THE EFFECTS OF PERINATAL OXYCODONE EXPOSURE ON THE STRESS AXIS AND NEUROBEHAVIOR

Opiate addiction is now a major public health problem. Pregnant women continue to use opiates during gestation; up to 5.4% of pregnant women report using illicit drugs during pregnancy. Previous studies have shown that perinatal insults and exposure to opiates such as morphine in utero can affect the development of the hypothalamic-pituitary-adrenal (HPA)-axis of the offspring and are associated with higher risk of developing neurobehavioral problems. Oxycodone, a semisynthetic putative kappa opioid receptor and partial mu opioid receptor agonist is now one of the most frequently abused pain killers during pregnancy, however limited data are available regarding whether and how perinatal oxycodone exposure (POE) alters the development and functions of the HPA-axis, the related stress axis and neurobehavioral outcomes of the offspring. Data from these experiments have provided novel evidence that POE indeed is associated with sex-specific changes in the HPA-axis in response to stress that persist beyond the neonatal period. 1) POE is associated with an increased adrenocorticotropic hormone (ACTH) response to corticotropin-releasing hormone (CRH), but not the corticosterone (CORT) response to CRH stimulation in late adolescent male offspring. 2) POE is associated with increased CORT, but not ACTH response to restraint stress test in adult female offspring. These changes in the HPA-axis response to stress may be partially explained by 1) an increase in the subpopulation of CRH neurons that also contain estrogen receptor-beta immunoreactivity following POE which then can exaggerate the stimulation of the HPA-axis, and 2) a decrease in mineralocorticoid receptor-mRNA expression in the hippocampus which may be associated with impaired negative feedback control of the HPA-axis by the limbic system. POE is also associated with cardiovascular changes in response to stress during a classical conditioning paradigm; adolescent male POE rats have a larger blood pressure increase than the control group. Although POE male rats can properly discriminate the stress versus non-stress cues in the conditioning paradigm, they do not retain this memory when retested during adulthood. When tested for learning and memory in a water maze, however, we did not find any differences between control rats and rats exposed to high dose oxycodone in utero. In addition, we demonstrated that exposure to the lower dose of oxycodone in utero is associated with hyperactivity in adult rats when tested in an open field. Our results make a significant contribution to the literature because they extend our knowledge about the effects of oxycodone on the developing brain and the resulting outcomes in animal models that are actually relevant to a current major public health problem in humans and will provide a platform for us to further study the underlying mechanisms and interventions that may mitigate these effects

Effects of Perinatal Oxycodone Exposure on the Cardiovascular Response to Acute Stress in Male Rats at Weaning and in Young Adulthood

Oxycodone (OXY) is one of the most commonly abused opiates during pregnancy. Perinatal opiate exposure (POE) is associated with neurobehavioral and hormone changes. Little is known about the effects of perinatal OXY on the cardiovascular (CV) responses to stress. Objectives: to determine the effects of POE on: (1) CV responses to acute stress and ability to discriminate using a classical conditioning paradigm; (2) changes in CV response to the paradigm and retention of the ability to discriminate from postnatal day (PD) 40 to young adulthood. Methods: Pregnant rats were given i.v. OXY or vehicle (CON) daily. OXY and CON males were fitted with BP telemetry units. Offspring were classically conditioned by following a pulsed tone (CS+) with tail shock. A steady tone (CS-) was not followed by shock. BP and HR were recorded during resting periods and conditioning. Changes in BP, HR from composite analysis were compared. The paradigm was repeated on PD 75. Results: At PD 40, OXY rats had a lower baseline mean BP (OXY: 114.8 ± 1.0 vs. CON: 118.3 ± 1.0 mm Hg; mean ± SEM) but larger amplitude of the conditional BP increase during the stress response (OXY: +3.9 ± 0.4 vs. CON: +1.7 ± 0.4 mm Hg). Both OXY and CON rats were able to discriminate between CS+ and CS-. At PD 75, the effects of OXY on the increased amplitude of the conditional BP had dissipated (CON: +3.4 ± 2.3 vs. OXY: +4.5 ± 1.4 mm Hg). BP responses to the stress and non-stress stimuli did not differ in the OXY group, suggesting that OXY may have decreased the ability of the offspring to discriminate (OXY: CS+: 147.1 ± 1.6, CS-: 145.9 ± 1.6 mm Hg vs. CON: CS+: 155.4 ± 2.7, CS-: 147.8 ± 2.7 mm Hg). Conclusion: POE is associated with subtle alterations in stress CV responses in weanling rats which dissipate when the conditioning is repeated at an early adult age. Although POE effect on the ability to discriminate at weanling age could not be detected, POE may impair retention of this ability in adulthood

The Effects of Perinatal Oxycodone Exposure on Behavioral Outcome in a Rodent Model

Opiate addiction is now a major public health problem. Perinatal insults and exposure to opiates such as morphine in utero are well known to affect development of the hypothalamic–pituitary–adrenal axis of the offspring adversely and are associated with a higher risk of developing neurobehavioral problems. Oxycodone is now one of the most frequently abused pain killers during pregnancy; however, limited data are available regarding whether and how perinatal oxycodone exposure (POE) alters neurobehavioral outcomes of the offspring. We demonstrated that exposure to 0.5 mg/kg/day oxycodone in utero was associated with hyperactivity in adult rats in an open field. No significant effects of POE were detected on isolation-induced ultrasonic vocalizations in the early postnatal period or on learning and memory in the water maze in adult offspring. Our findings are consistent with hyperactivity problems identified in children exposed to opiates in utero

Enhancement of PCA-based fault detection system through utilising dissimilarity matrix for continuous-based process

This research is about enhancement of PCA-based fault detection system through utilizing dissimilarity matrix. Nowadays, the chemical process industry is highly based on the non-linear relationships between measured variables. However, the conventional PCA-based MSPC is no longer effective because it only valid for the linear relationships between measured variables. Due in order to solve this problem, the technique of dissimilarity matrix is used in multivariate statistical process control as alternative technique which models the non-linear process and can improve the process monitoring performance. The conventional PCA system was run and the dissimilarity system was developed and lastly the monitoring performance in each technique were compared and analysed to achieve aims of this research. This research is to be done by using Matlab software. The findings of this study are illustrated in the form of Hotelling’s T2 and Squared Prediction Errors (SPE) monitoring statistics to be analysed. As a conclusion, the dissimilarity system is comparable to the conventional method. Thus can be the other alternative ways in the process monitoring performance. Finally, it is recommended to use data from other chemical processing systems for more concrete justification of the new technique

Plasma Brain-Derived Neurotrophic Factor Levels in Newborn Infants with Neonatal Abstinence Syndrome

Background: Brain-derived neurotrophic factor (BDNF) is a type of growth factor that promotes growth and survival of neurons. Fetal exposure to opiates can lead to postnatal withdrawal syndrome, which is referred as neonatal abstinence syndrome (NAS). Preclinical and clinical studies have shown an association between opiates exposure and alteration in BDNF expression in the brain and serum levels in adult. However, to date, there are no data available on the effects of opiate exposure on BDNF levels in infant who are exposed to opiates in utero and whether BDNF level may correlate with the severity of NAS. Objective: To compare plasma BDNF levels among NAS and non-NAS infants and to determine the correlation of BDNF levels and the severity of NAS. Methods: This is a prospective cohort study with no intervention involved. Infants ≥35 weeks of gestation were enrolled. BDNF level was measured using enzyme-linked immunosorbent assay technique from blood samples drawn within 48 h of life. The severity of NAS was determined by the length of hospital stay, number of medications required to treat NAS. Results: 67 infants were enrolled, 34 NAS and 33 non-NAS. Mean gestational age did not differ between the two groups. Mean birth weight of NAS infants was significantly lower than the non-NAS infants (3,070 ± 523 vs. 3,340 ± 459 g, p = 0.028). Mean BDNF level in NAS group was 252.2 ± 91.6 ng/ml, significantly higher than 211.3 ± 66.3 ng/ml in the non-NAS group (p = 0.04). There were no differences in BDNF levels between NAS infants that required one medication vs. more than one medication (254 ± 91 vs. 218 ± 106 ng/ml, p = 0.47). There was no correlation between the BDNF levels and length of hospital stay (p = 0.68) among NAS infants. Overall, there were no significant correlations between BDNF levels and NAS scores except at around 15 h after admission (correlation 0.35, p = 0.045). Conclusion: Plasma BDNF level was significantly increased in NAS infants during the first 48 h when compared to non-NAS infants. The correlations between plasma BDNF levels and the severity of NAS warrant further study. These results suggest that BDNF may play a neuromodulatory role during withdrawal after in utero opiate exposure

Autonomic Nervous System Function Following Prenatal Opiate Exposure

In utero exposure to opiates may affect autonomic functioning of the fetus and newborn. We investigated heart rate variability (HRV) as a measure of autonomic stability in prenatal opiate-exposed neonates (n = 14) and in control term infants (n = 10). Electrocardiographic data during both non-nutritive and nutritive sucking were evaluated for RR intervals, heart rate (HR), standard deviation of the consecutive RR intervals (SDRR), standard deviation of the differences of consecutive RR intervals (SDDRR), and the power spectral densities in low and high frequency bands. In controls, mean HR increased significantly, 143-161 per min (p = 0.002), with a trend toward a decrease in RR intervals from non-nutritive to nutritive sucking; these measures did not change significantly among exposed infants. Compared to controls, exposed infants demonstrated significantly greater HRV or greater mean SDRR and SDDRR during non-nutritive period (p \u3c 0.01), greater mean SDDRR during nutritive sucking (p = 0.02), and higher powers in the low and high frequency bands during nutritive feedings. Our findings suggest that prenatal opiate exposure may be associated with changes in autonomic nervous system (ANS) functioning involving both sympathetic and parasympathetic branches. Future studies are needed to examine the effects of prenatal opiate exposure on ANS function

Neonatal Abstinence Signs during Treatment: Trajectory, Resurgence and Heterogeneity

Neonatal abstinence syndrome (NAS) presents with a varying severity of withdrawal signs and length of treatment (LOT). We examined the course and relevance of each of the NAS withdrawal signs during treatment in a sample of 182 infants with any prenatal opioid exposure, gestational age ≥ 35 weeks, without other medical conditions, and meeting the criteria for pharmacological treatment. Infants were monitored using the Finnegan Neonatal Abstinence Scoring Tool. Daily mean Finnegan scores were estimated using linear mixed models with random subject effects to account for repeated withdrawal scores from the same subject. Daily item prevalence was estimated using generalized estimating equations with a within-subject exchangeable correlation structure. The median LOT was 12.86 days. The prevalence of withdrawal signs decreased from day one to day three of treatment. However, certain central nervous system (CNS) and gastrointestinal (GI) signs showed sporadic increases in prevalence notable around two weeks of treatment, accounting for increases in Finnegan scores that guided pharmacotherapy. We question whether the resurgence of signs with a prolonged LOT is mainly a consequence of opioid tolerance or withdrawal. Monitoring CNS and GI signs throughout treatment is crucial. Future studies directed to better understand this clinical phenomenon may lead to the refining of NAS pharmacotherapy and perhaps the discovery of treatment alternatives

Plasma Brain-Derived Neurotrophic Factor Levels in Newborn Infants with Neonatal Abstinence Syndrome

BackgroundBrain-derived neurotrophic factor (BDNF) is a type of growth factor that promotes growth and survival of neurons. Fetal exposure to opiates can lead to postnatal withdrawal syndrome, which is referred as neonatal abstinence syndrome (NAS). Preclinical and clinical studies have shown an association between opiates exposure and alteration in BDNF expression in the brain and serum levels in adult. However, to date, there are no data available on the effects of opiate exposure on BDNF levels in infant who are exposed to opiates in utero and whether BDNF level may correlate with the severity of NAS.ObjectiveTo compare plasma BDNF levels among NAS and non-NAS infants and to determine the correlation of BDNF levels and the severity of NAS.MethodsThis is a prospective cohort study with no intervention involved. Infants ≥35 weeks of gestation were enrolled. BDNF level was measured using enzyme-linked immunosorbent assay technique from blood samples drawn within 48 h of life. The severity of NAS was determined by the length of hospital stay, number of medications required to treat NAS.Results67 infants were enrolled, 34 NAS and 33 non-NAS. Mean gestational age did not differ between the two groups. Mean birth weight of NAS infants was significantly lower than the non-NAS infants (3,070 ± 523 vs. 3,340 ± 459 g, p = 0.028). Mean BDNF level in NAS group was 252.2 ± 91.6 ng/ml, significantly higher than 211.3 ± 66.3 ng/ml in the non-NAS group (p = 0.04). There were no differences in BDNF levels between NAS infants that required one medication vs. more than one medication (254 ± 91 vs. 218 ± 106 ng/ml, p = 0.47). There was no correlation between the BDNF levels and length of hospital stay (p = 0.68) among NAS infants. Overall, there were no significant correlations between BDNF levels and NAS scores except at around 15 h after admission (correlation 0.35, p = 0.045).ConclusionPlasma BDNF level was significantly increased in NAS infants during the first 48 h when compared to non-NAS infants. The correlations between plasma BDNF levels and the severity of NAS warrant further study. These results suggest that BDNF may play a neuromodulatory role during withdrawal after in utero opiate exposure

Autonomic Nervous System Function Following Prenatal Opiate Exposure

In utero exposure to opiates may affect autonomic functioning of the fetus and newborn. We investigated heart rate variability (HRV) as a measure of autonomic stability in prenatal opiate-exposed neonates (n = 14) and in control term infants (n = 10). Electrocardiographic data during both non-nutritive and nutritive sucking were evaluated for RR intervals, heart rate (HR), standard deviation of the consecutive RR intervals (SDRR), standard deviation of the differences of consecutive RR intervals (SDDRR), and the power spectral densities in low and high frequency bands. In controls, mean HR increased significantly, 143-161 per min (p = 0.002), with a trend toward a decrease in RR intervals from non-nutritive to nutritive sucking; these measures did not change significantly among exposed infants. Compared to controls, exposed infants demonstrated significantly greater HRV or greater mean SDRR and SDDRR during non-nutritive period (p \u3c 0.01), greater mean SDDRR during nutritive sucking (p = 0.02), and higher powers in the low and high frequency bands during nutritive feedings. Our findings suggest that prenatal opiate exposure may be associated with changes in autonomic nervous system (ANS) functioning involving both sympathetic and parasympathetic branches. Future studies are needed to examine the effects of prenatal opiate exposure on ANS function