Effects of Naloxone on the Preparturient Increase in Adrenocorticotrophin and Cortisol in Foetal Sheep

Abstract

Parturition in sheep is preceded by a rapid increase in foetal pituitary-adrenal activity. Administration of exogenous opioids increases foetal plasma adrenocorticotrophin (ACTH) and cortisol concentrations after Day 125 of pregnancy (term = 145 days). In order to test the hypothesis that endogenous opioids regulate the increase in pituitary-adrenal activity prior to parturition in foetal sheep, we measured changes in plasma ACTH and cortisol in response to administration of either naloxone (1.2 mg intravenous bolus followed by a 2.5 mg/h continuous infusion for 2 h; foetal body weight approximately 2.5 kg) or saline to chronically catheterized foetal sheep at 2-day intervals between Day 140 and the onset of parturition. In addition, we utilized a computerized algorithm (Munro) to examine the precise characteristics of ACTH and cortisol secretion in control and naloxone-treated foetuses.The pattern of ACTH and cortisol secretion in saline-infused control foetuses was highly pulsatile but varied considerably between individual foetuses. ACTH pulses occurred on average every 40 min but were not always coincident with pulses of cortisol.There were no significant changes in average ACTH concentrations, pulse frequency or amplitude between foetuses sampled at 3 to 4 and 1 to 2 days before parturition, In contrast, average cortisol concentrations and pulse amplitude were significantly (P<0.05) increased, whereas pulse frequency was reduced, in foetuses at 1 to 2 days before parturition. Naloxone caused a significant (P < 0.05) inhibition of ACTH concentrations when compared with pretreatment values and with saline-treated controls, an effect which persisted for at least 2 h after the end of naloxone infusion. However, there were no significant differences during naloxone treatment in the frequency or amplitude of ACTH or cortisol pulses nor in the mean cortisol concentration. We conclude that ACTH and cortisol are secreted in a pulsatile fashion in the late gestation foetal sheep and that these pulses are not always coincident with each other. Blockade of endogenous opioid activity during the preparturient increase in pituitaryadrenal activity in foetal sheep, results in a reduction in plasma concentrations of ACTH. These results therefore provide evidence for the tonic regulation of foetal pituitary-adrenal activity by endogenous opioids during the final days prior to birth in the sheep.In sheep, a dramatic preparturient increase in the activity of the roetal hypothalamo-pituitary-adrenal axis is pivotal to the onset of birth. However, the neuroendocrine mechanisms which control foetal pituitary-adrenal function in the sheep, are poorly understood (1). Indeed, there is scant information as to the nature of adrenocorticotrophin (ACTH) and cortisol secretion during this important stage of foetal development. In adult animals, ACTH m d cortisol secretion is pulsatile (2) and a complex interaction between a number of neurotransmitter and neuropeptide systems, regulate the activity of this axis (3). However, until...

Low-dose cortisol infusion increases plasma corticosteroid-binding globulin (CBG) and the amount of hepatic CBG mRNA in fetal sheep on day 100 of gestation

“…We have provided evidence that glucocorticoids stimulate the rise in plasma CBG in the late-gestation fetus (Challis et al 1985, Berdusco et al 1993 ), thereby maintaining a relatively low free cortisol concentration in fetal plasma (Ballard et al 1982). In this way, the negative feedback effects of glucocorticoids on the hypothalamus and pituitary are attenuated, and pituitary ACTH secretion continues to rise, presumably in response to sustained inputs to the hypothalamus (Challis & Brooks 1989, Brooks & Challis 1991, and increased pituitary responsiveness (Wintour et al 1984, Lü et al 1991. We have characterized these changes as components of a feedforward cascade that leads to fetal activation (Challis & Brooks 1989).…”

Dopaminergic regulation of adrenocorticotrophic hormone, α-melanocyte-stimulating hormone and cortisol secretion in the ovine fetus

“…Pulse analysis was performed using the MUNRO algorithm as previously described (Martin et al 1987, Brooks & Challis 1991, which detects significant excur¬ sions from a baseline followed by post-hoc i-test. A moving average of 100 min was used to determine baseline hor¬ mone concentrations, and values which increased by 2 standard deviations or more from the previous nadir were considered to be significant pulses.…”

“…Fetal hypophysectomy or adrenalectomy abolishes the prepar¬ tum rise in cortisol and hence delays parturition whilst infusion of ACTH or dexamethasone increases the levels of cortisol in the fetal circulation and results in premature delivery (Liggins et al 1973). Although ACTH is believed to be the main regulating hormone for the fetal adrenal cortex during the last third of gestation, discordance in the pulse characteristics of the two hormones (Brooks & Challis 1991, Apostolakis et al 1992) and adrenal acti¬ vation in the absence of increased plasma ACTH concen¬ trations (Jacobs et al 1994) has led some to suggest that ACTH may not be solely responsible for driving cortisol secretion from the fetal adrenal in late gestation. In this respect -melanocyte-stimulating hormone ( -MSH), a pro-opiomelanocortin (POMC)-derived peptide secreted from the intermediate lobe of the pituitary gland, has been implicated as a trophic factor for the fetal adrenal gland, and could be involved in adrenal activation during the prepartum cortisol surge.…”

Modulation of Arginine Vasopressin Secretion from Cultured Ovine Hypothalamic Cells by Glucocorticoids and Opioid Peptides

“…Exogenous admin istration of opioid peptide agonists to sheep either inhibit, stimulate or have no effects on circulating ACTH concen trations [14,15,17]. In fetal sheep, ACTH concentrations are elevated by an opioid agonist, FK33-824 [16], and nal oxone administration reduces ACTH secretion during the surge of adrenocortical activity associated with parturi tion in this species [27], In contrast, naloxone has no effect on hypoxia-induced ACTH secretion [28]. These data suggest that the role of opioid peptides in the control of pituitary-adrenal function is dependent on many fac tors including the physiological status of the animal and the nature of the signals which activate the hypothalamus.…”