Effects of maternal oral morphine consumption on neural tube development in Wistar rats

Nasiraei-Moghadam, Shiva; Sahraei, Hedayat; Bahadoran, H; Sadooghi, M; Salimi, Seyed Hossein; Kaka, Gholam Reza; Imani, H; Mahdavinasab, H; Dashtnavard, H

doi:10.1016/j.devbrainres.2005.06.012

Cited by 29 publications

(27 citation statements)

References 17 publications

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“…The dose of 0.01 mg/ml morphine more effective than those of 0.1 and 0.05 mg/ml delayed the development of neural tube and even disrupted the neuroectoderm layer morphologically (Nasiraei-Moghadam et al 2005). In another histomorphometric evaluation of developing rat fetus, it has been revealed that the thickness of cortical plate and the number of neurons in the frontal cerebral cortex would be decreased by prenatal exposure to morphine (Sadraie et al 2008).…”

Section: Discussionmentioning

confidence: 95%

“…Behavioral abnormalities such as hyperactivity, lower Mental Development Index, and lower Psychomotor Development Index in children of opioid-addicted mothers (Hans and Jeremy 2001;Weissman et al 1999) may be due to defects in the development of central nervous system. We previously demonstrated that neural tube development and its closure would be delayed by prenatal oral morphine consumption (Nasiraei-Moghadam et al 2005). In a recent study, it has been also shown that oral morphine consumption just during the second week of gestational period can significantly decrease the cortical thickness and the number of neurons in frontal cerebral cortex of rat fetus (Sadraie et al 2008).…”

Section: Introductionmentioning

confidence: 98%

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Maternal Oral Consumption of Morphine Increases Bax/Bcl-2 Ratio and Caspase 3 Activity During Early Neural System Development in Rat Embryos

et al. 2009

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Maternal morphine consumption has been shown to result in physical and neurobehavioral defects in fetus and offspring, but the underlying molecular mechanisms of these defects remain unclear. Regarding the critical role of apoptosis in normal development of central nervous system, the present study was designed to investigate the effect of intrauterine morphine exposure on programmed cell death of neuroblasts during the early development of neural system. Pregnant Wistar rats received morphine sulfate through drinking water at the concentration of 0.01 mg/ml (20 ml water per day for each rat) from the first day of gestation to the time of sampling. Control groups received tap water. Control and morphine-treated pregnant rats, each in five separated groups, were killed on gestational days 9.5 to 13.5, and the embryos were taken out, fixed, and embedded in paraffin. Immunohistochemical assay was used to reveal the protein expression of Bax, Bcl2, and the activation of caspase 3. The results showed a significant increase in Bax immunoreactivity in all of the mentioned embryonic days (E9.5 to E13.5) and a significant decrease in Bcl-2 immunoreactivity at days E10.5 and E12.5 in morphine-treated groups compared with control. Data analysis revealed that Bax/Bcl2 ratio was increased in all of the morphine-exposed groups. Consistent with these results, immunostaining of cleaved caspase 3 showed a significant increase at days E11.5 to E13.5. These findings suggest that morphine exposure during the first embryonic days may enhance the susceptibility of neuroblasts to apoptosis by upregulating the ratio of Bax to Bcl-2 protein expression and increasing downstream caspase-3 activity. The increased probability of neuroblast apoptosis may be the cause of morphine-induced defects in the central nervous system development and its structural and neurobehavioral consequences.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 98%

Maternal Oral Consumption of Morphine Increases Bax/Bcl-2 Ratio and Caspase 3 Activity During Early Neural System Development in Rat Embryos

et al. 2009

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“…Animal studies showed prenatal opioid exposure can lead to central nervous system malformations, 12 kinking of the spinal cord, 13,14 a reduction in neural tube volume and thickness, 15,24 and inhibited growth of the brain and nervous system. 25,26 Furthermore, opioids cross the blood–brain barrier and are detectable in fetal tissue 26–29 with the highest concentrations in the fetal nervous system.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 In animal studies, exposure to codeine, heroin, hydromorphone, meperidine, methadone, morphine, and propoxyphene during critical periods of gestation can lead to anomalies of the central nervous system. 12–15 Two epidemiologic studies also suggest that there may be an association between opioids as a class and central nervous system anomalies, specifically neural tube defects, with odds ratio (ORs) ranging from 1.7 to 2.9. 7,16 Few studies had sufficient numbers of exposed cases to examine individual opioids, but those that have observed an increased risk of neural tube defects with codeine and hydrocodone.…”

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confidence: 99%

Periconceptional Use of Opioids and the Risk of Neural Tube Defects

Yazdy

Mitchell

Tinker

et al. 2013

Obstetrics &Amp; Gynecology

126

102

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OBJECTIVE Opioid medications are among the most effective analgesics. However, the consequences of opioid exposure to the developing human offspring are not known. We assessed whether maternal opioid use in the periconceptional period was associated with the risk of neural tube defects in the offspring. METHODS We used data from 1998 to 2010 from the Slone Epidemiology Center Birth Defects Study, an ongoing case–control study. Mothers were interviewed by telephone within 6 months of delivery about sociodemographic factors and exposures during pregnancy including detailed questions on type and timing of medication use. Mothers of 305 offsprings with neural tube defect were compared with mothers of 7,125 offsprings in the nonmalformed control group and 13,405 offsprings in the malformed control group. Periconceptional opioid use was defined as any reported use in the 2 months after the last menstrual period. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for study center. RESULTS A higher percentage of mothers of offsprings with neural tube defects (3.9%) reported using an opioid medication than mothers of offsprings in the nonmalformed control group (1.6%) and offsprings in the malformed control group (2.0%) with adjusted ORs of 2.2 (95% CI 1.2 24.2) and 1.9 (95% CI 1.0 23.4), respectively. When offsprings were restricted to those with spina bifida, the adjusted ORs were 2.5 (95% CI 1.3–5.0) and 2.2 (95% CI 1.1–4.1), respectively. CONCLUSION A 2.2-fold increase in risk would translate to a neural tube defect prevalence of 5.9 per 10,000 live births among women who use opioids. Overall, opioid use in the periconceptional period appeared to be associated with a modest increased risk of neural tube defects.

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“…For example, previous studies have demonstrated that aberrant cannabinoid signaling exhibits detrimental effects on early pregnancy events, including derailing normal preimplantation development of early embryos and their timely oviductal transport, and disrupting blastocyst implantation competency, uterine receptivity, thus embryo implantation [5][6][7][8][9][10]. Moreover, illicit use of opioids during pregnancy is often associated with adverse pregnancy outcomes, such as poor fetal growth, preterm delivery, and fetal death [11][12][13][14][15][16][17]. In this respect, our recent study revealed while the opioid signaling is functionally operative during preimplantation embryo development, an aberrantly activated opioid signaling by morphine can remarkably impair the normal preimplantation embryo development via inhibiting intracellular calcium mobilization [18].…”

Section: Introductionmentioning

confidence: 97%

Systemic Morphine Treatment Derails Normal Uterine Receptivity, Leading to Embryo Implantation Failure in Mice1

Tang

Chen

Hao

et al. 2015

Biology of Reproduction

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Morphine is the oldest worldwide well-known opioid agonist used for pain treatment in clinic, and its illicit use is often associated with adverse pregnancy outcomes in humans. Because of recent dramatic increases in nonmedicinal morphine abuse, one emerging issue is the further revelation of the dark side of illicit opioid uses, particularly in early pregnancy events. In this respect, we have demonstrated that opioid signaling is functionally operative during preimplantation embryo development in mice. However, the pathophysiological significance of the opioid system on uterine functions at peri-implantation remained elusive. In the present study, we demonstrated that opioid receptors were spatiotemporally expressed in the uterus during the peri-implantation period. Employing a pharmacological approach combined with embryo transfer experiments, we further observed that although systemic morphine treatment exerts no apparent adverse influence on preimplantation ovarian secretion of progesterone and estrogen, this aberrant activation of opioid signaling by morphine induces impaired luminal epithelial differentiation, decreased stromal cell proliferation, and poor angiogenesis, and thus hampers uterine receptivity and embryo implantation. These novel findings add a new line of evidence to better understand the causes for obvious adverse effects of opioid abuse on pregnancy success in women.

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Effects of maternal oral morphine consumption on neural tube development in Wistar rats

Cited by 29 publications

References 17 publications

Maternal Oral Consumption of Morphine Increases Bax/Bcl-2 Ratio and Caspase 3 Activity During Early Neural System Development in Rat Embryos

Maternal Oral Consumption of Morphine Increases Bax/Bcl-2 Ratio and Caspase 3 Activity During Early Neural System Development in Rat Embryos

Periconceptional Use of Opioids and the Risk of Neural Tube Defects

Systemic Morphine Treatment Derails Normal Uterine Receptivity, Leading to Embryo Implantation Failure in Mice1

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