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J Pain Res. 2018 Apr 10;11:715-725. doi: 10.2147/JPR.S163611. eCollection 2018.

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

Author information

1
Evolution of Endocrine Regulations, Department AVIV, National Museum of Natural History, Paris, France.
2
AP-HP, Department of Endocrinology and Reproductive Medicine, Reference Center for Rare Endocrine Diseases, Pitié-Salpêtrière Hospital, UPMC, Paris, France.
3
Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
4
Interdepartmental Center "L. Galvani", University of Bologna, Bologna, Italy.
5
Department of Integrated Oncological Therapies, San Martino Hospital, Genova, Italy.
6
Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genoa, Genova, Italy.
7
Division of Anatomic Pathology, Department of Surgical Science and Integrated Diagnostics, University of Genoa, Genova, Italy.

Abstract

Background:

It has been repetitively shown that the transcription factors DLX5 and DLX6 are drastically downregulated in endometriotic lesions when compared with eutopic endometrium. These findings suggest that regulatory cascades involving DLX5/6 might be at the origin of endometriosis symptoms such as chronic pelvic pain (CPP). We have shown that inactivation of Dlx5 and Dlx5/6 in the mouse uterus results in an endometrial phenotype reminiscent of endometriosis.

Methods:

We focused on genes that present a similar deregulation in endometriosis and in Dlx5/6-null mice in search of new endometriosis targets.

Results:

We confirmed a strong reduction of DLX5 expression in endometriosis implants. We identified a signature of 30 genes similarly deregulated in human endometriosis implants and in Dlx5/6-null mouse uteri, reinforcing the notion that the downregulation of Dlx5/6 is an early event in the progress of endometriosis. CACNA2D3, a component of the α2δ family of voltage-dependent calcium channel complex, was strongly overexpressed both in mutant mouse uteri and in endometriosis implants, were also CACNA2D1 and CACNA2D2, other members of the α2δ family involved in nociception, are upregulated.

Conclusion:

Comparative analysis of gene expression signatures from endometriosis and mouse models showed that calcium channel subunits α2δ involved in nociception can be targets for the treatment of endometriosis-associated pain. CACNA2D3 has been associated with pain sensitization and heat nociception in animal models. In patients, CACNA2D3 variants were associated with reduced sensitivity to acute noxious stimuli. As α2δs were targets of gabapentinoid analgesics, the results suggested the use of these drugs for the treatment of endometriosis-associated pain. Indeed, recent small-scale clinical studies have shown that gabapentin could be effective in women with CPP. The findings of this study reinforce the need for a large definitive trial.

KEYWORDS:

CACNA2D3; Dlx5; endometriosis; gabapentin; pain

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

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