Mineralocorticoid Receptor Blocker Eplerenone Reduces Pain Behaviors In Vivo  and Decreases Excitability in Small-diameter Sensory Neurons from Local Inflamed Dorsal Root Ganglia In Vitro 

Abstract

Background Inflammation of the dorsal root ganglia (DRG) may contribute to low back pain, postherpetic neuralgia, and neuropathic pain. The mineralocorticoid receptor (MR) plays a pro-inflammatory role in many non-renal tissues, but its role in peripheral pain at the DRG level is not well studied. Methods Local inflammation of the L5 DRG with the immune activator zymosan rapidly leads to mechanical hypersensitivity and increased excitability of sensory neurons. Using this pain model, we applied the MR antagonist eplerenone locally to the inflamed DRG. Excitability of small diameter sensory neurons was examined in acute primary culture, using patch clamp techniques. Results Local eplerenone significantly reduced the mechanical hypersensitivity and shortened its duration. The same dose was ineffective systemically. Immunohistochemical studies showed the MR was present in most neurons, and rapidly translocated to the nucleus 1 day after local DRG inflammation. Activation of satellite glia (defined by expression of glial fibrillary acidic protein) in the inflamed DRG was also reduced by local eplerenone. Increased excitability of small diameter sensory neurons 1 day after inflammation could be observed in vitro. Eplerenone applied in vitro (8 – 12 hours) could reverse this increased excitability. Eplerenone had no effect in neurons isolated from normal, uninflamed DRG. The MR agonist aldosterone (10 nM) applied in vitro increased excitability of neurons isolated from normal DRG. Conclusions The MR may have a pro-nociceptive role in the DRG. Some of its effects may be mediated by neuronal MR. The MR may represent a novel therapeutic target in some pain syndromes.

Do Diuretics have Antinociceptive Actions: Studies of Spironolactone, Eplerenone, Furosemide and Chlorothiazide, Individually and with Oxycodone and Morphine

“…MRs are distributed in other tissues, including the brain. The activation of MRs has been further suggested to cause nociception in experimental models of back pain [5].…”

“…The antagonism of MR has been suggested to reduce pain via gene transcription in the model of back pain [5]. MR receptors also participate in synaptic transmission in hippocampus, amygdala and prefrontal cortex [10], which could contribute in antinociception in other pain models.…”

“…Recently, these drugs have also become of interest in the treatment of pain. Spironolactone [2,3] and eplerenone [4,5] have been shown to have antinociceptive effects in experimental neuropathic and back pain in the rat. Furosemide has been shown to reduce nociceptive behaviour in experimental inflammatory pain in the rat [6] and chlorothiazide [7] has been shown to have a weak thermal antinociceptive effect of its own.…”

Neuroactive steroids and the peripheral nervous system: An update

“…Neuroactive steroids may exert their effects by classical steroid receptors as well as non-classical steroid receptors. Indeed, classical intracellular steroid receptors, such as PROG (PR), androgen (AR), estrogen, glucocorticoid and mineralocorticoid receptors, which bind PROG, DHP, T, DHT, DHEA, estrogens and corticosteroids, have been detected in the glial (i.e., Schwann cells) and neuronal (i.e., DRG) compartments of the PNS [40][41][42][43][44][45][46][47]. Moreover, non-classical steroid receptors, such as progesterone receptor membrane component 1 (PGRMC1), GABA-A, GABA-B, NMDA, AMPA and kainate subunits, as well as sigma 1 receptor are also expressed by the different cellular components of the PNS [42,[48][49][50][51][52].…”

Stress-Induced Pain: A Target for the Development of Novel Therapeutics

“…Conversely, administration of a GR agonist, dexamethasone or triamcinolone, mimicked stress-induced exacerbation of withdrawal threshold (Wang et al, 2004;Gu et al, 2007). Similarly, intrathecal dosing of an MR antagonist, spironolactone (SPIRO) or eplerenone, also reversed the allodynic responses (Gu et al, 2011;Dong et al, 2012). Additional studies have provided evidence for antinociceptive mechanisms that involve NMDA and possibly opiate receptor modulation by GR (Wang et al, 2005;Dong et al, 2006;Alexander et al, 2009) and modulation of spinal microglia activity by MR (Sun et al, 2012).…”