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

ABSTRACT: BACKGROUND:Recently, 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. METHODS:Here, 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. RESULTS:Chronic 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. CONCLUSION:Taken 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.

SUBMITTER: Shaqura M

PROVIDER: S-EPMC7291517 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Shaqura Mohammed M Li Li L Mohamed Doaa M DM Li Xiongjuan X Treskatsch Sascha S Buhrmann Constanze C Shakibaei Mehdi M Beyer Antje A Mousa Shaaban A SA Schäfer Michael M

Journal of neuroinflammation 20200612 1

<h4>Background</h4>Recently, 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.<h4>Methods</h4>Here, we investigate whether endogenous aldosterone contributes to inflammation-induced hyperalgesia via the distinct genomic regulation of specific ...[more]

PMID: 32532285

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

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

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