Adrenal secretion of BAM-22P, a potent opioid peptide, is enhanced in rats with acute cholestasis

The adrenal gland is known to produce and release endogenous opioids into the circulation. Bovine adrenal medulla docosapeptide (BAM-22P) is a potent opioid agonist, derived from the proenkephalin A gene, which is present in the adrenal medulla. This study was undertaken to determine whether BAM-22P is released into plasma during acute cholestatic liver injury, which increases plasma total opioid activity. Acute cholestasis was induced by bile duct ligation or administration of the hepatotoxin alpha-naphthylisothiocyanate. Plasma levels of BAM-22P were determined by a sensitive radioimmunoassay, and the specificity of the assay was confirmed using high-performance liquid chromatography. Plasma BAM-22P levels was cholestatic rats were significantly higher than those in control rats. This increase in plasma BAM-22P levels was completely prevented by adrenalectomy. Adrenal steady-state levels of proenkephalin mRNA, as determined by Northern blot hybridization analyses, were also increased significantly in cholestatic rats. These increases in proenkephalin mRNA levels were not paralleled by changes in adrenal BAM-22P peptide levels, which were similar in cholestatic rats and their respective controls. Similar levels of proenkephalin mRNA expression were observed in innervated and denervated adrenal glands from cholestatic rats, suggesting that the increase in adrenal proenkephalin mRNA levels in acute cholestasis is not due to splanchnic nerve activation. Thus acute cholestasis in the rat is associated with adrenal secretion and accumulation in plasma of the highly potent opioid peptide BAM-22P and an augmentation of adrenal proenkephalin mRNA expression. The increase in plasma BAM-22P levels may contribute substantially to the increase in total circulating opioid activity documented in cholestatic rats.