Abstract
Low back pain, a leading cause of disability, is commonly treated by epidural steroid injections that target the anti-inflammatory glucocorticoid receptor (GR). However, their efficacy has been controversial. All currently used epidural steroids also activate the pro-inflammatory mineralocorticoid receptor (MR) with significant potency. Local inflammation of the dorsal root ganglia (DRG), a rat model of low back pain, was used. This model causes static and dynamic mechanical allodynia, cold allodynia and guarding behavior (a measure of spontaneous pain), and activates the MR, with pro-nociceptive effects. In this study, effects of local Dexamethasone (DEX; a glucocorticoid used in epidural injections), and eplerenone (EPL; a second generation, more selective MR antagonist) applied to the DRG at the time of inflammation were examined. Mechanical and spontaneous pain behaviors were more effectively reduced by the combination of DEX and EPL than by either alone. The combination of steroids was particularly more effective than DEX alone or the model alone (3-fold improvement for mechanical allodynia) at later times (day 14). Immunohistochemical analysis of the GR in the DRG showed that the receptor was expressed in neurons of all size classes, and in non-neuronal cells including satellite glia. The GR immunoreactivity was downregulated by DRG inflammation (48%) starting on day 1, consistent with the reduction of GR (57%) observed by Western blot, when compared to control animals. On day 14, the combination of DEX and EPL resulted in rescue of GR immunoreactivity that was not seen with DEX alone, and was more effective in reducing a marker for satellite glia activation/neuroinflammation. The results suggest that EPL may enhance the effectiveness of clinically used epidural steroid injections, in part by enhancing the availability of the GR. Thus, the glucocorticoid-mineralocorticoid interactions may limit the effectiveness of epidural steroids through the regulation of the GR in the DRG.
Highlights
Low back pain is a major health issue and common cause of chronic pain
Dexamethasone (DEX), a high potency, long acting glucocorticoid has been increasingly used as an epidural steroid injection for low back pain management, in part because it is viewed as a safer, non-particulate steroid (Schneider et al, 2015)
We examined the effects of DEX, which is used clinically for epidural steroid injections, and the mineralocorticoid receptor (MR) antagonist EPL, which is clinically approved for conditions other than low back pain, such as hypertension and heart failure
Summary
Low back pain is a major health issue and common cause of chronic pain It is prevalent in one third of the US population (Johannes et al, 2010; Ibrahim et al, 2016). Inflammation is a major player in all these conditions (Finnerup et al, 2010; Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education, 2011; Toblin et al, 2011). Epidural steroid injection has become a standard treatment for low back pain management, to reduce pain and inflammation in the aforementioned conditions. Other steroids commonly used for epidural injections include betamethasone, 6-α-methylprednisolone and triamcinolone (Ibrahim et al, 2016) These clinically used steroids activate the glucocorticoid receptor (GR). It may be beneficial to select the steroid with minimal MR affinity to maximize the anti-inflammatory effects
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