糖皮质激素受体在大鼠炎性疼痛模型中的差异调节
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糖皮质激素受体在大鼠炎性疼痛模型中的差异调节
背景：抗炎性激素是治疗慢性疼痛和炎症的常用药物。临床上使用的类固醇，靶向作用于糖皮质激素受体（GR）以达到其抗炎作用。我们前期研究发现，感觉神经元内的GR可能在某些疼痛模型中发挥核心作用，并且背根神经节（DRG）局部炎症后（一种低位的腰痛模型）GR免疫反应性信号会减弱。在当前研究中，我们的目的是确定GR信号在皮肤炎症模型[即Freund佐剂(CFA)模型（外周炎症疼痛模型）]中是否也存在类似的变化，在该模型中，炎症部位发生于感觉神经元末梢神经而非躯体。
方法：将低剂量CFA注射入SD大鼠（雌雄不拘）后爪以建立外周炎症模型，并通过行为学和测量足肿胀进行验证。使用免疫组化和western blotting技术检测GR在发炎的后爪和DRGs中的表达谱。用放射免疫法测定血浆皮质酮水平。
结果：免疫组化染色显示GR在正常DRG和皮肤组织中广泛表达。足趾注射CFA可引起注射后第1天皮肤组织中GR的上调，这一改变主要发生在真皮区。然而，在注射后1天足部炎症显著降低L5 DRG的GR信号。CFA炎症后14天GR仍明显下调。同时，western blotting也证实了注射后1天足部炎症显著下调L5 DRG的GR信号，并在对侧L5 DRG和L2 DRG中也可以观察到这种下调（不支配足趾的水平）。与第1天相比，CFA后第14天雌鼠和雄鼠的血浆皮质酮水平均升高，这提示皮质酮可能是第14天观察到GR自体下调的原因，而不是第1天GR自体下调的原因。
结论： 根据解剖位置的不同，GR在不同的疼痛条件下有不同的激活模式。本研究观察到的感觉神经元中GR的下调，可能会对使用类固醇治疗炎性疼痛以及内源性糖皮质激素的调节作用产生重大影响。
原始文献来源：Ibrahim SIA, Strong JA, Qualls KA, et al.Differential Regulation of the Glucocorticoid Receptor in a Rat Model of Inflammatory Pain[J]. Anesth Analg 2020;131:298–306.
Differential Regulation of the Glucocorticoid Receptor in a Rat Model of Inflammatory Pain
Abstract
BACKGROUND: Anti-inflammatory corticosteroids are a common treatment for different conditions involving chronic pain and inflammation. Clinically used steroids target the glucocorticoid receptor (GR) for its anti-inflammatory effects. We previously reported that GR in sensory neurons may play central roles in some pain models and that GR immunoreactivity signal in dorsal root ganglia (DRG) decreased after local inflammation of the DRG (a model of low back pain). In the current study, we aimed to determine if similar changes in GR signal also exist in a skin inflammation model, the complete Freund’s adjuvant (CFA) model (a model of peripheral inflammatory pain), in which the terminals of the sensory neurons rather than the somata are inflamed.
METHODS: A low dose of CFA was injected into the hind paw to establish the peripheral inflammation model in Sprague-Dawley rats of both sexes, as confirmed by measurements of behavior and paw swelling. Immunohistochemical and western blotting techniques were used to determine the expression pattern of the GR in the inflamed hind paw and the DRGs. Plasma corticosterone levels were measured with radioimmunoassay.
RESULTS: The immunohistochemical staining revealed that GR is widely expressed in the normal DRG and skin tissues. Paw injection with CFA caused upregulation of the GR in the skin tissue on postinjection day 1, mostly detected in the dermis area. However, paw inflammation significantly reduced the GR signal in the L5 DRG 1 day after the injection. The GR downregulation was still evident 14 days after CFA inflammation. On day 1, western blotting confirmed this downregulation and showed that it could also be observed in the contralateral L5 DRG, as well as in the L2 DRG (a level which does not innervate the paw). Plasma corticosterone levels were elevated in both sexes on day 14 after CFA compared to day 1, suggesting autologous downregulation of the GR by corticosterone may have contributed to the downregulation observed on day 14 but not day 1.
CONCLUSIONS: There are distinctive patterns of GR activation under different pain conditions, depending on the anatomical location. The observed downregulation of the GR in sensory neurons may have a significant impact on the use of steroids as treatment in these conditions and on the regulatory effects of endogenous glucocorticoids.
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翻译：任文鑫 编辑：冯玉蓉 审校：曹莹