Up-regulation of central mu-opioid receptors in a model of hepatic encephalopathy: a potential mechanism for increased sensitivity to morphine in liver failure.
Increased GABA-mediated neurotransmission, reported to occur in hepatic encephalopathy (HE), is associated with a decrease in the release of Met-enkephalin and the expression of its coding gene in the brain. Furthermore, patients with cirrhosis and a history of HE exhibit increased sensitivity to the neuroinhibitory effects of morphine. Thus, there is a rationale to study the status of the endogenous opioid system in HE. The aim of this study was to determine whether mu-opioid receptors in the brain are up-regulated in a well characterized model of HE. Binding parameters of mu-opioid receptors were derived by assaying the binding of the opiate agonist [3H]-tyr-D-Ala-Gly-N-Methyl-Phe-Gly-ol (DAMGO) to brain membranes from rats with precisely defined stages of HE and control animals. The mean density of mu-opioid receptor sites (Bmax) in rats with stage II, III, and IV HE was 15, 29, and 33% higher, respectively, than the corresponding control value (p<0.01). In addition, the affinity of mu opioid receptors for the agonist (1/Kd) also increased with progression of HE (mean for stage IV HE vs. corresponding control mean, p<0.01). In conclusion, in liver failure, increased density and affinity of central mu-opioid receptors in the brain may: (i) be the basis for the documented increased sensitivity to opiate agonists; and (ii) occur as a consequence of increased GABAergic tone reducing neuronal synthesis and release of opioid agonist peptides.
Bergasa
Nora V
NV
Liver Diseases Section, National Institutes of Health, Bethesda, Maryland, USA. nb343@columbia.edu
Rothman
Richard B
RB
Mukerjee
Erik
E
Vergalla
John
J
Jones
E Anthony
EA
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000209:etiology / Q000378:metabolism*; D017093:Liver Failure / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D051381:Rats; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013853:Thioacetamide; D014316:Tritium; D015854:Up-Regulation; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D017450:Receptors, Opioid, mu; D013853:Thioacetamide; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005680:gamma-Aminobutyric Acid; D009020:Morphine