Effect of opioid receptor antagonists on hypothalamic–pituitary–adrenal activity in rhesus monkeys

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Some opioid antagonists increase the release of adrenocorticotropic hormone (ACTH) and cortisol in humans and, therefore, may indicate that endogenous opioids modulate hypothalamic–pituitary–adrenal axis activity. The type of opioid receptor that may be related to these endocrine effects is unknown. The purpose of this experiment was to evaluate the ability of different opioid antagonists to increase ACTH and cortisol plasma levels in rhesus monkeys. Eight monkeys received intramuscular injections of various antagonists: 0.0032–1.0 mg/kg naltrexone, 0.1–3.2 mg/kg naltrindole (delta-selective), 0.032–0.32 mg/kg clocinnamox (mu-selective), and 1–3.2 mg/kg nor-binaltorphimine (kappa-selective). Naltrexone, 0.1–1.0 mg/kg, increased ACTH levels, whereas naltrindole and clocinnamox failed to increase ACTH levels. Nor-binaltorphimine, 1–3.2 mg/kg, increased ACTH concentrations on the day of injection, but not at a time when other assays continue to demonstrate κ-antagonism (24 h). Cortisol concentrations generally followed the same pattern as the ACTH concentrations, but the incremental differences in cortisol release between doses were less clear. Thus, opioid modulation of ACTH and cortisol plasma levels is not clearly associated with a particular opioid receptor. Although the κ-antagonist increased ACTH and cortisol release on the day of injection, some evidence suggests that this endocrine effect may be due to mechanisms other than those mediated by the κ-receptor. Alternatively, the naltrexone-induced increase of ACTH and cortisol plasma levels may be caused by activity at multiple opioid receptors or some uncharacterized receptor. Finally, the increased release of ACTH and cortisol may be a response to naltrexone’s aversive properties.