats were randomly divided into SNI group, Sham group,SNI + dexamethasone(SNI + DEX) group and SNI + saline(SNI + saline) group,(n=15). Mechanical pain threshold were measured by Von Frey at the preoperative1 day, and 3, 7, l4, 21 days after operation. And we detect the change of GR, Nav1.7,and p-NF-?B expression in L4 and L5 DRG at 3d and 14 d after operation, using immunofluorescence and western blot. SNI + DEX group and SNI + saline group rats were intrathecal injected DEX10μL(4μg) as well as the same amount of Saline,then measure the mechanical pain threshold and the changes of GR, Nav1.7, and p-NF-?B expression.Results:Compared with sham group, mechanical paw withdrawal threshold in ipsilateral is significantly decreased in SNI group and the pain lasted to 21 d after operation.( P < 0.05).and the Nav1.7, p-NF-?B expression were Increased significantly on 3d and 14 d after operation, while the GR expression decreased.(P<0.05). Double immunofluorescence display that, GR co-expressed with p-NF-?B and Nav1.7 in DRG, respectively, indicating there may be a correlation among them.Compared with SNI + saline group, mechanical paw withdrawal threshold was increased in SNI + DEX group,(P<0.05). then we collected the L5 DRG on 14 d after operation,then found that GR expression was significantly increased, while the Nav1.7 and p-NF-?B expression reduced in SNI + DEX group, compared with SNI + saline group, through immunofluorescence and western blot method.(P<0.05).Conclusion:During the Neuropathic pain which is caused by nerve injury, GR expression decreased, while p-NF-?B and Nav1.7 expression.increased in DRG. intrathecal injection of dexamethasone could increase the expression of GR, as well as inhibit expression of p-NF-?B and Nav1.7, also relieve pain, indicating GR participate in nerve injury-induced neuropathic pain.by regulating NF-?B and Nav1.7...