From the Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (X.L., M. Shaqura, D.M., S.A.M., M. Schäfer); the Department of Anaesthesiology, Ludwig-Maximilians-University Munich, Munich, Germany (A.B.); and the Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kyoto, Japan (S.Y.).
Anesthesiology. 2018 Apr;128(4):796-809. doi: 10.1097/ALN.0000000000002087.
In naive rats, corticosteroids activate neuronal membrane-bound glucocorticoid and mineralocorticoid receptors in spinal cord and periphery to modulate nociceptive behavior by nongenomic mechanisms. Here we investigated inflammation-induced changes in neuronal versus glial glucocorticoid and mineralocorticoid receptors and their ligand-mediated nongenomic impact on mechanical nociception in rats.
In Wistar rats (n = 5 to 7/group) with Freund's complete adjuvant hind paw inflammation, we examined glucocorticoid and mineralocorticoid receptor expression in spinal cord and peripheral sensory neurons versus glial using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, immunohistochemistry, and radioligand binding. Moreover, we explored the expression of mineralocorticoid receptors protecting enzyme 11-betahydroxysteroid dehydrogenase type 2 as well as the nociceptive behavioral changes after glucocorticoid and mineralocorticoid receptors agonist or antagonist application.
Hind paw inflammation resulted in significant upregulation of glucocorticoid receptors in nociceptive neurons of spinal cord (60%) and dorsal root ganglia (15%) as well as mineralocorticoid receptors, while corticosteroid plasma concentrations remained unchanged. Mineralocorticoid (83 ± 16 fmol/mg) but not glucocorticoid (104 ± 20 fmol/mg) membrane binding sites increased twofold in dorsal root ganglia concomitant with upregulated 11-betahydroxysteroid dehydrogenase type 2 (43%). Glucocorticoid and mineralocorticoid receptor expression in spinal microglia and astrocytes was small. Importantly, glucocorticoid receptor agonist dexamethasone or mineralocorticoid receptor antagonist canrenoate-K rapidly and dose-dependently attenuated nociceptive behavior. Isobolographic analysis of the combination of both drugs showed subadditive but not synergistic or additive effects.
The enhanced mechanical sensitivity of inflamed hind paws accompanied with corticosteroid receptor upregulation in spinal and peripheral sensory neurons was attenuated immediately after glucocorticoid receptor agonist and mineralocorticoid receptor antagonist administration, suggesting acute nongenomic effects consistent with detected membrane-bound corticosteroid receptors.
在未成熟的大鼠中，皮质类固醇通过非基因组机制激活脊髓和外周神经元膜结合的糖皮质激素和盐皮质激素受体，从而调节痛觉行为。在这里，我们研究了炎症引起的神经元与神经胶质糖皮质激素和盐皮质激素受体的变化，以及它们的配体对机械性痛觉的非基因组影响。
在弗氏完全佐剂致后爪炎症的 Wistar 大鼠（每组 5 到 7 只）中，我们使用定量逆转录聚合酶链反应（qRT-PCR）、Western blot、免疫组织化学和放射性配体结合检测脊髓和外周感觉神经元与神经胶质中的糖皮质激素和盐皮质激素受体表达。此外，我们还探讨了糖皮质激素和盐皮质激素受体激动剂或拮抗剂应用后，痛觉行为变化及盐皮质激素受体保护酶 11β-羟类固醇脱氢酶 2 的表达情况。
后爪炎症导致脊髓（60%）和背根神经节（15%）的伤害性神经元中糖皮质激素受体和盐皮质激素受体显著上调，而皮质类固醇的血浆浓度保持不变。盐皮质激素（83±16 fmol/mg）而不是糖皮质激素（104±20 fmol/mg）膜结合位点在背根神经节中增加了两倍，同时伴有 11β-羟类固醇脱氢酶 2 的上调（43%）。脊髓小胶质细胞和星形胶质细胞中的糖皮质激素和盐皮质激素受体表达较少。重要的是，糖皮质激素受体激动剂地塞米松或盐皮质激素受体拮抗剂坎尼诺酸-K 可迅速、剂量依赖性地减轻痛觉行为。两种药物联合使用的等辐射分析显示，其作用是亚加和的，而不是协同或相加的。
炎症后爪的机械敏感性增强，同时脊髓和外周感觉神经元中的皮质类固醇受体上调，在给予糖皮质激素受体激动剂和盐皮质激素受体拮抗剂后立即减轻，表明存在与检测到的膜结合皮质类固醇受体一致的急性非基因组效应。
