Cannabinoids stimulate prostaglandin production by human gestational tissues through a tissue- and CB1-receptor-specific mechanism

Abstract

Endocannabinoids have been implicated in the mechanisms of implantation, maintenance of pregnancy, and parturition in women. Intrauterine prostaglandin production and actions are also critical in each of these mechanisms. Hence, we have evaluated the effects of cannabinoids on prostaglandin biosynthesis by human gestational membranes. Explants of term amnion and choriodecidua were established and treated with the endogenous endocannabinoids 2-arachidonoyl glycerol and anandamide, as well as the synthetic cannabinoid CP55,940, to determine their ability to modulate PGE(2) production. The explants were also treated with CP55,940 in the presence of either SR141716A (a potent and selective antagonist of the cannabinoid receptor CB1) or NS398 [a cyclooxygenase (COX)-2 inhibitor] to determine whether any observed stimulation of PGE(2) production was mediated through the CB1-receptor and/or COX-2 activity. All three cannabinoids caused a significant increase in PGE(2) production in the amnion but not in the choriodecidua. However, separated fetal (chorion) explants responded to cannabinoid treatment in a similar manner to amnion, whereas maternal (decidual) explants did not. The enhanced PGE(2) production caused by CP55,940 was abrogated by cotreatment with either SR141716A or NS398, illustrating that the cannabinoid action on prostaglandin production in fetal membranes is mediated by CB1 agonism and COX-2. Data from Western blotting show that cannabinoid treatment results in the upregulation of COX-2 expression. This study demonstrates a potential role for endocannabinoids in the modulation of prostaglandin production in late human pregnancy, with potentially important implications for the timing and progression of term and preterm labor and membrane rupture.

Endocannabinoid signaling directs differentiation of trophoblast cell lineages and placentation

“…7B), suggesting that Cnr1 −/− EPC cells are less invasive. This is consistent with previous findings that AEA increases PGE 2 levels via CNR1 (22). Western blotting results are consistent with immunohistochemistry signals (Fig.…”

“…Endocannabinoid signaling via CNR1 is operative in both human and rodent placentas (20,23,42,43) and is associated with recurrent miscarriages (20), initiation of labor (21), and placental production of vasoactive mediators (22). However, it is not yet known how endocannabinoid signaling regulates TS cell proliferation and differentiation in the initial stage of placentation.…”

“…In humans and rats, the endocannabinoid system is associated with recurrent miscarriages (20), parturition (21), as well as placental production of PGE 2 (22) and nitric oxide (23). However, the role of endocannabinoid signaling in TS cell differentiation and growth that occur early in placentation remains undefined.…”

A neurotoxicidade da Cannabis sativa e suas repercussões sobre a morfologia do tecido cerebral

“…Enquanto estudos demonstraram aumento da disponibilidade de AA e síntese de PGE 2 e PGF 2 no tecido uterino 34 , outros verificaram ação anti-inflamatória com inibição da síntese de PGs em cultura de células do cólon humano 35 . Evidências têm demonstrado que a ação anti-inflamatória desencadeada pelos canabinoides através da estimulação de receptores canabinoides, estaria relacionada com a apoptose de células tumorais, diminuição de metástases, diminuição da proliferação celular, analgesia, redução de efeitos colaterais do uso de quimioterápicos etc., por meio da inibição das enzimas COX 33,[35][36][37] .…”

The endocannabinoid pathway and the female reproductive organs

“…However, some peripheral tissues express both receptor isotypes (Zygmunt et al 2000). The effects of exogenous cannabinoids on human fertility have been extensively studied in marijuana smokers, and it has been clearly demonstrated that, at high doses, they can alter trophoblast development and invasiveness, oviductal transport, prostaglandin production by human gestational tissues and endometrial decidualisation (Kessler et al 2005, Mitchell et al 2008. Recent studies have underlined that endocannabinoids, under the control of sex hormones and cytokines, mimic similar effects in female reproduction (Karasu et al 2011).…”