Spinal Sigma-1 Receptor-mediated Dephosphorylation of Astrocytic Aromatase Plays a Key Role in Formalin-induced Inflammatory Nociception

Hoon Seong Choi, Mi Ji Lee, Sheu Ran Choi, Branden A. Smeester, Al J Beitz, Jang Hern Lee

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Aromatase is a key enzyme responsible for the biosynthesis of estrogen from testosterone. Although recent evidence indicates that spinal cord aromatase participates in nociceptive processing, the mechanisms underlying its regulation and its involvement in nociception remain unclear. The present study focuses on the potential role of astrocyte aromatase in formalin-induced acute pain and begins to uncover one mechanism by which spinal aromatase activation is controlled. Following intraplantar formalin injection, nociceptive responses were quantified and immunohistochemistry/co-immunoprecipitation assays were used to investigate the changes in spinal Fos expression and the phospho-serine levels of spinal aromatase. Intrathecal (i.t.) injection of letrozole (an aromatase inhibitor) mitigated both the late phase formalin-induced nociceptive responses and formalin-induced spinal Fos expression. Furthermore, formalin-injected mice showed significantly reduced phospho-serine levels of aromatase, which is associated with the rapid activation of this enzyme. However, sigma-1 receptor inhibition with i.t. BD1047 blocked the dephosphorylation of aromatase and potentiated the pharmacological effect of letrozole on formalin-induced nociceptive responses. In addition, i.t. administration of a sub-effective dose of BD1047 potentiated the pharmacological effect of cyclosporin A (a calcineurin inhibitor) on both the formalin-induced reduction in phospho-serine levels of aromatase and nociceptive behavior. These results suggest that dephosphorylation is an important regulatory mechanism involved in the rapid activation of aromatase and that spinal sigma-1 receptors mediate this dephosphorylation of aromatase through an intrinsic calcineurin pathway.

Original languageEnglish (US)
Pages (from-to)181-191
Number of pages11
JournalNeuroscience
Volume372
DOIs
StatePublished - Feb 21 2018

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea Grant funded by the Korean Government ( NRF-2017R1A2A2A05001402 ).

Keywords

  • acute pain
  • aromatase
  • dephosphorylation
  • inflammatory pain
  • sigma-1 receptor

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