Steroids and Steroid Receptors in Low Back Pain

腰痛是一种常见的疾病，它会使人虚弱，30%的病例会变成慢性病。 许多患者无法用目前的治疗方法充分缓解这种慢性疼痛状况。 腰椎背根神经节(DRG)的炎症，例如继发于对破裂的免疫反应 腰椎间盘突出，可能会导致某些形式的腰痛。因为炎症在背部起着重要的作用 疼痛，一种常见的治疗方法是局部注射抗炎皮质类固醇。不过，这个 治疗方法一直备受争议。这些治疗的随机临床试验结果喜忧参半。 并不是所有的患者都能从类固醇中得到缓解。皮质类固醇药物的标称靶点是糖皮质激素 受体(GR)。然而，最近的体外研究表明，许多类固醇在临床上用于背痛注射。 (包括6-α甲基强的松龙和曲安奈龙)也能激活盐皮质激素受体(MR)。 具有相似的效力。MR最为人所知的是作为醛固酮的靶标，促进钠在脑内的重吸收 肾脏。然而，这种受体在其他类型的细胞中也有表达，包括心肌细胞、脑神经元和 背根神经节神经元。在许多组织中，MR扮演着促炎作用，预计这将抵消 GR激活的抗炎作用。我们的假设是，避免MR激活会增加 激素治疗下腰痛的疗效观察。我们将通过三个具体目标来检验这一假设 (Sa)，使用两个已建立的下腰痛临床前模型。SA1.为了进一步描述局部的影响 MR激活导致背部疼痛与炎症的分子相关性。我们将确定 局部阻断或激活盐皮质激素对大鼠下腰痛模型MR受体的影响 疼痛，检查疼痛行为，感觉神经元兴奋性，细胞因子谱，和组织化学测量 炎症和受体激活。SA2.检验临床使用糖皮质激素(GR)的假设 激动剂)也会激活盐皮质激素受体，降低它们改善背痛和分子水平的能力 炎症的相关因素。我们将检查几种常用于下腰痛的类固醇的效果。 注射(所有这些都在体外激活MR)，一种用于其他临床的高度糖皮质激素选择性类固醇 设置，和内源性糖皮质激素皮质酮。SA3.评估一种新的治疗方法 联合应用GR激动剂和MR拮抗剂改善背痛及其分子相关性 发炎。在SA2中检查的类固醇将与盐皮质激素拮抗剂或 击倒对手。我们的长期目标是为临床试验建立临床前基础，以检验我们的假设 盐皮质激素拮抗剂可以改善局部注射的类固醇的反应，通常用于低血压 背部疼痛治疗。一种选择性的矿物皮质激素使这类试验更具可行性 拮抗剂依普利酮已经在美国被批准用于治疗心力衰竭和高血压。

Low back pain is a common ailment which can be debilitating and which becomes chronic in 30% of cases. Many patients fail to achieve adequate relief for such chronic pain conditions with current therapies. Inflammation of the lumbar dorsal root ganglia (DRG), e.g. secondary to an immune response to a ruptured disc, may contribute to some forms of low back pain. Because inflammation plays an important role in back pain, a common treatment involves local injections of anti-inflammatory corticosteroids. However, this treatment has been controversial. Randomized clinical trials of these treatments have had mixed results, and not all patients obtain relief from steroids. The nominal target of corticosteroid drugs is the glucocorticoid receptor (GR). However, recent in vitro studies show that many steroids clinically used for back pain injections (including 6-α methylprednisolone and triamcinolone) can also activate the mineralocorticoid receptor (MR) with similar potency. The MR is best known as the target of aldosterone, promoting sodium reabsorption in the kidney. However, this receptor is expressed in other cell types including cardiomyocytes, brain neurons, and DRG neurons. In many tissues MR plays a pro-inflammatory role which would be expected to counteract the anti-inflammatory effects of GR activation. Our hypothesis is that avoiding MR activation will increase the efficacy of steroids used in treatment of low back pain. We will test this hypothesis with three specific aims (SA), using two established preclinical models of low back pain. SA1. To further characterize effects of local MR activation in contributing to back pain and molecular correlates of inflammation. We will determine the effects of local mineralocorticoid blockade or activation, and MR receptor knockdown, in rat models of low back pain, examining pain behaviors, sensory neuron excitability, cytokine profile, and histochemical measures of inflammation and receptor activation. SA2. To test the hypothesis that clinically used glucocorticoids (GR agonists) also activate the mineralocorticoid receptor, reducing their ability to improve back pain and molecular correlates of inflammation. We will examine the effects of several steroids commonly used in low back pain injections (all of which activate the MR in vitro), a highly glucocorticoid selective steroid used in in other clinical settings, and the endogenous glucocorticoid corticosterone. SA3. To assess a novel therapeutic approach for back pain by combining GR agonists with MR antagonists to improve back pain and molecular correlates of inflammation. The steroids examined in SA2 will be tested in combination with mineralocorticoid antagonists or knockdown. Our long term goal is to establish the preclinical basis for clinical trials testing our hypothesis that mineralocorticoid antagonists may improve the response to locally injected steroids commonly used for low back pain treatment. Such trials are made more feasible by the fact that a selective mineralocorticoid antagonist, eplerenone, is already approved for use in the United States for heart failure and hypertension.