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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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Loss of CB1 overrides delayed parturition that occurs in Ptgs1−/− mice.(A & B) The onset of parturition and survival rate of newborn pups in mice missing both Cnr1 and Ptgs1 are substantially improved in contrast to delayed parturition in Ptgs1−/− mice. (C & D) Parturition defects were largely restored in pregnant Ptgs1−/− mice receiving a CB1-selective antagonist SR141716 (SR1), but not a CB2-selective antagonist SR144528 (SR2), on days 14–18. Numbers within the bars indicate number of mice examined in panels A and C. The bars with different letters are significantly different (P<0.01).
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pone-0003320-g005: Loss of CB1 overrides delayed parturition that occurs in Ptgs1−/− mice.(A & B) The onset of parturition and survival rate of newborn pups in mice missing both Cnr1 and Ptgs1 are substantially improved in contrast to delayed parturition in Ptgs1−/− mice. (C & D) Parturition defects were largely restored in pregnant Ptgs1−/− mice receiving a CB1-selective antagonist SR141716 (SR1), but not a CB2-selective antagonist SR144528 (SR2), on days 14–18. Numbers within the bars indicate number of mice examined in panels A and C. The bars with different letters are significantly different (P<0.01).

Mentions: In mice, genetic ablation of Ptgs1, encoding cyclooxygenase (COX)-1, results in delayed or failure of parturition because of impaired luteolysis with sustained P4 production [40], [41]. To confirm our finding that early decline in serum P4 levels is a trigger for preterm birth in Cnr1−/− mice, we introduced CB1 deficiency into Ptgs1−/− mice to examine their parturition status. It was exciting to see that the loss of CB1 overrides COX-1 deficiency-induced delayed parturition (Figure 5A) and remarkably improves the survival rate of newborn pups (Figure 5B). Similar observations were also noted in pregnant Ptgs1−/− mice receiving SR1, but not SR2, on days 14–18 (Figure 5C & D). These results suggest that CB1 signaling has a unique role in regulating normal parturition that is independent of COX-1-derived prostaglandin F2α, but CB1 deficiency can correct the effects produced by COX-1 deficiency. Recent evidence suggests that cyclooxygenases participate in oxidative metabolism of endocannabinoids, owing to their structural similarity to polyunsaturated fatty acids. For example, both anandamide and 2-arachidonoylglycerol can serve as substrates for COX-2 [42]–[44], and COX-1 [45] in the context of cell types and conditions. Moreover, there is evidence that endocannabinoids via CB1 can upregulate COX-2 expression and thus prostaglandin E2 production in human gestational membranes during late pregnancy [46]. It remains to be determined whether COX-1 deficiency induced delayed parturition is associated with aberrant cannabinoid-CB1 signaling in mice.


Loss of cannabinoid receptor CB1 induces preterm birth.

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

Loss of CB1 overrides delayed parturition that occurs in Ptgs1−/− mice.(A & B) The onset of parturition and survival rate of newborn pups in mice missing both Cnr1 and Ptgs1 are substantially improved in contrast to delayed parturition in Ptgs1−/− mice. (C & D) Parturition defects were largely restored in pregnant Ptgs1−/− mice receiving a CB1-selective antagonist SR141716 (SR1), but not a CB2-selective antagonist SR144528 (SR2), on days 14–18. Numbers within the bars indicate number of mice examined in panels A and C. The bars with different letters are significantly different (P<0.01).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2553193&req=5

pone-0003320-g005: Loss of CB1 overrides delayed parturition that occurs in Ptgs1−/− mice.(A & B) The onset of parturition and survival rate of newborn pups in mice missing both Cnr1 and Ptgs1 are substantially improved in contrast to delayed parturition in Ptgs1−/− mice. (C & D) Parturition defects were largely restored in pregnant Ptgs1−/− mice receiving a CB1-selective antagonist SR141716 (SR1), but not a CB2-selective antagonist SR144528 (SR2), on days 14–18. Numbers within the bars indicate number of mice examined in panels A and C. The bars with different letters are significantly different (P<0.01).
Mentions: In mice, genetic ablation of Ptgs1, encoding cyclooxygenase (COX)-1, results in delayed or failure of parturition because of impaired luteolysis with sustained P4 production [40], [41]. To confirm our finding that early decline in serum P4 levels is a trigger for preterm birth in Cnr1−/− mice, we introduced CB1 deficiency into Ptgs1−/− mice to examine their parturition status. It was exciting to see that the loss of CB1 overrides COX-1 deficiency-induced delayed parturition (Figure 5A) and remarkably improves the survival rate of newborn pups (Figure 5B). Similar observations were also noted in pregnant Ptgs1−/− mice receiving SR1, but not SR2, on days 14–18 (Figure 5C & D). These results suggest that CB1 signaling has a unique role in regulating normal parturition that is independent of COX-1-derived prostaglandin F2α, but CB1 deficiency can correct the effects produced by COX-1 deficiency. Recent evidence suggests that cyclooxygenases participate in oxidative metabolism of endocannabinoids, owing to their structural similarity to polyunsaturated fatty acids. For example, both anandamide and 2-arachidonoylglycerol can serve as substrates for COX-2 [42]–[44], and COX-1 [45] in the context of cell types and conditions. Moreover, there is evidence that endocannabinoids via CB1 can upregulate COX-2 expression and thus prostaglandin E2 production in human gestational membranes during late pregnancy [46]. It remains to be determined whether COX-1 deficiency induced delayed parturition is associated with aberrant cannabinoid-CB1 signaling in mice.

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