Steroids and Steroid Receptors in Low Back Pain

下背痛是一种常见的疾病，可以使人衰弱，并且在30%的情况下成为慢性病。 许多患者用当前疗法不能实现对此类慢性疼痛病症的充分缓解。 腰椎背根神经节（DRG）炎症，例如继发于对破裂的脊髓损伤的免疫应答。 椎间盘，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包括局部注射抗炎皮质类固醇。但这 治疗一直存在争议。这些治疗方法的随机临床试验结果喜忧参半， 并非所有患者都能从类固醇中得到缓解。皮质类固醇药物的名义靶点是糖皮质激素 受体（GR）。然而，最近的体外研究表明，许多临床上用于背部疼痛注射的类固醇 （包括6-α甲基强的松龙和曲安西龙）也能激活盐皮质激素受体（MR） 具有相似的功效。MR最为人所知的是作为醛固酮的靶点，其促进脑组织中的钠重吸收。 肾然而，这种受体在其他细胞类型中表达，包括心肌细胞、脑神经元和神经细胞。 DRG神经元。在许多组织中，MR起促炎作用，预期其会抵消炎症反应。 GR激活的抗炎作用。我们的假设是，避免MR激活将增加 类固醇用于治疗腰痛的疗效。我们将以三个具体目标来检验这一假设 (SA)，使用两个已建立的腰痛临床前模型。SA 1.为了进一步描述当地 MR激活导致背痛和炎症的分子相关性。康贝特人将以 局部盐皮质激素阻断或激活以及MR受体敲低对大鼠下背部模型的影响 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， 炎症和受体活化。SA 2.为了验证临床上使用的糖皮质激素（GR） 激动剂）也激活盐皮质激素受体，降低其改善背痛和分子水平的能力。 炎症的相关因素。我们将研究几种常用的类固醇在腰痛中的作用 注射（所有这些都在体外激活MR），一种高度糖皮质激素选择性类固醇，用于其他临床 和内源性糖皮质激素皮质酮。SA 3.评估一种新的治疗方法， 通过将GR激动剂与MR拮抗剂组合以改善背痛和以下的分子相关性， 炎症在SA 2中检查的类固醇将与盐皮质激素拮抗剂或 击倒。我们的长期目标是为临床试验建立临床前基础，测试我们的假设， 盐皮质激素拮抗剂可以改善对局部注射类固醇的反应， 背部疼痛治疗这样的试验是更可行的事实，选择性盐皮质激素 拮抗剂依普利酮已经在美国被批准用于心力衰竭和高血压。

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.