Effects Of Prenatal Morphine Exposure Research Articles

Prenatal exposure to morphine impairs attention and impulsivity in adult rats.

An alarming number of neonates born with prenatal exposure to morphine has resulted from the opioid epidemic; however, the long-term effects of prenatal opioid exposure on offspring behavior remain relatively unknown. In this study, we evaluated whether prenatal exposure to the mu opioid receptor agonist, morphine, has enduring effects on cognitive functions in adult life. On embryonic days 11-18 (E11-E18), female pregnant rats were injected subcutaneously with either morphine or saline twice daily. Adult male offspring that was prenatally exposed to saline or morphine was trained in the 5-choice serial reaction time test (5-CSRTT) to test their cognitive abilities under baseline conditions. Next, these rats were treated with saline (1ml/kg), naloxone (1mg/kg), and acute morphine (1, 3, 5mg/kg), subcutaneously, once daily and following drug challenges rats were tested in the 5-CSRTT. Meanwhile, behavioral performance on training days between opioid drug challenges were analyzed to monitor possible drug-induced shifts in baseline performance. As a final experiment in order to investigate subchronic exposure to morphine, rats were injected with 5mg/kg morphine for 5days and then naloxone in the last day of the experiment (day 6). Firstly, during acquisition of a stable baseline in the training phase, rats prenatally exposed to morphine showed delayed learning of the task demands. Furthermore, under baseline responding the rats prenatally exposed to morphine showed declined inhibitory control demonstrated by increased impulsive and compulsive-like responding compared to rats prenatally exposed to saline. Moreover, acute and subchronic morphine challenges in the rats prenatally exposed to morphine caused a deficit in visuospatial attention in comparison with saline treatment as well as the rats prenatally exposed to saline. These effects were abolished by naloxone. The current findings indicate a direct causal effect of prenatal morphine exposure on inhibitory control and task learning later in life, as well as deficits in attention following morphine exposure in adulthood.

Opioid withdrawal behavior in spiny mice: A novel preclinical model of neonatal opioid withdrawal syndrome (NOWS)

As the opioid epidemic continues to grow, opioid use among pregnant women is increasing significantly. This has led to a steady rise in the number of infants born with neonatal opioid withdrawal syndrome (NOWS). Although short-term withdrawal symptoms associated with NOWS are well characterized, there are many gaps in our understanding of the short and long-term effects of prenatal opioid exposure. Current animal models of NOWS are limited by shortened gestational periods, large litter sizes, and primary organogenesis occurring after birth. This often leads to postnatal treatment to mimic drug exposure during third-trimester development. Using the unique rodent species Acomys cahirinus, more commonly known as spiny mice, which have an extended 40-day gestation period, small litter sizes, and increased in utero organogenesis we aim to study the short-term effects of prenatal morphine exposure by assessing withdrawal behavior. To model maternal opioid use, dams were treated daily with morphine (10 and 30 mg/kg S.C.) beginning on gestation day 19 until the day of birth; this resulted in a cumulative exposure of 19–21 days. Withdrawal behaviors for each pup were recorded daily between postnatal days 0–7 (PND 0–7). Our study found that prenatal morphine exposure in spiny mice led to an increase in withdrawal behavior throughout the early postnatal period and validated the use of this species as a novel pre-clinical model of NOWS. We are hopeful this rodent model will further our understanding of the short and long-term consequences of prenatal opioid exposure on neurodevelopment and behavior.

Long‐term Cardiorespiratory Anomalies in Rat Offspring Following Prenatal Morphine Exposure

The incidence of opioid‐related pregnancies is a growing public health concern. Although not all infants born from opioid using mothers require hospitalization, many exhibit a variety of withdrawal symptoms (Neonatal Opioid Withdrawal Syndrome, NOWS) often requiring weeks of neonatal intensive care. There are longer‐term effects of prenatal opioid use including altered CNS function comprising cognitive impairments, neurobehavioral abnormalities and increased risk of Sudden Infant Death Syndrome (SIDS). In fact, abnormal cardiorespiratory regulation in infants born following prenatal opioid exposure includes reduced vagal tone, tachypnea, delayed arousal, and altered ventilatory responses to hypoxia and hypercapnia. In the present study, we used a rat model to characterize long‐term (postnatal (P) 10 days of age) cardiorespiratory responses of the offspring following in utero morphine exposure. Pregnant dams received twice daily (morning and evening) subcutaneous injections of various doses of morphine (1, 5 or 10mg/kg) during the 3rd week of pregnancy to mimic 3rd trimester maternal opioid use. Following birth, rat pups (and the nursing dam) were left untreated and whole‐body plethysmography was used to assess the acute hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses at P10 days of age. Heart rate was also assessed in rats fitted with a custom‐made jacket with built‐in ECG electrodes. Generally, the postnatal effects of morphine were dose‐dependent: 1) increasing doses of in utero morphine exposure caused a progressive attenuation of the HCVR in 10 day old rats; 2) there was a high rate of neonatal (within 24hrs of birth) mortality in the highest (10mg/kg) prenatal dose; 3) however, the rats who survived exhibited both an attenuated HVR and HCVR; and 4) rats also exhibited resting tachycardia and tachypnea (at 5–10 mg/kg) compared to in utero saline treated rats. These data demonstrate a long‐term (10 days) effect of prenatal morphine exposure on resting cardiorespiratory function, including impairments in ventilatory defense responses to acute hypoxia and hypercapnia. These cardiorespiratory anomalies could offer a window of insight into the pathophysiology of the increased risk of SIDS seen in infants born from mothers of substance use.

Implication of protein kinase C of the left intermediate medial mesopallium in memory impairments induced by early prenatal morphine exposure in one-day old chicks

Previously we reported that prenatal morphine exposure during embryonic days 5–8 can cause cognitive deficits of one-trial passive avoidance learning (PAL) in one-day old chicks. Because protein kinase C (PKC) has been associated with memory capacity, we investigated the effects of prenatal morphine exposure on PKC isoforms expression in the left intermediate medial mesopallium (IMM) of chick brain at a time when memory tests were performed at 30, 120 and 360min respectively following training in PAL paradigm. We found that the level of PKCα in the membrane fractions in left IMM was decreased but that in the cytosol fractions showed a increased trend in prenatally morphine-exposed chicks with impaired long-term memory (120 and 360min). Moreover, the translocation of PKC δ from cytosol to membrane in left IMM was shown in prenatal morphine group which had significantly impaired long-term memory at 360min after training. Furthermore, there were no statistical differences between the two groups regarding the expressions of PKCα and PKC δ in the membrane fraction, although their levels in the cytosol fraction of prenatal morphine group which showed impaired intermediate-term memory at 30min after training, were quite different from that of prenatal saline group. Taken together, these results indicate that PKCα and PKC δ in the left IMM are differentially involved in the impairments of long-term memory induced by prenatal morphine exposure. Neither PKCα nor PKC δ in left IMM may be associated with the disruption of intermediate-term memory of chicks prenatally exposed to morphine.

The effects of prenatal morphine exposure on pain response

Background: Drug abuse during pregnancy is a growing problem in all developed countries of the world. Maternal drug abuse affects the developing system and its long-term effects can persist till adulthood so it can decrease /INS;the rate of their maturation. Since endogenous opioid induced analgesia and morphine can interact with it, the present study was designed to determine whether the exposure to the morphine during gestation permanently alters /INS;pain response.

1599 – The effects of prenatal morphine exposure on pain response

Drug abuse during pregnancy is a growing problem in all developed countries of the world. Maternal drug abuse affects the developing system and its long-term effects can persist till adulthood so it can decreases the rate of their maturation. Since endogenous opioid induced analgesia, and morphine can interact with it, Thus the present study was designed to determine whether the exposure to the morphine during gestation permanently alter pain response. To determine the effects of prenatal morphine exposure on pain response. 12 Pregnant rats were divided to morphine and control groups. Morphine was administrated (S.C) to female rats twice a day (08 h and 20 h) on gestational days 11-18, (5 mg/kg morphine for 3 days and 10 mg/kg for 5 days). Analgesic response of pups (P90, n=6) were tested by formaline test. The results of our experiment demonstrated that prenatal morphine exposure rats exhibited significantly lower pain thersholds. Prenatal morphine exposure impair pain sensitivity.

Reversal of Prenatal Morphine Exposure-Induced Memory Deficit in Male But Not Female Rats

Impaired memory performance in offspring is one of the long-lasting neurobehavioral consequences of prenatal opiate exposure. Here, we studied the effects of prenatal morphine exposure on inhibitory avoidance memory performance in male and female offspring and also investigated whether these deficits are reversible during the postnatal development. Pregnant Wistar rats received morphine sulfate through drinking water, from the first day of gestation up to the day 13, M₁₋₁₃, or to the time of delivery, M₁₋₂₁. Four- and ten-week-old (adolescent and adult, respectively) male and female offspring were subjected to behavioral assays and then analysis of proteins involved in apoptosis or in synaptic plasticity. Results revealed that adolescent and adult female rats failed in passive avoidance retention task in both M₁₋₁₃ and M₁₋₂₁ groups. Adolescent and adult male offspring were similar to control animals in M₁₋₁₃ group. However M₁₋₂₁ impaired retention task in prepubertal male offspring, and this memory loss was repaired in postpubertal stage. Consistently, Bax/Bcl-2 ratio and cleaved caspase-3 were significantly increased in both M₁₋₁₃ and M₁₋₂₁ adolescent and adult female rats, but only in M₁₋₂₁ adolescent male rats. Furthermore, prenatal morphine exposure reduced the expression of brain-derived neurotrophic factor precursor protein in adolescent and adult female offspring and also decreased p-ca(2+)/calmodulin-dependent kinase II/ca(2+)/calmodulin-dependent kinase II ratio in adolescent male and female rats. Altogether, the results show that prenatal morphine exposure, depending on the time or duration of exposure, has distinct effects on male and female rats, and postnatal development may reverse these deficits more likely in males.

Dextromethorphan attenuated the higher vulnerability to inflammatory thermal hyperalgesia caused by prenatal morphine exposure in rat offspring

BackgroundCo-administration of dextromethorphan (DM) with morphine during pregnancy and throughout lactation has been found to reduce morphine physical dependence and tolerance in rat offspring. No evidence was presented, however, for the effect of DM co-administered with morphine during pregnancy on inflammatory hyperalgesia in morphine-exposed offspring. Therefore, we attempt to investigate the possible effect of prenatal morphine exposure on the vulnerability to hyperalgesia and the possible therapeutic effect of DM in the present study.MethodsFifty μl of carrageenan (20 mg/ml) was injected subcutaneously into the plantar surface of the right hind paw in p18 rats to induce hyperalgesia. Mean paw withdrawal latency was measured in the plantar test to index the severity of hyperalgesia. Using Western blotting and RT-PCR, the quantitative analyses of NMDA receptor NR1 and NR2B subunits were performed in spinal cords from different groups of animals.ResultsIn the carrageenan-induced hyperalgesia model, rat offspring passively exposed to morphine developed a severe hyperalgesia on postnatal day 18 (p18), which also had a more rapid time course than those in the controls. Co-administration of DM with morphine in the dams prevented this adverse effect of morphine in the offspring rats. Western blot and RT-PCR analysis showed that the levels of protein and mRNA of NMDA receptor NR1 and NR2B subunits were significantly higher in the lumbar spinal cords of rats (p14) exposed to prenatal morphine; the co-administration of DM could reverse the effect of morphine on NR1 and attenuate the effect on NR2B.ConclusionsThus, DM may have a great potential in the prevention of higher vulnerability to inflammatory thermal hyperalgesia in the offspring of morphine-addicted mothers.

P02-393 - The effects of prenatal morphine exposure on pain response

BackgroundDrug abuse during pregnancy is a growing problem in all developed countries of the world. Maternal drug abuse affects the developing system and its long-term effects can persist till adulthood so it can decreases the rate of their maturation. Since endogenous opioid induced analgesia, and morphine can interact with it, Thus the present study was designed to determine whether the exposure to the morphine during gestation permanently alter pain response.ObjectiveTo determine the effects of prenatal morphine exposure on pain responseMaterials and methods12 Pregnant rats were divided to morphine and control groups.Morphine was administrated (S.C) to female rats twice a day (08 h and 20 h) on gestational days 11–18, (5 mg/kg morphine for 3 days and 10 mg/kg for 5 days). Analgesic response of pups (P90, n = 6) were tested by formaline test.FindingThe results of our experiment demonstrated that prenatal morphine exposure rats exhibited significantly lower pain thersholds.ConclusionPrenatal morphine exposure impair pain sensitivity

Detour behavior changes associated with prenatal morphine exposure in 11-day-old chicks

The central nervous system exhibits remarkable plasticity in early life. Prenatal morphine exposure may induce adverse behavioral effects on the neonate and the developing offspring. In the present study, we investigated the effect of prenatal morphine exposure (daily from embryonic days 12–16, 20mg/kg) on 11-day-old chicks using two forms of spatial paradigms: one trial detour behavior task in which animals must bypass an obstacle to reach the desired goal without any training and detour learning task which required several trials of training to reach the detour criterion.The results showed that, on the condition that chicks could successfully detour in the first trial, morphine exposed chicks exhibited longer detour latency to finish the task, coupled by a preference for turning right versus turning left. In contrast, no significant difference in learning and memory was found in detour learning task between morphine exposed chicks and saline chicks. These findings suggest specific behavioral changes associated with prenatal exposure to opioids during mid to late gestation, also raise attention to the possible health hazard from pregnancy drug use in everyday life.

The effects of prenatal morphine exposure on pain response

The effects of prenatal morphine exposure on pain response

Prenatal morphine alters the synaptic complex of postsynaptic density 95 with N-methyl-d-aspartate receptor subunit in hippocampal CA1 subregion of rat offspring leading to long-term cognitive deficits

Infants who are passively exposed to morphine or heroin through their addicted mothers usually develop neurobiological changes. The postsynaptic density 95 (PSD-95) protein, a submembranous cytoskeletal specialization, is dynamically linked with N-methyl-d-aspartate receptors (NMDARs) to form a synaptic complex in postsynaptic neurons. This complex serves important neurobiological functions, including mammalian learning and memory. However, the effects of prenatal morphine exposure on this synaptic complex are not well understood. In this study, we determined whether prenatal morphine exposure altered the synaptic complex association between PSD-95 and three major NMDAR subunits (NR1, NR2A, and NR2B), at the mRNA and protein levels, within the hippocampal CA1 subregion (an important integration area for mammalian learning and memory) of rat offspring along with the performance of long-term cognitive functions. Sprague–Dawley rat offspring from morphine-addicted mothers were studied at a younger age (postnatal day 14; P14) and at an older age (P45). Subsequently, an eight-arm radial maze task was applied to analyze the working and cued reference memory in such offspring (P45). The real-time polymerase chain reaction results showed that prenatal morphine exposure caused significant decreases in mRNA levels of the PSD-95 and three NMDAR subunits (NR1, NR2A, and NR2B) in offspring (P14 and P45). Similarly, at the protein level, immunoblotting showed that decreased whole levels of PSD-95 and NMDAR subunits were seen in offspring subjected with prenatal morphine. Furthermore, the protein interaction of the synaptic complex between the PSD-95 and NMDAR subunit, as indicated by coimmunoprecipitation, was less in prenatal morphine samples than in vehicle controls (P14 and P45). The prenatal morphine group also showed poorer performance for an eight-arm radial maze task than the vehicle-control group. These results are particularly important for a better understanding of certain opioid-mediated neurobehavioral cognitive changes in offspring associated with altered protein interaction between PSD-95 and NMDAR subunits within the developing brain.

The Effects of Prenatal Morphine Exposure on Pain Response

The Effects of Prenatal Morphine Exposure on Pain Response

710: The Effects of Prenatal Morphine Exposure on Pain Response

710: The Effects of Prenatal Morphine Exposure on Pain Response

Morphine exposure prevents up-regulation of MR and GR binding sites in the brain of adult male and female rats due to prenatal stress

Our previous work demonstrated that the hormone response to stress and the negative feedback inhibition to these hormones are sex-dependently altered by prenatal morphine exposure in adult rats. An alteration in the glucocorticoid negative feedback inhibition is mediated by glucocorticoid receptors (GR) that are distributed throughout the brain, and mineralocorticoid receptors (MR) localized mainly in the hippocampus and involved in a tonic influence of brain functions. Therefore, the present study examined the binding characteristics of MR and GR in young adult male and female rats exposed prenatally (E11–E18) to morphine (10mg/kg/2×/day), saline or no treatment at all (controls). At 60–90 days of age, animals were adrenalectomized (ADX) 24h prior to decapitation. The hippocampus and hypothalamus were dissected for saturation binding assays. The data demonstrate that prenatal stress due to maternal saline injections up-regulates MR and GR binding in the hippocampus of adult male rats and this effect is prevented by prenatal morphine exposure. There is no effect of prenatal morphine exposure on GR binding in the hypothalamus of males. In female rats, prenatal morphine exposure does not affect the binding of MR and GR in the hippocampus or GR in the hypothalamus relative to controls; however, they are affected by ovarian hormone fluctuation. Moreover, prenatal stress decreases MR binding in the hippocampus of diestrous females and GR binding in the hypothalamus of estrous females. Both decreases are prevented by prenatal morphine exposure. Thus, the present study demonstrates that: (1) prenatal stress due to maternal saline injections alters MR and GR binding of adult male and female rats and is prevented by prenatal morphine exposure; (2) the MR and GR binding in adult female rats are affected by ovarian hormone fluctuations.

Alterations of postsynaptic density proteins in the hippocampus of rat offspring from the morphine‐addicted mother: Beneficial effect of dextromethorphan

Infants passively exposed to morphine or heroin through their addicted mothers usually develop characteristic withdrawal syndrome of morphine after birth. In such early life, the central nervous system exhibits significant plasticity and can be altered by various prenatal influences, including prenatal morphine exposure. Here we studied the effects of prenatal morphine exposure on postsynaptic density protein 95 (PSD-95), an important cytoskeletal specialization involved in the anchoring of the NMDAR and neuronal nitric oxide synthase (nNOS), of the hippocampal CA1 subregion from young offspring at postnatal day 14 (P14). We also evaluated the therapeutic efficacy of dextromethorphan, a widely used antitussive drug with noncompetitive antagonistic effects on NMDARs, for such offspring. The results revealed that prenatal morphine exposure caused a maximal decrease in PSD-95 expression at P14 followed by an age-dependent improvement. In addition, prenatal morphine exposure reduced not only the expression of nNOS and the phosphorylation of cAMP responsive element-binding protein at serine 133 (CREB(Serine-133)), but also the magnitude of long-term depression (LTD) at P14. Subsequently, the morphine-treated offspring exhibited impaired performance in long-term learning and memory at later ages (P28-29). Prenatal coadministration of dextromethorphan with morphine during pregnancy and throughout lactation could significantly attenuate the adverse effects as described above. Collectively, the study demonstrates that maternal exposure to morphine decreases the magnitude of PSD-95, nNOS, the phosphorylation of CREB(Serine-133), and LTD expression in hippocampal CA1 subregion of young offspring (e.g., P14). Such alterations within the developing brain may play a role for subsequent neurological impairments (e.g., impaired performance of long-term learning and memory). The results raise a possibility that postsynaptic density proteins could serve an important role, at least in part, for the neurobiological pathogenesis in offspring from the morphine-addicted mother and provide tentative therapeutic strategy.

Prenatal morphine exposure affects sympathoadrenal axis activity and serotonin metabolism in adult male rats both under basal conditions and after an ether inhalation stress

We have previously shown that prenatal morphine exposure inhibited the hypothalamo-pituitary-adrenal (HPA) axis and altered the hypothalamic metabolism of serotonin during the early postnatal period in the rat and induced a chronic sympathoadrenal hyperactivity under resting conditions in adult male rats. In this study, we examined the effects of prenatal morphine exposure on the responsiveness to an acute ether inhalation stress of the sympathoadrenal and HPA axis and the hippocampal and hypothalamic concentrations of serotonin (5HT) and 5-hydroxylindoleacetic acid (5HIAA) in 3-month-old male rats. The plasma levels of adrenocorticopic hormone (ACTH) and corticosterone (B) did not differ between the two groups both under resting conditions and after ether exposure. Ether inhalation increased adrenal tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) mRNA expression as well as adrenal epinephrine (E) concentration in control rats but not in prenatally morphine-exposed (PM) animals. Under basal conditions, hypothalamic concentrations of 5HT and 5HIAA increased in PM animals. In contrast to control animals, PM rats showed, in response to stress, an increased level of 5HT and 5HIAA in both the hypothalamus and in the hippocampus. In conclusion, prenatal morphine exposure produces long-lasting alterations in brain serotonin transmission and in the sympathoadrenal responsiveness to an acute systemic stress.

The effect of prenatal morphine exposure on memory consolidation in the chick

The central nervous system exhibits remarkable plasticity in early life and can be altered significantly by prenatal morphine exposure. Previous studies show that prenatal morphine exposure may alter the capacity for learning and memory in post-partum chicks. The one-trial passive avoidance learning paradigm with 1-day-old chicks is an excellent model to study several mechanisms of memory formation, including STM, ITM, and LTM. The following represents our investigation of the effect of prenatal morphine exposure on learning and memory deficits in the chick. In these experiments, morphine was injected into the airspace of eggs (20 mg/kg) and the one-trial passive avoidance learning paradigm was used to test the effect of prenatal morphine exposure on memory consolidation. The data suggest that chicks injected with morphine daily from E12 to E16 had significantly impaired long-term memory at 120 min after training ( p < 0.001) but not intermediate-term memory at 30 min after training.

Cross-generational effect of prenatal morphine exposure on neurobehavioral development of rat pups.

Prenatal exposure to opiates can have devastating effects on the development of human fetuses and may induce long-term physical and neurobehavioral changes during postnatal maturation. The present study was aimed at identifying cross-generational effects of prenatal morphine exposure in Sprague-Dawley rats. Pregnant rats were injected subcutaneously with either saline or morphine (10 mg/kg) twice daily during gestational days 11-18. Litter size, percentage of males and females, anogenital distances (AGDs), righting reflex, and body weight were assessed in prenatally morphine-exposed pups (first generation) and their offspring (second generation). Both prenatally morphine-exposed pups and offspring of prenatally morphine-exposed dams exhibited an increased latency to right. Additionally, second generation pups were slower in righting than first generation pups. During the early postnatal period the second generation pups weighed less than the first generation regardless of drug exposure. The AGDs of second generation male pups were decreased relative to the first generation. Our data provide important novel information about the trans-generational effects of maternal opiate abuse that may be useful for understanding/evaluating the teratogenic effects of prenatal opiate exposure.

Hypothalamo-Pituitary-Adrenal Axis-Regulated Stress Response and Negative Feedback Sensitivity Is Altered by Prenatal Morphine Exposure in Adult Female Rats

It has been shown that adult female rats react to stressors more intensely than adult male rats. Our previous work demonstrated that the adrenocorticotropic hormone (ACTH) but not corticosterone (CORT) response to stress is altered by prenatal morphine exposure in adult male rats. Response of the hypothalamo-pituitary-adrenal (HPA) axis to stress is known to be sex specific and dependent on the hormonal fluctuation of the estrous cycle. Therefore, the present study examined the effect of prenatal morphine exposure on the levels of ACTH and CORT before and after restraint stress in adult female rats. Experiment 1 tested ACTH and CORT plasma levels before and after restraint stress in prenatally morphine- and saline-exposed, adult diestrus and proestrus female rats. Prenatal morphine exposure suppressed the restraint stress-induced ACTH levels in both diestrus and proestrus females, but did not have any effects on the basal or stress-induced CORT levels. Experiment 2 examined the sensitivity of negative feedback using the dexamethasone (DEX) (0.001, 0.01, 0.1 and 1.0 mg/kg) suppression test in adult, prenatally morphine- and saline-exposed female rats. In saline-exposed, proestrus but not diestrus females, all doses of DEX were effective in suppressing the restraint stress-induced increase in CORT levels. In both diestrus and proestrus, morphine-exposed females, only the two highest doses of DEX (0.1 and 1.0 mg/kg) were successfully suppressing the stress-induced CORT levels. The stress-induced increase in the ACTH level was suppressed only by the highest dose of DEX (1.0 mg/kg) in both saline- and morphine-exposed, diestrus and proestrus females. Thus, the present study demonstrates that prenatal morphine exposure alters the HPA axis-regulated stress response and the sensitivity of negative feedback that are affected by the fluctuation of ovarian hormones.