Comparative analysis of molecular signatures suggests the use of gabapentin for the management of endometriosis-associated pain

Brice Bellessort, Anne Bachelot, Virginie Grouthier, Camille de Lombares, Nicolas Narboux‐Nême, Paolo Garagnani, Chiara Pirazzini, Simonetta Astigiano, Luca Mastracci, Anastasia Fontaine, Gladys Alfama, Evelyne Duvernois‐Berthet, Giovanni Levi
In: bioRxiv · 2018 · doi:10.1101/251397 · W2952449465
preprint OA: green CC0 ⤵ 1 in-corpus citation
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Comparing gene expression in human endometriosis and mouse models revealed CACNA2D subunits are overexpressed and suggest gabapentinoids as potential treatments for endometriosis-associated pain.

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Abstract

Capsule Comparative analysis of gene expression signatures from endometriosis and mouse models shows that CACNAα2δs calcium-channel components involved in nociception are targets for the treatment of endometriosis-associated pain. Context Differential gene expression analyses comparing endometriotic lesions to eutopic endometrium have shown that the transcription factors DLX5 and DLX6 are drastically down-regulated in the ectopic implants. These finding suggests that regulatory cascades involving DLX5/6 might be involved in the origin of endometriosis symptoms such as chronic pelvic pain. We have shown that mice in which Dlx5 and Dlx6 are selectively inactivated in the uterus present an endometrial phenotype reminiscent of endometriosis implants. Objective Identify new targets for the treatment of endometriosis. Design To better focus the search for endometriosis targets we have compared the profile of genes deregulated in normal and ectopic women endometrium to those deregulated in the uterus of normal and Dlx5/Dlx6 -null mice. Settings Academic research unit and University Hospital research laboratory Animals Mice carrying a uterus-specific deletion of Dlx5/Dlx6 . Interventions Analysis of archive sections from normal endometrium and endometriosis implants. Main Outcome A novel endometriosis signature suggests that α2δs subunits of voltage-gated calcium channel are targets for the management of endometriosis-associated pain. Results We identify a signature of 30 genes similarly deregulated in human endometriosis implants and in Dlx5/6 -null mouse uteri reinforcing the notion that the down-regulation of Dlx5/6 is an early event in the progress of endometriosis. CACNA2D3 , a component of the voltage-dependent calcium channel complex is strongly overexpressed both in endometriosis implants and in mutant mouse uteri; other members of the alfa2delta family, CACNA2D1 and CACNA2D2, are also overexpressed in endometriosis. Conclusion CACNA2D1, CACNA2D2 and CACNA2D3 are directly involved in pain perception. In particular, CACNA2D3 has been associated to pain sensitization and heat nociception in animal models while, in patients, variants of this gene are associated to reduced sensitivity to acute noxious stimuli. As CACNA2Ds are targets of gabapentinoids analgesics, our results suggest to consider the use of these drugs for the treatment of endometriosis-associated pain. Indeed, recent small-scale clinical studies have shown that gabapentin can be effective in the treatment of women chronic pelvic pain. Our findings reinforce the need for a large definitive trial.

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endometriosischronic_pelvic_pain

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