The use of naloxone for investigating disorders of the hypothalamic-pituitary-adrenal axis

The hypothalamic-pituitary-adrenal (HPA) axis forms an integral and vital p art of the stress response system. Pituitary ACTH secretion is regulated by two hypothalamic peptides, corticotropin-rereasing hormone (CRH) and argin ine vasopressin (AVP), with CRH being the primary mediator in humans. Numer ous neuronal circuits within the brain influence the activity of the CRH ne urons in the paraventricular nuclei of the hypothalamus, including endogeno us opioid systems. Opioid receptors are widely distributed in the brain but have a particular association with three major neural networks: the sensor y, limbic and neuroendocrine systems. Opioidergic agents affect HPA activit y in humans and animals, al though important species differences exist. In vitro and in vivo studies provide considerable evidence for a centrally med iated effect of opioidergic agents on the HPA axis, most likely by direct a ction on the hypothalamus. Naloxone is a competitive antagonist at multiple opioid receptor subtypes. Clinical investigations utilizing naloxone administration in humans have ha d three primary aims:1) to elucidate the role of endogenous opioid systems in the normal physiology of the HPA axis; 2) to study the pathophysiology o f disorders associated with or caused by dysfunction of the HPA axis; 3) to develop new diagnostic tests. High doses of naloxone stimulate the human H PA ards causing rises in plasma ACTH and cortisol concentrations. Pharmacol ogical stud ies strongly suggest that naloxone blocks a tonic inhibitory ef fect of endogenous opioids on central alpha-adrenergic pathways, which in t urn stimulate ACTH secretion via CRH release from the hypothalamus. Therefo re, the naloxone test provides a means of evaluating hypothalamic CRH reser ve and assesses the integrity of the entire HPA axis. Several disorders are associated with dysregulation of the HPA axis includi ng major depression, post-traumatic stress disorder, alcoholism, chronic fa tigue syndrome, Gushing's syndrome, and obesity. Major depression is a cond ition often associated with clinical and biochemical evidence of hypercorti solism (pseudo-Cushing's syndrome) and may be very difficult to distinguish from patients with true Gushing's syndrome. Patients with pseudo-Cushing's syndrome are postulated to have hypersecretion of hypothalamic CRH produci ng an upregulation of an otherwise normal HPA axis. Patients with major dep ression have an ACTH hyperresponse to naloxone compared with healthy subjec ts and patients with Gushing's disease. This increased ACTH response is fur ther exaggerated by combining naloxone administration with the direct corti cotrope stimulation provided by exogenous AVP. The naloxone test also has p otential diagnostic utility-when central adrenal insufficiency is suspected . Naloxone applies a specific pharmacological stimulus at the hypothalamic level, therefore a normal ACTH and cortisol response implies functional int egrity of all three components of the HPA axis. Preliminary studies compari ng naloxone administration with the insulin hypoglycemia and metyrapone tes ts are promising. The naloxone test may provide an alternative in patients with suspected central adrenal insufficiency who are unable to undergo an i nsulin hypoglycemia test or a metyrapone test because of safety issues.