The Use of Naloxone for Investigating Disorders of the Hypothalamic-Pituitary-Adrenal Axis

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis forms an integral and vital part of the stress response system. Pituitary ACTH secretion is regulated by two hypothalamic peptides, corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), with CRH being the primary mediator in humans. Numerous neuronal circuits within the brain influence the activity of the CRH neurons in the paraventricular nuclei of the hypothalamus, including endogenous opioid systems. Opioid receptors are widely distributed in the brain but have a particular association with three major neural networks: the sensory, limbic and neuroendocrine systems. Opioidergic agents affect HPA activity in humans and animals, al though important species differences exist. In vitro and in vivo studies provide considerable evidence for a centrally mediated effect of opioidergic agents on the HPA axis, most likely by direct action on the hypothalamus. Naloxone is a competitive antagonist at multiple opioid receptor subtypes. Clinical investigations utilizing naloxone administration in humans have had 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 of disorders associated with or caused by dysfunction of the HPA axis; 3) to develop new diagnostic tests. High doses of naloxone stimulate the human HPA ards causing rises in plasma ACTH and cortisol concentrations. Pharmacological stud ies strongly suggest that naloxone blocks a tonic inhibitory effect of endogenous opioids on central alpha-adrenergic pathways, which in turn stimulate ACTH secretion via CRH release from the hypothalamus. Therefore, the naloxone test provides a means of evaluating hypothalamic CRH reserve and assesses the integrity of the entire HPA axis. Several disorders are associated with dysregulation of the HPA axis including major depression, post-traumatic stress disorder, alcoholism, chronic fatigue syndrome, Cushing's syndrome, and obesity. Major depression is a condition often associated with clinical and biochemical evidence of hypercortisolism (pseudo-Cushing's syndrome) and may be very difficult to distinguish from patients with true Cushing's syndrome. Patients with pseudo-Cushing's syndrome are postulated to have hypersecretion of hypothalamic CRH producing an upregulation of an otherwise normal HPA axis. Patients with major depression have an ACTH hyperresponse to naloxone compared with healthy subjects and patients with Cushing's disease. This increased ACTH response is further exaggerated by combining naloxone administration with the direct corticotrope stimulation provided by exogenous AVP. The naloxone test also has potential 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 integrity of all three components of the HPA axis. Preliminary studies comparing naloxone administration with the insulin hypoglycemia and metyrapone tests are promising. The naloxone test may provide an alternative in patients with suspected central adrenal insufficiency who are unable to undergo an insulin hypoglycemia test or a metyrapone test because of safety issues.