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-? 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.
We propose 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.
