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.