Endogenous opioids accumulate in plasma in a rat model of acute cholestasis.

To obtain data on the degree to which the opioid system is changed in cholestasis, endogenous opioid activity in plasma of rats with acute cholestasis was determined 5 days after bile duct resection. Total plasma opioid activity was determined using a radioreceptor technique that measured the displacement of the opiate receptor ligand [3H]-DAMGO from lysed synaptosomal fractions of normal rat brain. Plasma total opioid activity was threefold greater in bile duct-resected rats than in sham-operated and unoperated controls (P less than or equal to 0.05). Plasma levels of the individual endogenous opioid, methionine-enkephalin, were determined using a sensitive radioimmunoassay, and the specificity of the assay was confirmed using high-performance liquid chromatography. In cholestatic rats, plasma methionine-enkephalin levels were more than six-fold greater than in sham-operated controls (P less than or equal to 0.001) and more than 17-fold greater than in unoperated controls (P less than or equal to 0.001). However, plasma methionine-enkephalin levels accounted for less than 5% of total plasma opioid activity after bile duct resection. Plasma methionine-enkephalin levels in both cholestatic plasma and plasma from sham-operated animals were stable when incubated in vitro despite the presence of undiminished activity of the major enkephalin-degrading enzymes. Thus, protection of methionine-enkephalin from degradation may be a factor contributing to the elevated plasma levels of methionine-enkephalin found in cholestasis. The magnitude of the increase in plasma endogenous opioid activity in bile duct-resected rats provides support for the hypothesis that endogenous opioids contribute to the pathophysiology of cholestasis.