Opioid peptide and α-adrenoceptor pathways in the regulation of the pituitary-adrenal axis in man

Abstract

Opioid peptides are well established as potent inhibitors of the pituitary-adrenal axis, while alpha 1-adrenoceptor drugs have recently been shown to stimulate this axis: both classes of agents appear to work principally above the level of the pituitary, most probable directly on the hypothalamus. There is also evidence that these drugs interact in their control of pituitary-adrenal function, although the specific hypothalamic releasing hormone involved has remained unclear. We have therefore carried out a study into the interaction of methoxamine, an alpha 1-adrenoceptor agonist and naloxone, an opioid antagonist, together with human corticotrophin-releasing hormone (CRH), in a group of healthy volunteers in order to establish the mode of action of these drugs. The following drugs were administered to a group of seven healthy male subjects in a randomized double-blind manner: methoxamine (6 micrograms/kg per min over 3 h); naloxone (10 mg bolus); human CRH (100 micrograms bolus); methoxamine plus CRH; naloxone plus CRH; methoxamine plus naloxone; saline (control). Plasma ACTH and serum cortisol were measured at intervals in each subject, and blood pressure and pulse rate recorded with each sample. Both CRH and naloxone produce a marked rise in ACTH and cortisol, peaking at approximately 45 min after infusion. In combination, the drugs produced a peak response in plasma ACTH at the same time, but its magnitude was greater than that after either drug alone. Methoxamine produced a rise in plasma ACTH which was maximal at approximately 75 min, as well as a peak rise in serum cortisol at 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)

During a corticotropin-releasing hormone test in healthy subjects, administration of a beta-adrenergic antagonist induced secretion of cortisol and dehydroepiandrosterone sulfate and inhibited secretion of ACTH

“…One study has shown a methoxamine (a1-adrenergic agonist)-induced increase of CRH-stimulated ACTH and subsequent serum cortisol increase which are compatible with our results (25). In another experiment, the unspecific a1,2-adrenergic antagonist, phentolamine, had no influence on CRHstimulated ACTH and cortisol levels (24).…”

“…In contrast to two earlier studies with propranolol and CRH injection (24,25) or propranolol and hypoglycemia (e.g. 24,26,27), this study extended the earlier view by consideration of molar hormone ratios such as cortisol/adrenocorticotropin (ACTH), cortisol/17-hydroxyprogesterone (17OHP), cortisol/DHEA, and DHEAS/DHEA.…”

The Effects of Endogenous Opioids and Cortisol on Thyrotropin and Prolactin Secretion in Patients with Addison’s Disease1

“…In normal subjects, the infusion of naloxone elevates plasma ACTH and cortisol but only if given in high doses, above 10 -15 mg (1,3,32,36,39,40). In agreement with these data, we found that the infusion of approximately 9 mg naloxone, over 6 1 ⁄2 h, had no effect on plasma ACTH levels during normocortisolism.…”

Hypothalamic-Pituitary-Adrenocortical (HPA) Axis Response and Biotransformation of Oral Naltrexone Preliminary Examination of Relationship to Family History of Alcoholism

“…Opioid antagonist administration blocks the tonic opioid inhibition of HPA axis activity, thereby resulting in release of POMC-derived hormones in the pituitary and cortisol from the adrenal gland. Indeed, numerous studies have demonstrated acute increases in adrenocorticotropin (ACTH) and cortisol levels in man after intravenous infusion of the opioid antagonists naloxone (Cohen et al 1983;Conaglen et al 1985;Delitala et al 1994;Naber et al 1981;Martin del Campo et al 1994;Morley et al 1980;Schluger et al 1998;Volavka et al 1979a) and nalmefene . However, few studies have examined acute neuroendocrine response to the opioid antagonist naltrexone, which, in contrast to naloxone and nalmefene, is not available for intravenous administration.…”