Aldosterone Synthase in Peripheral Sensory Neurons Contributes to Mechanical Hypersensitivity during Local Inflammation in Rats

Abstract

Background: Recent emerging evidence suggests that extra-adrenal synthesis of aldosterone occurs (e.g., within the failing heart and in certain brain areas). In this study, the authors investigated evidence for a local endogenous aldosterone production through its key processing enzyme aldosterone synthase within peripheral nociceptive neurons. Methods: In male Wistar rats (n = 5 to 8 per group) with Freund's complete adjuvant hind paw inflammation, the authors examined aldosterone, aldosterone synthase, and mineralocorticoid receptor expression in peripheral sensory neurons using quantitative reverse transcriptase-polymerase chain reaction, Western blot, immunohistochemistry, and immunoprecipitation. Moreover, the authors explored the nociceptive behavioral changes after selective mineralocorticoid receptor antagonist, canrenoate-K, or specific aldosterone synthase inhibitor application. Results: In rats with Freund's complete adjuvant-induced hind paw inflammation subcutaneous and intrathecal application of mineralocorticoid receptor antagonist, canrenoate-K, rapidly and dose-dependently attenuated nociceptive behavior (94 and 48% reduction in mean paw pressure thresholds, respectively), suggesting a tonic activation of neuronal mineralocorticoid receptors by an endogenous ligand. Indeed, aldosterone immunoreactivity was abundant in peptidergic nociceptive neurons of dorsal root ganglia and colocalized predominantly with its processing enzyme aldosterone synthase and mineralocorticoid receptors. Moreover, aldosterone and its synthesizing enzyme were significantly upregulated in peripheral sensory neurons under inflammatory conditions. The membrane mineralocorticoid receptor consistently coimmunoprecipitated with endogenous aldosterone, confirming a functional link between mineralocorticoid receptors and its endogenous ligand. Importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by a specific aldosterone synthase inhibitor attenuated nociceptive behavior after hind paw inflammation (a 32% reduction in paw pressure thresholds; inflammation, 47 ± 2 [mean ± SD] vs. inflammation + aldosterone synthase inhibitor, 62 ± 2). conclusions: Local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity during local inflammation via intrinsic activation of neuronal mineralocorticoid receptors.

Neuronal aldosterone elicits a distinct genomic response in pain signaling molecules contributing to inflammatory pain

“…For the first time, we have systematically investigated the potential long-lasting genomic effects of endogenous MR agonist aldosterone on the transcriptional regulation of several pain signaling molecules in peripheral sensory DRG neurons during inflammatory pain. Previous studies have demonstrated MR and its endogenous ligand aldosterone in these neurons [8,9]. Here, chronic i.t.…”

“…Previously, we have demonstrated that the final conversion of 18-hydroxycorticosterone into aldosterone by aldosterone synthase also occurs in peripheral sensory DRG neurons [9] confirming preceding reports on the expression of aldosterone synthase outside the adrenal gland, e.g., in brain, heart, aortic endothelial cells, and in vascular smooth muscle [24][25][26]. Moreover, we have shown that a single systemic or intrathecal administration of the MR antagonist canrenoate-K resulted in an immediate and short-lasting (up to 30 min) reversal of mechanical hypersensitivity most likely through a nongenomic effect [9]. In contrast to this short-lasting effect, we investigated in this study whether chronic antagonism of aldosterone's action or continuous inhibition of aldosterone synthesis (over 4 days) resulted in alterations of the genomic expression of specific pain signaling molecules such as TRPV1, CGRP, Nav1.8, and trkA and First, we demonstrated that chronic i.t.…”

“…Surprisingly, the mRNA and protein of enzyme aldosterone synthase, the enzyme that processes the last step of conversion to aldosterone, were detected in the same nociceptive neurons [9]. Immunohistochemical doublestaining showed great overlap between aldosterone synthase, aldosterone, and MR in peripheral nociceptive neurons.…”

“…Immunohistochemical doublestaining showed great overlap between aldosterone synthase, aldosterone, and MR in peripheral nociceptive neurons. Following a localized painful hindpaw inflammation, the expression of aldosterone synthase and the production of aldosterone were upregulated [9]. Intrathecal administration of the MR antagonist canrenoate-K resulted in an immediate and short-lasting (up to 30 min) reversal of mechanical hypersensitivity most likely through a non-genomic effect [9].…”

Functional and anatomical characterization of corticotropin-releasing factor receptor subtypes of the rat spinal cord involved in somatic pain relief

“…Spinal cord from adult rats were solubilized and extracted for immunoblotting investigations as previously described [24]. Brie y, the samples were homogenized in boiling SDS sample buffer (100 mM Tris, 2% SDS, 20% glycerol).…”