Sexually dimorphic effects of prenatal diazepam exposure on respiratory control and the monoaminergic system of neonate and young rats

Silva, Carlos Aparecido da; Patrone, Luís Gustavo A.; Biancardi, Vivian; Vilela-Costa, Heloísa H.; Marques, Danuzia A.; Cristina-Silva, Caroline; Silva, Kaoma Stephani da Costa; Bícego, Kênia C.; Szawka, Raphael E.; Gargaglioni, Luciane H.

doi:10.1007/s00424-022-02730-7

Cited by 4 publications

(4 citation statements)

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“…Our results demonstrating maternal opioids decrease respiratory burst amplitude and emergence of a distinct respiratory pattern at all ages provide support for the hypothesis that maternal opioids disrupt perinatal maturation of central respiratory networks. Many early life stressors, such as gestational intermittent hypoxia ( Gozal et al, 2003 ; Johnson et al, 2017 ), gestational ethanol exposure ( Dubois and Pierrefiche, 2020 ), prenatal anxiety drug exposure ( da Silva Junior et al, 2022 ), perinatal inflammation ( Morrison et al, 2019 ; Camacho-Hernández et al, 2022 ), perinatal nicotine exposure ( Luo et al, 2004 ; Ferng and Fregosi, 2015 ; Cholanian et al, 2017 ), perinatal anti-depressant drug exposure ( Biancardi et al, 2022 ) and neonatal maternal separation ( Kinkead et al, 2005 ; Kinkead and Gulemetova, 2010 ; Rousseau et al, 2017 ; reviewed in Tenorio-Lopes and Kinkead, 2021 ), acutely disrupt neonatal respiratory control. Some of these stressors even have enduring consequences on the adult respiratory system ( Genest et al, 2004 ; Kinkead et al, 2009 ; Soliz et al, 2016 ; Hocker et al, 2019 ; Dubois and Pierrefiche, 2020 ; Biancardi et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…Many early life stressors, such as gestational intermittent hypoxia (Gozal et al, 2003;Johnson et al, 2017), gestational ethanol exposure (Dubois and Pierrefiche, 2020), prenatal anxiety drug exposure (da Silva Junior et al, 2022), perinatal inflammation (Morrison et al, 2019;Camacho-Hernández et al, 2022), perinatal nicotine exposure (Luo et al, 2004;Ferng and Fregosi, 2015;Cholanian et al, 2017), perinatal anti-depressant drug exposure (Biancardi et al, 2022) and neonatal maternal separation (Kinkead et al, 2005;Kinkead and Gulemetova, 2010;Rousseau et al, 2017;reviewed in Tenorio-Lopes and Kinkead, 2021), acutely disrupt neonatal respiratory control. Some of these stressors even have enduring consequences on the adult respiratory system (Genest et al, 2004;Kinkead et al, 2009;Soliz et al, 2016;Hocker et al, 2019;Dubois and Pierrefiche, 2020;Biancardi et al, 2022). This research supports maternal opioids as a significant early life stressor, despite aspects of neonatal breathing normalizing over time after maternal opioids and has the potential to induce lasting impairments on central respiratory networks into adulthood.…”

Section: Discussionmentioning

confidence: 99%

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Maternal opioids age-dependently impair neonatal respiratory control networks

et al. 2023

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Infants exposed to opioids in utero are an increasing clinical population and these infants are often diagnosed with Neonatal Abstinence Syndrome (NAS). Infants with NAS have diverse negative health consequences, including respiratory distress. However, many factors contribute to NAS, confounding the ability to understand how maternal opioids directly impact the neonatal respiratory system. Breathing is controlled centrally by respiratory networks in the brainstem and spinal cord, but the impact of maternal opioids on developing perinatal respiratory networks has not been studied. Using progressively more isolated respiratory network circuitry, we tested the hypothesis that maternal opioids directly impair neonatal central respiratory control networks. Fictive respiratory-related motor activity from isolated central respiratory networks was age-dependently impaired in neonates after maternal opioids within more complete respiratory networks (brainstem and spinal cords), but unaffected in more isolated networks (medullary slices containing the preBötzinger Complex). These deficits were due, in part, to lingering opioids within neonatal respiratory control networks immediately after birth and involved lasting impairments to respiratory pattern. Since opioids are routinely given to infants with NAS to curb withdrawal symptoms and our previous work demonstrated acute blunting of opioid-induced respiratory depression in neonatal breathing, we further tested the responses of isolated networks to exogenous opioids. Isolated respiratory control networks also demonstrated age-dependent blunted responses to exogenous opioids that correlated with changes in opioid receptor expression within a primary respiratory rhythm generating region, the preBötzinger Complex. Thus, maternal opioids age-dependently impair neonatal central respiratory control and responses to exogenous opioids, suggesting central respiratory impairments contribute to neonatal breathing destabilization after maternal opioids and likely contribute to respiratory distress in infants with NAS. These studies represent a significant advancement of our understanding of the complex effects of maternal opioids, even late in gestation, contributing to neonatal breathing deficits, necessary first steps in developing novel therapeutics to support breathing in infants with NAS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Maternal opioids age-dependently impair neonatal respiratory control networks

et al. 2023

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“…The SampEn results found here corroborate with possible sex-specific differences in exercise-associated respiratory control in children and adolescents in recent studies (21). Furthermore, there is a growing body of literature demonstrating in murine models that sexual dimorphism in respiratory control occurs very early in life with consequences for development across the life span (51,52).…”

Section: Discussionmentioning

confidence: 99%

Signal Variability Comparative Analysis of Healthy Early- and Late-Pubertal Children during Cardiopulmonary Exercise Testing

BLANKS,

BROWN,

COOPER

et al. 2023

Medicine &Amp; Science in Sports &Amp; Exercise

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Purpose The kinetics of physiological responses to exercise have traditionally been characterized by estimating exponential equation parameters using iterative best-fit techniques of heart rate (HR) and gas exchange [respiratory rate, RR; oxygen uptake, ; carbon dioxide output, ; and ventilation, V̇E]. In this study, we present a novel approach to characterizing the maturation of physiological responses to exercise in children by accounting for response uncertainty and variability. Methods Thirty-seven early-pubertal (17 females, 20 males) and 44 late-pubertal (25 females, 19 males) participants performed three multiple brief exercise bouts (MBEB). MBEB consisted of ten 2-min bouts of cycle ergometry at constant work rate interspersed by 1-min rest. Exercise intensity was categorized as low, moderate, or high, corresponding to 40%, 60%, and 80% of peak work rate, and performed in random order on three separate days. We evaluated sample entropy (SampEn), approximate entropy, de-trended fluctuation analysis, and average absolute local variability (AALV) of HR and gas exchange. Results SampEn of HR and gas exchange responses to MBEB was greater in early- compared to late-pubertal participants (e.g., V̇O2 early-pubertal 1.70 ± 0.023 versus late-pubertal 1.41 ± 0.027, p = 2.97 × 10−14), and decreased as MBEB intensity increased [e.g., HR for low-intensity: 0.37 ± 0.01 compared to 0.21 ± 0.014 for high intensity, p = 3.56 × 10−17]. Females tended to have higher SampEn than males (e.g., V̇O2 for females: 1.61 ± 0.025 versus 1.46 ± 0.031 for males, p = 1.28 × 10−4). AALV was higher in younger participants for both gas exchange and HR (e.g., early-pubertal V̇O2: 17.48 ± 0.56% versus 10.24 ± 0.34% late-pubertal, p = 1.18 × 10−21). Conclusions The greater entropy in signal response to a known, quantifiable exercise perturbation in the younger children might represent maturation-dependent, enhanced competition among physiological controlling mechanisms that originate at the autonomic, subconscious, and cognitive levels.

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“…The vehicle or drug was delivered to the pregnant female rats through osmotic pumps (Alzet Osmotic Pumps, Cupertino, CA, USA; Model 2ML4; 2.5 μl.h −1 ·28 days −1 ) implanted subcutaneously into the back of the animals between the scapulars, after confirmation of sperm via vaginal smear, and under inhalation anaesthesia with 5% of isoflurane (Cristália, São Paulo, Brazil) for induction or 1% isoflurane for maintenance. After giving birth, the mothers were anaesthetized with isoflurane and the osmotic pump was removed, as previously performed (Biancardi et al, 2022; da Silva Junior et al, 2022).…”

Section: Methodsmentioning

confidence: 99%

Sex‐ and age‐specific respiratory alterations induced by prenatal exposure to the cannabinoid receptor agonist WIN 55,212‐2 in rats

Patrone

Ferrari

Silva

et al. 2023

British J Pharmacology

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Background and Purpose: Cannabis legalization has risen in many countries, and its use during pregnancy has increased. The endocannabinoid system is present in the CNS at early stages of embryonic development, and regulates functional brain maturation including areas responsible for respiratory control, data on the influence of external cannabinoids on the development of the respiratory system and possible consequences during postnatal life are limited.Experimental Approach: We evaluated the effects of prenatal exposure to synthetic cannabinoid (WIN 55,212-2 [WIN], 0.5 mgÁkg À1 Áday À1 ) on the respiratory control system in neonatal (P0, P6-7 and P12-13) and juvenile (P27-28) male and female rats.Key Results: WIN administration to pregnant rats interfered sex-specifically with breathing regulation of offspring, promoting a greater sensitivity to CO 2 at all ages in males (except P6-7) and in juvenile females. An altered hypoxic chemoreflex was observed in P0 (hyperventilation) and P6-7 (hypoventilation) males, which was absent in females. Along with breathing alterations, brainstem analysis showed an increase in the number of catecholaminergic neurons and cannabinoid receptor type 1 (CB 1 ) and changes in tissue respiration in the early males. A reduction in pulmonary compliance was observed in juvenile male rats. Preexposure to WIN enhanced spontaneous apnoea and reduced the number of serotoninergic (5-HT) neurons in the raphe magnus nucleus of P0 females.Conclusions and Implications: These data demonstrate that excess stimulation of the endocannabinoid system during gestation has prolonged and sex-specific consequences for the respiratory control system.

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Sexually dimorphic effects of prenatal diazepam exposure on respiratory control and the monoaminergic system of neonate and young rats

Cited by 4 publications

References 60 publications

Maternal opioids age-dependently impair neonatal respiratory control networks

Maternal opioids age-dependently impair neonatal respiratory control networks

Signal Variability Comparative Analysis of Healthy Early- and Late-Pubertal Children during Cardiopulmonary Exercise Testing

Sex‐ and age‐specific respiratory alterations induced by prenatal exposure to the cannabinoid receptor agonist WIN 55,212‐2 in rats

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