Characterizing the Role of Endocannabinoid Receptor Cnr1 in Mouse Ovarian Granulosa Cells

• Published in: Cell biochemistry and function Vol. 43; no. 3; pp. e70070 - n/a
• Main Authors: Randhawa, Jasmine, Madogwe, Ejimedo, McCall, Aire, Singh, Jaswinder, Duggavathi, Raj
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.03.2025
• Subjects: Amidohydrolases; Animals; Cnr1; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; endocannabinoid system; Endocannabinoids - metabolism; Female; granulosa cells; Granulosa Cells - cytology; Granulosa Cells - drug effects; Granulosa Cells - metabolism; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases - genetics; Monoacylglycerol Lipases - metabolism; mouse; ovulation; Piperidines - pharmacology; Pyrazoles - pharmacology; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - genetics; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - genetics; Receptor, Cannabinoid, CB2 - metabolism; mouse; Cnr1; endocannabinoid system; granulosa cells; ovulation
• ISSN: 0263-6484; 1099-0844; 1099-0844
• DOI: 10.1002/cbf.70070

ABSTRACT The endocannabinoid receptors Cnr1 and Cnr2 have been found in reproductive organs such as the oviduct and uterus. These receptors bind to endocannabinoids, the arachinodoylethanolamine (AEA) and arachinodoylglycerol (2‐AG), respectively. Both cannbinoid receptors have been investigated for their role in implantation and fertilization. However, not much is explored in terms of their role in ovarian granulosa cells. As these two receptors (especially Cnr1) have affinity towards the major component of Cannabis, tetrahydrocannabinol (THC), its usage raises concerns about the potential effects of THC on ovarian functions. Hence, it is important to characterize the role of endocannabinoid system in the ovarian granulosa cells. The objectives of this study were to use the mouse model to: (1) profile the expression pattern of the Cnr1 and Cnr2 and the endocannabinoid metabolizing enzymes (Faah and Mgll) in granulosa cells and (2) to determine the effect of the Cnr1 antagonist, AM251 on ovarian functions. We found that Cnr1 transcript abundance was higher (p < 0.05) at 4 h hCG than 24 h and 48 h eCG timepoints, whereas Cnr2 transcript decreased (p < 0.05) with follicular development. Conversely, Faah and Mgll transcripts were higher at 14 h hCG (p < 0.05) suggesting their upregulation after ovulation. The ovulation rate was lower in AM251 than vehicle‐treated mice (p < 0.05), indicating that Cnr1 signaling may regulate ovulation. Further investigating the effect of AM251, we found that it significantly downregulated Ptgs2 and Pappa (p < 0.05). Overall, these data suggest that Cnr1, an important player in the endocannabinoid system, is important for ovulation. Summary The Cnr1 and Cnr2 receptors are well‐studied cannabinoid receptors in the brain. Their presence in ovaries hints at a regulatory role in ovarian functions. This study aimed to examine how the expression of these receptors and cannabinoid metabolizing enzymes changes during follicular development and the role of Cnr1 in ovulation using the mouse model. We found that Cnr1 is upregulated by the preovulatory hCG treatment in immature superovulated mice. Inhibition of Cnr1 reduced ovulation rate and downregulated key ovulatory genes. These data demonstrate that the cannabinoid receptor, Cnr1 plays a key role in ovulation in mice.