A5 noradrenergic neurons and breathing control in neonate rats

Taxini, Camila L.; Marques, Danuzia A.; Bícego, Kênia C.; Gargaglioni, Luciane H.

doi:10.1007/s00424-021-02550-1

Cited by 7 publications

(10 citation statements)

References 53 publications

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“…The respiratory network must be functional at birth to maintain homeostasis, but the respiratory network continues to mature postnatally ( Patrone et al, 2018 ; Patrone et al, 2020 ; Taxini et al, 2021 ; reviewed in Wong-Riley et al, 2019 ), including refinement of respiratory rhythm generation ( Bissonnette et al, 1991 ; Kobayashi et al, 2001 ), shifts in oscillator dominance ( Onimaru and Dutschmann, 2012 ; Hocker et al, 2021 ), and shifts in neurotransmitter/neuromodulator receptor expression ( Liu and Wong-Riley, 2002 ; Gao et al, 2011 ; Wong-Riley et al, 2013 ). While lingering neonatal opioids contribute to reductions in respiratory amplitude in neonates after maternal opioids, we hypothesize that reduced respiratory frequency in neonates after maternal opioids is caused by disruption of perinatal maturation of respiratory networks after maternal opioids.…”

Section: Discussionmentioning

confidence: 99%

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%

Maternal opioids age-dependently impair neonatal respiratory control networks

et al. 2023

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“…Sighs were considered as inspiratory events, in which V T was at least twice as large as the regular V T . Post‐sigh apnoea occurred immediately or until 6 s after a sigh (Taxini et al, 2021). The

\overset{V}{true} normalO 2

was calculated with the suitable formula and presented per body mass.…”

Section: Methodsmentioning

confidence: 99%

“…Post-sigh apnoea occurred immediately or until 6 s after a sigh (Taxini et al, 2021). The _ VO2 was calculated with the suitable formula and presented per body mass.…”

Section: Data and Statistical Analysismentioning

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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“…It is well established that their activation produces an increase in sympathetic tone. In the case of dlPAG, it includes an increase in cardiorespiratory parameters (blood pressure, heart rate and respiratory frequency) [3,9], whereas the activation of the A5 region produces similar cardiovascular changes but associated with a decrease in respiratory frequency [4,5,22,31].…”

Section: Introductionmentioning

confidence: 99%

Impact of the glutamatergic neurotransmission within the A5 region on the cardiorespiratory response evoked from the midbrain dlPAG

Gonzalez-Garcia

Carrillo-Franco

Peinado-Aragonés

et al. 2022

Pflugers Arch - Eur J Physiol

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Stimulation of the dorsolateral periaqueductal grey matter (dlPAG) in rats evokes an active defensive behaviour together with a cardiorespiratory response characterised by tachypnoea, tachycardia and hypertension. The dlPAG neurons involved in these responses are excitatory, presumably glutamatergic, due to the presence of vesicular glutamate transporter VGLUT2 within their axon terminals. Previously, our group described a functional interaction between dlPAG and the pontine A5 region. Accordingly, in the present work, in order to characterize the role of glutamate within this interaction, experiments were carried out in spontaneously breathing anaesthetized rats (sodium pentobarbitone 60 mg/kg i.p., suplemented with 20 mg/kg i.p.). The cardiorespiratory response evoked by electrical stimulation of the dlPAG (1 ms pulses, 20–50 μA, given at 100 Hz, during 5 s) was analysed before and after the microinjection, within the A5 region, of either kynurenic acid (non-specific glutamate receptor antagonist; 5–10 nmol), DAP-5 (NMDA antagonist; 1 pmol), CNQX (non-NMDA antagonist; 1 pmol) or MCPG (metabotropic antagonist; 0,1 nmol). Kynurenic acid decreased the intensity of both the tachypnoea (p < 0,001) and tachycardia (p < 0,001) induced by dl-PAG stimulation. Blockade of no-NMDA receptors reduced the increase of respiratory frequency, heart rate and pressor response to dl-PAG stimulation (p < 0,01, p < 0,001, p < 0,05 respectively). Blockade of either NMDA or metabotropic receptors reduced the dlPAG-evoked tachycardia and pressor response (p < 0,01; p < 0,05 respectively). These results suggest a neuromodulatory role for A5 region via glutamate neurotransmission of the dlPAG-evoked cardiorespiratory response, confirming the role of the ventrolateral pons in the neuronal circuits involved in respiratory and heart rate control.

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A5 noradrenergic neurons and breathing control in neonate rats

Cited by 7 publications

References 53 publications

Maternal opioids age-dependently impair neonatal respiratory control networks

Maternal opioids age-dependently impair neonatal respiratory control networks

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

Impact of the glutamatergic neurotransmission within the A5 region on the cardiorespiratory response evoked from the midbrain dlPAG

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