Naloxone Has a Direct Effect on the Adrenal Cortex*

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Abstract
The effects of naloxone on basal and ACTHstimulated corticosterone secretion from superfused rat adrenocortical tissue were investigated. High doses (10-3 and 10-4M) of naloxone produced a decline in basal steroidogenesis, whereas lower doses (10-5-10-7 M) of naloxone resulted in elevations of corticosterone secretion. The simultaneous addition of an aliquot of ACTH and varying amounts of naloxone resulted in a dose-dependent alteration in the steroidgenic response by the tissue to ACTH. With higher doses (10-3 and 10-4 M) of naloxone, there were little or no significant alterations in the response to an initial dose of ACTH; however, the steroidogenic responses to ACTH administered 2 and 4 h after the single aliquot of naloxone were significantly potentiated. The lower dose of naloxone (10-610-10 M) resulted only in the potentiation of the initial ACTH response. The simultaneous administration of ACTH and 10-12 M naloxone resulted in no apparent alteration in the response to ACTH at any period in the studies. Methionine enkephalin (1.7 × 10-9 to 1.7 × 10-7 M) significantly potentiated ACTH-stimulated steroid secretion 2 h after the enkephalin was given. Naloxone also had direct effects on the cell membrane potential (MP) of superfused adrenocortical tissue. The addition of 10-5-10-10 M naloxone resulted in a rapid depolarization of the MP. The initial depolarizations lasted for approximately 15–25 min. Action potential-like spikes were often characteristic of the MP changes. These findings clearly demonstrate a direct effect of both opioid agonist and antagonist on adrenal steroid secretion. The most prominent effect was a potentiation of the steroidogenic action of ACTH. We suggest that naloxone and possibly other opioids exert their effects on the adrenal cortex by interacting with one or more relatively nonspecific membrane receptors which are distinct from the ACTH receptor. The data also suggest that one mechanism by which the opioids might exert their potentiating effect is via an alteration in membrane permeability to one or more ions, resulting in more optimal intracellular ion concentration.