Neonatal Adaptation: Naloxone Increases the Catecholamine Surge at Birth

Abstract

ABSTRACT. A marked increase in plasma catecholamines at birth has been described in animals and man. Because the factors that regulate catecholamine secretion are incompletely understood and because it has recently been suggested-that endogenous opiates are important in the regulation of catecholamine secretion, we designed studies to2etermine the influence of opiate receptor blockade prior to delivery on the increase in plasma catecholamines at birth. Term fetal sheep were delivered by cesarean section and randomly assigned to receive naloxone or vehicle. Naloxone was given just prior to umbilical cord cutting as a 2 mg/kg bolus followed by 2 mg/kg/h. Naloxone administration resulted in significantly greater peak levels of plasma norepinephrine (peak levels of 1.5 f 0.4 versus 0.9 f 0.1 ng/ml) and epinephrine (peak levels of 1.4 f 0.7 versus 0.9 f 0.3 ng/ml) and higher norepinephrine values throughout the study period. Naloxone administration was associated with significantly elevated heart rate (peak 184 f 12 versus 207 f 13 beats per min) and blood pressure (peak 95 f 6 versus 88 f 2 mm Hg). These studies demonstrate that opiate receptor blockade from birth markedly augments the neonatal sympathoadrenal response in the term newborn lamb. Fetal and newborn animals secrete catecholamines in response to a variety of stimuli including hypoxia (I), hemorrhage (2), hypothermia (3), labor (4), and delivery (5). The marked increase in catecholamine secretion at birth is particularly important because of the wide range of physiological changes which occur at birth and the importance of the sympathoadrenal system in modulating these changes. In the chronically catheterized fetal sheep, plasma catecholamines begin to rise in the last 3 h of Received September 30, 1986; accepted January 9, 1987 spontaneous labor prior to delivery (4). There is then a further augmentation in plasma levels of both NE and E following delivery and cord cutting (6). We were interested to extend our observations to study the factors that regulate catecholamine release at birth.Two levels of control of catecholamine release have been recognized, including oc 2 receptor-mediated presynaptic inhibition of NE release and inhibition by endogenous opiate peptides. BEND is secreted in response to stress (7) and degrees of hypoxia in fetal sheep known to produce marked catecholamine secretion result in markedly increased levels of circulating BEND (8).Catecholamines and ENK are costored and secreted by the adrenal medulla in response to cholinergic or splanchnic nerve stimulation (9-12). Opiate peptides inhibit catecholamine release by inhibition of neurotransmission in sympathetic ganglia (13,14) and inhibition of adrenal medullary catecholamine secretion (1 5). The physiological significance of these observations in vivo is unclear. In the present study, in order to investigate the role of endogenous opiates in vivo as modulators of sympathoadrenal activity at birth, we compared plasma catecholamine levels with and without continuous opiate receptor...

Fetal Adrenalectomy Does Not Affect Circulating Enkephalins in the Sheep Fetus during Late Gestation

“…It is clear that the fetal adrenal me dulla secretes catecholamines during fetal hypoxaemia and asphyxia [22,23] and we have also shown that the plasma concentrations of MERF are also significantly in creased during periods of fetal asphyxia associated with acute reductions in uterine blood flow [10]. Furthermore, it has been demonstrated that extra-and/or intra-adrenal opioid peptides play a key role in the fetal cardiovascular response to asphyxia and delivery [24,25], During birth or periods of reduced uterine blood flow, naloxone ad ministration to the fetal sheep results in an increase in fetal heart rate and blood pressure and a decrease in blood flow to the fetal kidneys and carcass. This suggests that during asphyxia, intra-or extra-adrenal opioids act to inhibit the catecholamine-induced vasoconstriction of these vascular beds [24], The source and identity of these opioid peptides remain to be established.…”

Birth-Related Up-Regulation of mRNA Encoding Tyrosine Hydroxylase, Dopamine β-Hydroxylase, Neuropeptide Tyrosine, and Prepro-Enkephalin in Rat Adrenal Medulla Is Dependent on Postnatal Oxygenation

“…Previous studies have shown that ENK inhibits the release of catecholamines in the immature adrenal gland (19,20). The high postnatal levels of ENK mRNA may relate to a surge of adrenal ENK at birth, e.g.…”

“…stress induced (35)(36)(37). The function of this ENK may be to ensure that release and synthesis of catecholamines are not overstimulated at birth (19,20). It may also be speculated that adrenal ENK has an endogenous analgesic effect in the fetus during the parturition process and during the immediate period thereafter.…”

“…The functional role of such adrenal peptides has not yet been clarified. However, ENK has been suggested to exert an inhibitory modulation of the catecholamine release from the adrenal medulla in early life (19), and the opiate antagonist naloxone increases the surge of catecholamines at birth in fetal sheep (20). Thus, ENK might act as an autoregulating factor of adrenal catecholamine release (and synthesis) before the onset of a functional innervation.…”

Chronic Prenatal Nicotine Exposure Alters Enkephalin mRNA Regulation in the Perinatal Rat Adrenal Medulla

“…At birth a surge of CAs, mainly originating from the adrenals (1), serves important roles in protecting the newborn against hypoxia, in maintaining homeostasis, and in adaptation to extrauterine life (2)(3)(4). This surge is paralleled by a significant increase in CA enzyme and peptide mRNA levels in the adrenal medulla (5,6).…”