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Loss of cannabinoid receptor CB1 induces preterm birth.

Wang H, Xie H, Dey SK - PLoS ONE (2008)

Bottom Line: Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition.In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation.Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

ABSTRACT

Background: Preterm birth accounting approximate 10% of pregnancies in women is a tremendous social, clinical and economic burden. However, its underlying causes remain largely unknown. Emerging evidence suggests that endocannabinoid signaling via cannabinoid receptor CB1 play critical roles in multiple early pregnancy events in both animals and humans. Since our previous studies demonstrated that loss of CB1 defers the normal implantation window in mice, we surmised that CB1 deficiency would influence parturition events.

Methods and findings: Exploiting mouse models with targeted deletion of Cnr1, Cnr2 and Ptgs1 encoding CB1, CB2 and cyclooxygenase-1, respectively, we examined consequences of CB1 or CB2 silencing on the onset of parturition. We observed that genetic or pharmacological inactivation of CB1, but not CB2, induced preterm labor in mice. Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition. More strikingly, the phenotypic defects of prolonged pregnancy length and parturition failure in mice missing Ptgs1 were corrected by introducing CB1 deficiency into Ptgs1 mice. In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation. The pathophysiological significance of this altered corticotrophin-releasing hormone-driven endocrine activity in the absence of CB1 was evident from our subsequent findings that a selective corticotrophin-releasing hormone antagonist was able to restore the normal parturition timing in Cnr1 deficient mice. In contrast, wild-type females receiving excessive levels of corticosterone induced preterm birth.

Conclusions: CB1 deficiency altering normal progesterone and estrogen levels induces preterm birth in mice. This defect is independent of prostaglandins produced by cyclooxygenase-1. Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.

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Genetic or pharmacological silencing of CB1 induces preterm labor.(A & B) Mice missing Cnr1, but not Cnr2, show early onset of labor with reduced fetal weights at birth. (C & D) Preterm labor occurs in wild-type (WT) pregnant mice receiving a CB1-selective antagonist SR141716 (SR1), but not a CB2-selective antagonist SR144528 (SR2), on days 14–18 with little effects on fetal weights. Numbers within bars indicate the number of mice examined in panels A and C. The average fetal weights (mg) at birth are shown in panels B and D. The bars with different letters are significantly different (P<0.01).
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pone-0003320-g001: Genetic or pharmacological silencing of CB1 induces preterm labor.(A & B) Mice missing Cnr1, but not Cnr2, show early onset of labor with reduced fetal weights at birth. (C & D) Preterm labor occurs in wild-type (WT) pregnant mice receiving a CB1-selective antagonist SR141716 (SR1), but not a CB2-selective antagonist SR144528 (SR2), on days 14–18 with little effects on fetal weights. Numbers within bars indicate the number of mice examined in panels A and C. The average fetal weights (mg) at birth are shown in panels B and D. The bars with different letters are significantly different (P<0.01).

Mentions: Increasing evidence points toward critical roles of endocannabinoid signaling during early pregnancy [8]–[10]. We recently demonstrated that loss of CB1 derails oviductal embryo transport, leading to deferral of on-time embryo implantation [19]. Since an initial deferral of implantation is often associated with delayed parturition [22], we speculated that CB1 deficiency would result in delayed parturition in mice. However, we observed that genetic loss of Cnr1, but not Cnr2, leads to preterm labor (Figure 1A). Consequently, fetal weight at birth in Cnr1−/− mice is significantly reduced compared with wild-type (WT) mice (Figure 1B). In contrast, the parturition events in mice missing Cnr2 are apparently normal (Figure 1A & B).These results may explain why Cnr1−/− pups display poor suckling activities during early days after birth and why their weight gain during postnatal development remains significantly lower than WT control pups [29].


Loss of cannabinoid receptor CB1 induces preterm birth.

Wang H, Xie H, Dey SK - PLoS ONE (2008)

Genetic or pharmacological silencing of CB1 induces preterm labor.(A & B) Mice missing Cnr1, but not Cnr2, show early onset of labor with reduced fetal weights at birth. (C & D) Preterm labor occurs in wild-type (WT) pregnant mice receiving a CB1-selective antagonist SR141716 (SR1), but not a CB2-selective antagonist SR144528 (SR2), on days 14–18 with little effects on fetal weights. Numbers within bars indicate the number of mice examined in panels A and C. The average fetal weights (mg) at birth are shown in panels B and D. The bars with different letters are significantly different (P<0.01).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553193&req=5

pone-0003320-g001: Genetic or pharmacological silencing of CB1 induces preterm labor.(A & B) Mice missing Cnr1, but not Cnr2, show early onset of labor with reduced fetal weights at birth. (C & D) Preterm labor occurs in wild-type (WT) pregnant mice receiving a CB1-selective antagonist SR141716 (SR1), but not a CB2-selective antagonist SR144528 (SR2), on days 14–18 with little effects on fetal weights. Numbers within bars indicate the number of mice examined in panels A and C. The average fetal weights (mg) at birth are shown in panels B and D. The bars with different letters are significantly different (P<0.01).
Mentions: Increasing evidence points toward critical roles of endocannabinoid signaling during early pregnancy [8]–[10]. We recently demonstrated that loss of CB1 derails oviductal embryo transport, leading to deferral of on-time embryo implantation [19]. Since an initial deferral of implantation is often associated with delayed parturition [22], we speculated that CB1 deficiency would result in delayed parturition in mice. However, we observed that genetic loss of Cnr1, but not Cnr2, leads to preterm labor (Figure 1A). Consequently, fetal weight at birth in Cnr1−/− mice is significantly reduced compared with wild-type (WT) mice (Figure 1B). In contrast, the parturition events in mice missing Cnr2 are apparently normal (Figure 1A & B).These results may explain why Cnr1−/− pups display poor suckling activities during early days after birth and why their weight gain during postnatal development remains significantly lower than WT control pups [29].

Bottom Line: Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition.In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation.Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

ABSTRACT

Background: Preterm birth accounting approximate 10% of pregnancies in women is a tremendous social, clinical and economic burden. However, its underlying causes remain largely unknown. Emerging evidence suggests that endocannabinoid signaling via cannabinoid receptor CB1 play critical roles in multiple early pregnancy events in both animals and humans. Since our previous studies demonstrated that loss of CB1 defers the normal implantation window in mice, we surmised that CB1 deficiency would influence parturition events.

Methods and findings: Exploiting mouse models with targeted deletion of Cnr1, Cnr2 and Ptgs1 encoding CB1, CB2 and cyclooxygenase-1, respectively, we examined consequences of CB1 or CB2 silencing on the onset of parturition. We observed that genetic or pharmacological inactivation of CB1, but not CB2, induced preterm labor in mice. Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition. More strikingly, the phenotypic defects of prolonged pregnancy length and parturition failure in mice missing Ptgs1 were corrected by introducing CB1 deficiency into Ptgs1 mice. In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation. The pathophysiological significance of this altered corticotrophin-releasing hormone-driven endocrine activity in the absence of CB1 was evident from our subsequent findings that a selective corticotrophin-releasing hormone antagonist was able to restore the normal parturition timing in Cnr1 deficient mice. In contrast, wild-type females receiving excessive levels of corticosterone induced preterm birth.

Conclusions: CB1 deficiency altering normal progesterone and estrogen levels induces preterm birth in mice. This defect is independent of prostaglandins produced by cyclooxygenase-1. Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.

Show MeSH
Related in: MedlinePlus