From the Department of Anesthesiology, Pain Research Center.
Graduate Program in Molecular, Cellular, and Biochemical Pharmacology.
Anesth Analg. 2020 Jul;131(1):298-306. doi: 10.1213/ANE.0000000000004652.
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.
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.
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.
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.
抗炎皮质类固醇是一种常用于治疗慢性疼痛和炎症的常见方法。临床上使用的类固醇针对糖皮质激素受体 (GR) 发挥其抗炎作用。我们之前报道过，感觉神经元中的 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) 中的 GR 免疫反应信号在 DRG 局部炎症后减少（腰痛模型）。在目前的研究中，我们旨在确定在皮肤炎症模型（完全弗氏佐剂 (CFA) 模型，一种周围炎症性疼痛模型）中是否也存在类似的 GR 信号变化，在该模型中，感觉神经元的末梢而不是体被炎症。
向 SD 大鼠的后爪注射低剂量 CFA 以建立周围炎症模型，通过行为和爪肿胀测量来确认。使用免疫组织化学和 Western blot 技术确定炎症后爪和 DRG 中 GR 的表达模式。用放射免疫法测量血浆皮质酮水平。
免疫组织化学染色显示 GR 在正常 DRG 和皮肤组织中广泛表达。CFA 后爪注射导致注射后第 1 天皮肤组织中的 GR 上调，主要在真皮区域检测到。然而，注射后第 1 天，爪炎症显著降低了 L5 DRG 中的 GR 信号。CFA 炎症后 14 天，GR 下调仍然明显。第 1 天，Western blot 证实了这种下调，并且还可以在对侧 L5 DRG 以及不支配爪子的 L2 DRG 中观察到。与第 1 天相比，CFA 后第 14 天，两性血浆皮质酮水平均升高，提示皮质酮自身对 GR 的下调可能导致第 14 天而非第 1 天观察到的下调。
在不同的疼痛条件下，GR 的激活存在不同的模式，这取决于解剖位置。感觉神经元中观察到的 GR 下调可能对这些情况下类固醇作为治疗方法的使用以及内源性糖皮质激素的调节作用产生重大影响。
