Portacaval Anastomosis Induces Region–Selective Alterations of the Endogenous Opioid System in the Rat Brain

Abstract

Portacaval anastomosis (PCA) in the rat results in a broad spectrum of neurological and neurobehavioral changes, including alterations of circadian rhythms, impaired locomotor activity, and reflexes, as well as decreased threshold to noxious stimuli. In addition, following portacaval shunting, rats drink significantly more ethanol in a free-choice drinking paradigm. Available evidence suggests that many of these behavioral changes may be modulated by the endogenous opioid system of the brain. To evaluate this possibility, the effects of PCA on circulating beta-endorphin (beta-EP), as well as beta-EP content in the pituitary and specific brain nuclei, was evaluated using a sensitive radioimmunoassay. Furthermore, the characteristics and regional densities of mu and delta opioid receptors in the brains of PCA and sham-operated control rats were studied using an in vitro technique, as well as quantitative receptor autoradiography and the specific ligands 125I [D-Ala2, MePhe4, Met(o)ol5]enkephalin (FK 33-824) and 125I [2-D-penicillamine, 5-D-penicillamine]-enkephalin (DPDPE) for micro and delta sites, respectively. PCA resulted in region-selective modifications of beta-EP in brain, but not in pituitary or blood. Autoradiographic studies revealed a generalized decrease in mu binding sites (up to 70% decreases compared with sham-operated controls) and region-selective alterations of delta receptor densities following PCA. Portacaval-shunted rats drank significantly more ethanol in a free-choice drinking paradigm, an effect that was significantly attenuated by the administration of the opiate antagonist naloxone. Increased ethanol preference thus appeared to result from modifications of the endogenous opioid system in nucleus accumbens of rats following PCA.

Cerebral magnetic resonance imaging reveals marked abnormalities of brain tissue density in patients with cirrhosis without overt hepatic encephalopathy

“…A possible explanation is that the decreased brain density observed in cirrhosis does not totally reverse or reverse very slowly after liver transplantation. This is in keeping with old and recent studies in patients with cirrhosis and encephalopathy suggesting that the neurological injury caused by neurotoxins may be persistent or permanent [19,[27][28][29]. Along this line, a recent study observed that even after the first episode of overt hepatic encephalopathy there are residual effects on cognitive function.…”

Minimal hepatic encephalopathy: Consensus statement of a working party of the Indian National Association for Study of the Liver

“…These include the end‐to‐side portacaval‐shunted rat and the rat with graded portal vein ligation 75 . These models recapitulate several characteristic features of MHE including moderate hyperammonemia, manganese accumulation in basal ganglia, 53 alterations of day–night and circadian rhythms 76 and changes in glutamate, 77 monoamine, 78 opioid 79 and histamine 80 neurotransmission comparable to those described in cirrhotic patients. Decreased cortical activation has also been described in both experimental and human MHE 81 .…”

Persistence of Cognitive Impairment After Resolution of Overt Hepatic Encephalopathy

“…There is also conflicting evidence regarding the molecular mechanisms of these persistent cognitive changes in overt HE. Autopsy and animal studies have implicated changes in neurotransmitter systems such as neurosteroids, mono-amines and opioids in the hippocampus and frontal cortex in metabolic encephalopathies such as overt HE16, 17, 32–34. Kril et al also suggested that thalamic neuronal cell loss in overt HE in patients may contribute to persistent changes in cognition in alcoholic cirrhotics20; however there was no specific difference in the cognitive impairment between alcoholics and non-alcoholics in our patient population.…”