Mineralocorticoid Antagonist Improves Glucocorticoid Receptor Signaling and Dexamethasone Analgesia in an Animal Model of Low Back Pain

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.

The Role of Neuro-Immune Interactions in Chronic Pain: Implications for Clinical Practice

“… 342–344 Co-administration of mineralocorticoid receptor antagonist with dexamethasone is more effective in reducing SGC activation in the DRG, evoked and spontaneous pain behaviors than dexamethasone alone in rodent models of lower back pain. 342 , 343 , 345 It is interesting to wonder if the propensity to activate different steroid receptors may account for why steroids are sometimes ineffective or wane in efficacy over time in clinical practice. Ultimately, this could be a promising area of future clinical research as mineralocorticoid receptor antagonists (spironolactone, eplerenone) are widely used in the clinical treatment of hypertension and heart failure.…”

“…331,341 Steroids used in clinical practice (dexamethasone, triamcinolone, methylprednisolone, betamethasone) can activate pro-inflammatory mineralocorticoid receptors found in DRG sensory neurons. [342][343][344] Co-administration of mineralocorticoid receptor antagonist with dexamethasone is more effective in reducing SGC activation in the DRG, evoked and spontaneous pain behaviors than dexamethasone alone in rodent models of lower back pain. 342,343,345…”

“…[342][343][344] Co-administration of mineralocorticoid receptor antagonist with dexamethasone is more effective in reducing SGC activation in the DRG, evoked and spontaneous pain behaviors than dexamethasone alone in rodent models of lower back pain. 342,343,345…”

Comprehensive study of dexamethasone on albumin biogenesis during normal and pathological renal conditions

“…In addition, DXM inhibits cell proliferation, arresting cells in the G0/G1 phase, which is accompanied by apoptosis (He et al 2016;Li et al 2018). DXM is the ligand of the glucocorticoid receptor (GR), acting on GR and phosphorylating the receptor, which translocates into the nucleus, promoting the expression of genes as a transcription factor and inducing effects (Marchetti et al 2003;Ibrahim et al 2018;Dey and Bishayi 2019;Murani et al 2019).…”

Dexamethasone as a Treatment of COVID-19

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Dexamethasone is a potent synthetic corticosteroid that possesses anti-inflammatory and immunosuppression effects, which are commonly used to prevent chemotherapy-induced nausea and vomiting, and to treat acute exacerbation of multiple sclerosis, cerebral edema, shock, severe allergies, and multiple myeloma [1]. Unlike some synthetic corticosteroids such as prednisolone, methylprednisolone, and hydrocortisone, dexamethasone is a selective stimulator of glucocorticoid receptors and does not exert any mineralocorticoid activity [2].

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