Central mu-opioid receptors are down-regulated in a rat model of cholestasis.
Ameliorations of the pruritus of cholestasis by opioid antagonists are consistent with this form of pruritus being centrally mediated by the opioid system. To determine whether the central opioid system is altered in cholestasis, the specific binding of a selective mu-opioid receptor ligand, 3H-DAMGO, to mu-opioid receptors was studied in rats with acute cholestasis due to bile duct resection. Using whole brain membranes and subcellular mitochondrial-synaptosomal fractions the density of mu-receptor sites was 30% (p less than 0.01) and 22% (p = 0.03) less in bile-duct-resected rats than in sham-resected rats. Using membranes from individual brain regions specific binding of 3H-DAMGO was reduced by 43-53% in the cerebral cortex, hippocampus and caudate nucleus of bile-duct-resected rats. Thus mu-opioid receptors in the brain are down-regulated in a classical model of cholestasis. This alteration of the central opioid system could be a consequence of increased exposure of opioid receptors to endogenous opioids in cholestasis and may reflect an important mechanism in the pathogenesis of the pruritus of cholestasis.
Bergasa
N V
NV
Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Rothman
R B
RB
Vergalla
J
J
Xu
H
H
Swain
M G
MG
Jones
E A
EA
D000818:Animals; D002421:Caudate Nucleus / Q000166:cytology / Q000648:ultrastructure; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000166:cytology / Q000648:ultrastructure; D002779:Cholestasis / Q000503:physiopathology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000648:ultrastructure; D008024:Ligands; D008099:Liver / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism / Q000502:physiology*; D017450:Receptors, Opioid, mu; D014316:Tritium
D004745:Enkephalins; D008024:Ligands; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-