Unlocking Pregnancy Protection: How Cannabinoid Receptors Influence Birth Risks

The endocannabinoid system (ECS) plays a crucial role in various physiological processes, including reproduction. Canonical cannabinoid receptors type 1 (CB1) and type 2 (CB2) are activated by 2-acyl glycerol and anandamide, members of a broader endocannabinoid (ECB) lipidome. This study investigated the effect of CB1 receptor signaling on inflammatory mediators and ECS regulation in late pregnancy and its contribution to inflammation-induced preterm birth (PTB) using a murine model. CB1-knock-out (KO) and wild-type (WT) pregnant mice were treated with lipopolysaccharide (LPS) to induce PTB. CB1-KO mice exhibited significantly lower PTB rates compared to WT, suggesting a protective effect of CB1 deficiency. We also analyzed ECS components in decidual tissue and found that CB1-KO displayed lower basal fatty acid amide hydrolase activity than WT. LPS treatment reduced decidual CB2 protein levels only in CB1-KO mice. The pattern of ECBs and related lipids was similar in WT and CB1-KO decidua and serum, with a few key exceptions. Free fatty acids significantly increased in WT decidua with LPS but were unchanged in CB1-KO. Inflammatory markers such as prostaglandin E2, prostaglandin F2α, and matrix metalloproteinase 9 activity were also elevated in WT but not in CB1-KO after LPS administration. These findings suggest that CB1 deficiency modulates endogenous lipids and inflammatory responses during late pregnancy, decreasing the risk of LPS-induced PTB. This study provides new insights into the role of CB1 in pregnancy and its potential as a therapeutic target for PTB prevention.