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

Abstract

CapsuleComparative analysis of gene expression signatures from endometriosis and mouse models shows that CACNA2{delta}s calcium-channel components involved in nociception are targets for the treatment of endometriosis-associated pain.\n\nContextDifferential 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.\n\nObjectiveIdentify new targets for the treatment of endometriosis.\n\nDesignTo 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.\n\nSettingsAcademic research unit and University Hospital research laboratory\n\nAnimalsMice carrying a uterus-specific deletion of Dlx5/Dlx6.\n\nInterventionsAnalysis of archive sections from normal endometrium and endometriosis implants.\n\nMain OutcomeA novel endometriosis signature suggests that 2{delta}s subunits of voltage-gated calcium channel are targets for the management of endometriosis-associated pain.\n\nResultsWe 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.\n\nConclusionCACNA2D1, 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.