OPIOID PEPTIDE AND ALPHA-ADRENOCEPTOR PATHWAYS IN THE REGULATION OF THE PITUITARY-ADRENAL AXIS IN MAN

Opioid peptides are well established as potent inhibitors of the pitui tary-adrenal axis, while alpha(1)-adrenoceptor drugs have recently bee n shown to stimulate this axis: both classes of agents appear to work principally above the level of the pituitary, most probable directly o n the hypothalamus. There is also evidence that these drugs interact i n their control of pituitary-adrenal function, although the specific h ypothalamic releasing hormone involved has remained unclear. We have t herefore carried out a study into the interaction of methoxamine, an a lpha(1)-adrenoceptor agonist and naloxone, an opioid antagonist, toget her with human corticotrophin-releasing hormone (CRH), in a group of h ealthy volunteers in order to establish the mode of action of these dr ugs. The following drugs were administered to a group of seven healthy male subjects in a randomized double-blind manner: methoxamine (6 mu g/kg per min over 3 h); naloxone (10 mg bolus); human CRH (100 mu g bo lus); methoxamine plus CRH; naloxone plus CRH; methoxamine plus naloxo ne; 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 combi nation, 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 appro ximately 75 min, as well as a peak rise in serum cortisol at 120 min. This was greater than after either CRH or naloxone alone but, in combi nation, both drugs produced peak responses not significantly greater t han when methoxamine alone was given. While the interaction of drugs w ith differing pharmacokinetic profiles renders interpretation difficul t, our data suggest that naloxone increases pituitary-adrenal activity via a mechanism independent of CRH, most probably hypothalamic vasopr essin. This, albeit indirect, evidence suggests that alpha(1)-adrenoce ptor activation with methoxamine activates hypothalamic pathways invol ving both endogenous CRH and vasopressin.