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

Mohammed Shaqura,Sascha Treskatsch,Li Li,Mehdi Shakibaei,Shaaban A Mousa,Doaa M Mohamed,Antje Beyer,Xiongjuan Li,Constanze Buhrmann,Michael Schäfer

doi:10.1186/s12974-020-01864-8

Abstract

BackgroundRecently, mineralocorticoid receptors (MR) were identified in peripheral nociceptive neurons, and their acute antagonism was responsible for immediate and short-lasting (non-genomic) antinociceptive effects. The same neurons were shown to produce the endogenous ligand aldosterone by the enzyme aldosterone synthase.MethodsHere, we investigate whether endogenous aldosterone contributes to inflammation-induced hyperalgesia via the distinct genomic regulation of specific pain signaling molecules in an animal model of Freund’s complete adjuvant (FCA)-induced hindpaw inflammation.ResultsChronic intrathecal application of MR antagonist canrenoate-K (over 4 days) attenuated nociceptive behavior in rats with FCA hindpaw inflammation suggesting a tonic activation of neuronal MR by endogenous aldosterone. Consistently, double immunofluorescence confocal microscopy showed abundant co-localization of MR with several pain signaling molecules such as TRPV1, CGRP, Nav1.8, and trkA whose enhanced expression of mRNA and proteins during inflammation was downregulated following i.t. canrenoate-K. More importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by continuous intrathecal delivery of a specific aldosterone synthase inhibitor prevented the inflammation-induced enhanced transcriptional expression of TRPV1, CGRP, Nav1.8, and trkA and subsequently attenuated nociceptive behavior. Evidence for such a genomic effect of endogenous aldosterone was supported by the demonstration of an enhanced nuclear translocation of MR in peripheral sensory dorsal root ganglia (DRG) neurons.ConclusionTaken together, chronic inhibition of local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons may contribute to long-lasting downregulation of specific pain signaling molecules and may, thus, persistently reduce inflammation-induced hyperalgesia.

Highlights

Apart from their role of maintaining the homeostasis of the body through regulation of numerous physiologic processes [1, 2], there is increasing evidence for the presence and functional role of glucocorticoid (GR) and mineralocorticoid receptors (MR) within the central nervous system [3,4,5]
The significantly enhanced mRNA expression of pain signaling molecules TRPV1, CGRP, Nav1.8, and trkA in sensory dorsal root ganglia (DRG) ipsilateral to the Freund’s complete adjuvant (FCA) hindpaw inflammation was significantly attenuated by chronic i.t. canrenoate-K delivery (P < 0.05, one-way ANOVA, followed by Dunnett’s test; Fig. 3a–d)
We have shown that a single systemic or intrathecal administration of the MR antagonist canrenoate-K resulted in an immediate and short-lasting 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 resulted in alterations of the genomic expression of specific pain signaling molecules such as TRPV1, CGRP, Nav1.8, and trkA and whether this resulted in changes of nociceptive behavior following FCA-induced hindpaw inflammation

Summary

Introduction

Apart from their role of maintaining the homeostasis of the body through regulation of numerous physiologic processes [1, 2], there is increasing evidence for the presence and functional role of glucocorticoid (GR) and mineralocorticoid receptors (MR) within the central nervous system [3,4,5]. Both genomic and non-genomic effects of these steroid receptors were described contributing to an enhanced plasticity of the central nervous system [3,4,5]. The same neurons were shown to produce the endogenous ligand aldosterone by the enzyme aldosterone synthase

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Discussion

Conclusion