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

• Main Authors: Mohammed Shaqura, Li Li, Doaa M. Mohamed, Xiongjuan Li, Sascha Treskatsch, Constanze Buhrmann, Mehdi Shakibaei, Antje Beyer, Shaaban A. Mousa, Michael Schäfer
• Format: Article
• Language: English
• Published: BMC 2020-06-01
• Series: Journal of Neuroinflammation
• Subjects: Aldosterone synthase; Pain signaling molecules; Sensory neurons
• Online Access: http://link.springer.com/article/10.1186/s12974-020-01864-8

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.