The cannabinoid receptor CB1 contributes to the development of ectopic lesions in a mouse model of endometriosis

Does signaling via the cannabinoid (CB₁) receptor play a role in the pathogenesis of endometriosis in a mouse model?

Mice treated with a CB₁ agonist developed larger ectopic lesions, while less severe lesions developed in the absence of functional CB₁ expression.

The expression of components of the endocannabinoid system has been demonstrated in both mouse and human uteri. CB₁ receptors are expressed in human epithelial and stromal cell lines derived from eutopic endometrium and deep infiltrating endometriosis nodules.

This was a randomized study in a mouse model of endometriosis. In a first set of experiments, mice with endometriosis were treated with the CB₁ receptor agonist methanandamide (MET) (5 mg/kg, n = 20) on Days 1-5 and 8-12. In a second set of experiments, endometriosis development was evaluated in CB₁^-/- mice and in their wild-type (WT) littermates.

Endometriosis-like lesions were induced in Balb/c and C57/Bl6 mice. Two weeks after disease induction, the lesions were counted, measured and either included for immunohistochemistry analysis or frozen for gene expression profiling by semi-quantitative real-time PCR. To limit the role of chance, the experiments were conducted under standardized laboratory conditions with appropriate controls.

The lesion total volume was significantly higher in MET-treated compared with vehicle-treated mice (P < 0.05). Expression levels of mRNA for survivin, N-cadherin, integrin β1 and interleukin-6 were increased in the ectopic endometrium of MET-treated versus vehicle-treated mice (P < 0.05). CB₁^-/- recipients that received endometrial tissue fragments from CB₁^-/- donors, WT recipients that received endometrial tissue fragments from CB₁^-/- donors and CB₁^-/- recipients that received endometrial tissue fragments from WT donors all showed a significant reduction in total lesion volume and lower expression of survivin and N-cadherin compared with WT recipients receiving uterine fragments from WT donors (P < 0.05).

N/A.

We provide evidence that endocannabinoid signaling via CB₁ receptor plays a role in the development of endometriosis in a mouse model. However, the relative contribution of the CB₁-mediated signaling pathways active in inflammatory, uterine and peritoneal cells remains to be ascertained. Since the study was performed in a mouse model, the significance of the findings in the human system warrants further investigation.

Clarifying the function and regulation of CB₁ and its molecular interactions with endogenous ligands, and how endocannabinoids levels are regulated in women with endometriosis, represent critical areas of research for the potential development of a novel medical treatment of the disease.

A.M.S. was supported by a fellowship from Fondazione Giorgio Pardi. The authors have no conflicts of interest to declare.