The role of cannabinoid agonists and antagonists on folliculogenesis and evolutionary events in the mouse ovary

Abstract

Objectives: Cannabinoids, derivatives of Cannabis sativa L., can activate the endocannabinoid system via two endogenous receptors, CB1 and CB2. This system is crucial in regulating folliculogenesis, fertility, and reproductive function. This study investigated the potential effects of cannabinoid agonists and antagonists on ovarian health and function in female mice.

Materials and methods: 80 NMRI mice were divided into 10 groups. Treatment groups received CB1 or CB2 agonists, antagonists, or their combinations for five days. The animals were then sacrificed, the ovaries were excised and weighed, and their volume was measured. Total RNA was extracted from the left ovary for qPCR analysis, while the right ovary was fixed in Bouin's solution for histological evaluation following H&E staining.

Results: Treatment with CB1/CB2 agonist+CB1 antagonist (W102+AM251) decreased the level of NAPE-PLD (a key factor in the production of endocannabinoids in cells) and increased the level of FAAH (responsible for cannabinoid degradation) genes compared to all groups. CB2 antagonist (AM630) increased the number of primary, preantral, and antral follicles, the volume and weight of ovaries, and estrogen levels. Meanwhile, the CB1 antagonist (AM251) significantly increased microvascular density in the ovaries.

Conclusion: Cannabinoids modulate ovarian physiology and folliculogenesis, with CB2 receptors playing a particularly significant role. Antagonism at CB2 appeared to differentially affect cannabinoid-metabolizing enzymes in ovarian follicles and differentially affect their maturation. However, our preliminary novel findings in mice require human studies before clinical application.

Keywords: CB1 receptor; CB2 receptor; Cannabinoid; Cannabinoid agonist; Cannabinoid antagonist; Folliculogenesis; Ovary.

Figure 1

Ovarian expression of NAPE-PLD and FAAH genes among different groups in NMRI mice after cannabinoid agonist and antagonist administration

Figure 2

Primary follicle (PF), Secondary follicle (SF), Preantral follicle (PAF), Antral follicle (AF) and Luteal body (LB)

Figure 3

Quantification of (A) primary, (B) secondary,(C) preantral, and (D) antral follicles across different experimental groups of NMRI mice after cannabinoid agonist and antagonist administration

Figure 4

Number of (A) luteal bodies, (B) microvessel counts, and ovarian (C) volume and (D) weight across different experimental groups of NMRI mice after cannabinoid agonist and antagonist administration

Figure 5

Estradiol hormone levels across different experimental groups of NMRI mice after cannabinoid agonist and antagonist administration