eplerenone and Pain

Osteoarthritis (OA) is a multifactorial degenerative disease marked by the progressive deterioration of articular cartilage with inflammation of the synovium. OA's main symptoms include pain and function loss. Monosodium Iodoacetate (MIA) experimental model is widely-used for OS induction since it produces symptoms comparable to those occurring in humans.. Thirty-two rats were divided into four groups (n = 8). The 1st group received saline and included the normal-control rats. Groups 2-4 received intra-articular injections of MIA (3 mg/50 μL) in the rats' knee joints to induce OA. Group 2 included the MIA-control rats. Groups 3 and 4 received intra-articular MIA followed by a 14-day oral eplerenone (50 and 100 mg/kg); respectively.. Intra-articular injection of MIA in rats' knee joints caused significant inflammation and pain, elevation of Akt and ERK gene expression in knee joints along with significant alterations in the histological pictures of knee joints and OARSI scores. RANKL/OPG Axis was significantly disrupted.. Eplerenone treatment produced a significant improvement in motor coordination and spontaneous locomotor activity in rats and modulated the key inflammatory mediators in OA (TNF-α, NF-κβ, and IL-6). Eplerenone also suppressed the qRT-PCR gene expression of Akt and ERK in knee joint tissues and improved the histological pictures and OARSI scores of knee joints of treated rats. Eplerenone caused a decline in RANKL concentration accompanied by a rise in OPG concentration thus modulating the RANKL/OPG Axis. Consequently, eplerenone is a candidate for OA therapy due to its potential anti-inflammatory effects.

Topics: Animals; Cartilage, Articular; Disease Models, Animal; Eplerenone; Humans; Inflammation; Iodoacetic Acid; Osteoarthritis, Knee; Pain; Proto-Oncogene Proteins c-akt; Rats

Stress evokes age-dependent effects on pain sensitivity and commonly occurs during adolescence. However, the mechanisms linking adolescent stress and pain remain poorly understood, in part due to a lack of information regarding how stress hormones modulate the function of nociceptive circuits in the adolescent CNS. Here we investigate the short- and long-term effects of corticosterone (CORT) on the excitability of GABAergic and presumed glutamatergic neurons of the spinal superficial dorsal horn (SDH) in Gad1-GFP mice at postnatal days (P)21-P34. In situ hybridization revealed that glutamatergic SDH neurons expressed significantly higher mRNA levels of both glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) compared to adjacent GABAergic neurons. The incubation of spinal cord slices with CORT (90 min) evoked select long-term changes in spontaneous synaptic transmission across both cell types in a sex-dependent manner, without altering the intrinsic firing of either Gad1-GFP+ or GFP- neurons. Meanwhile, the acute bath application of CORT significantly decreased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), as well as the frequency of miniature inhibitory postsynaptic currents (mIPSCs), in both cell types leading to a net reduction in the balance of spontaneous excitation vs. inhibition (E:I ratio). This CORT-induced reduction in the E:I ratio was not prevented by selective antagonists of either GR (mifepristone) or MR (eplerenone), although eplerenone blocked the effect on mEPSC amplitude. Collectively, these data suggest that corticosterone modulates synaptic function within the adolescent SDH which could influence the overall excitability and output of the spinal nociceptive network.

Topics: Animals; Corticosterone; Eplerenone; GABAergic Neurons; Mice; Pain; Posterior Horn Cells; Spinal Cord Dorsal Horn; Synaptic Transmission

Spironolactone, eplerenone, chlorothiazide and furosemide are diuretics that have been suggested to have antinociceptive properties, for example via mineralocorticoid receptor antagonism. In co-administration, diuretics might enhance the antinociceptive effect of opioids via pharmacodynamic and pharmacokinetic mechanisms. Effects of spironolactone (100 mg/kg, i.p.), eplerenone (100 mg/kg, i.p.), chlorothiazide (50 mg/kg, i.p.) and furosemide (100 mg/kg, i.p.) were studied on acute oxycodone (0.75 mg/kg, s.c.)- and morphine (3 mg/kg, s.c.)-induced antinociception using tail-flick and hot plate tests in male Sprague Dawley rats. The diuretics were administered 30 min. before the opioids, and behavioural tests were performed 30 and 90 min. after the opioids. Concentrations of oxycodone, morphine and their major metabolites in plasma and brain were quantified by mass spectrometry. In the hot plate test at 30 and 90 min., spironolactone significantly enhanced the antinociceptive effect (% of maximum possible effect) of oxycodone from 10% to 78% and from 0% to 50%, respectively, and that of morphine from 12% to 73% and from 4% to 83%, respectively. The brain oxycodone and morphine concentrations were significantly increased at 30 min. (oxycodone, 46%) and at 90 min. (morphine, 190%). We did not detect any independent antinociceptive effects with the diuretics. Eplerenone and chlorothiazide did not enhance the antinociceptive effect of either opioid. The results suggest that spironolactone enhances the antinociceptive effect of both oxycodone and morphine by increasing their concentrations in the central nervous system.

Topics: Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Brain; Chlorothiazide; Disease Models, Animal; Diuretics; Drug Interactions; Drug Therapy, Combination; Eplerenone; Furosemide; Male; Morphine; Neurons; Oxycodone; Pain; Rats, Sprague-Dawley; Spironolactone; Tissue Distribution

Inflammation of the dorsal root ganglia (DRG) may contribute to low back pain, postherpetic neuralgia, and neuropathic pain. The mineralocorticoid receptor (MR) plays a proinflammatory role in many nonrenal tissues, but its role in peripheral pain at the DRG level is not well studied.. 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, the authors applied the MR antagonist eplerenone locally to the inflamed DRG. Excitability of small-diameter sensory neurons was examined in acute primary culture by using patch clamp techniques.. 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 h) 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.. The MR may have a pronociceptive 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.

Topics: Animals; Behavior, Animal; Eplerenone; Ganglia, Spinal; Inflammation; Male; Mineralocorticoid Receptor Antagonists; Pain; Pain Measurement; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Sensory Receptor Cells; Spironolactone

Topics: Animals; Eplerenone; Ganglia, Spinal; Male; Mineralocorticoid Receptor Antagonists; Pain; Sensory Receptor Cells; Spironolactone