untary ethanol consumption in a free-choice paradigm has Portacaval anastomosis (PCA) in the rat results in a been reported both in rats with PCA 4 and in rats with CCl 4broad spectrum of neurological and neurobehavioral induced cirrhosis. 5 Several observations suggest that ethanol changes, including alterations of circadian rhythms, impreference and consumption are mediated, at least in part, paired locomotor activity, and reflexes, as well as deby the endogenous opioid system of the brain. Administration creased threshold to noxious stimuli. In addition, followof opiate antagonists reduces voluntary ethanol consumption ing portacaval shunting, rats drink significantly more in animals, [6][7][8][9] and such antagonists are currently employed ethanol in a free-choice drinking paradigm. Available to control alcoholism in humans. 10,11 evidence suggests that many of these behavioral b-Endorphin (b-EP), an endogenous opioid peptide with changes may be modulated by the endogenous opioid potent analgesic properties, 12 is synthesized mainly in neusystem of the brain. To evaluate this possibility, the efrons of the arcuate nucleus of the hypothalamus, 13 with axons fects of PCA on circulating b-endorphin (b-EP), as well projecting to various regions of the brain. These projections as b-EP content in the pituitary and specific brain nuinclude nuclei involved in pain modulation, 14 memory, and clei, was evaluated using a sensitive radioimmunoassay.
social behaviors, 15 as well as nuclei of the limbic system in-Furthermore, the characteristics and regional densities volved in the mediation of the rewarding and positive-reinof m and d opioid receptors in the brains of PCA and forcing effects of many drugs of abuse, including ethanol. 16 sham-operated control rats were studied using an in b-EP binds with equal affinity to both m and d opioid classes vitro technique, as well as quantitative receptor autoraof receptors. 17 diography and the specific ligands 125 I [D-Ala 2 , MePhe 4 , Alterations of the endogenous opioid system have been re-Met(o)ol 5 ]enkephalin (FK 33-824) and 125 I [2-D-penicillaported in patients with liver disease. Significant increases in mine, 5-D-penicillamine]-enkephalin (DPDPE) for m and the plasma levels of met-enkephalin were observed in pad sites, respectively. PCA resulted in region-selective tients with primary biliary cirrhosis compared with healthy modifications of b-EP in brain, but not in pituitary or control subjects, 18 but there were no changes in plasma conblood. Autoradiographic studies revealed a generalized centrations of b-EP in primary biliary cirrhosis patients. 19 decrease in m binding sites (up to 70% decreases com-Previous studies have demonstrated alterations in the levels pared with sham-operated controls) and region-selective of b-EP in the hypothalamus and frontal cortex of rats and alterations of d receptor densities following PCA. Portadogs showing signs of mild or severe portal-systemic encephacaval-shunted rats drank significantly more ethanol in lopathy, 20 and in the hypothalamus of rats with CCl 4 -induced a free-choice drinking paradigm, an effect that was sigcirrhosis. 21 nificantly attenuated by the administration of the opiate The aims of the present study were fourfold, namely to antagonist naloxone. Increased ethanol preference thus evaluate the effects of PCA in the rat on: (1) circulating and appeared to result from modifications of the endogenous pituitary b-EP concentrations; (2) b-EP content as well as m opioid system in nucleus accumbens of rats following and d receptor densities in specific brain nuclei; (3) voluntary PCA. (HEPATOLOGY 1996;24:895-901.)
ethanol consumption in a free-choice paradigm; and (4) the effects of administration of the opioid receptor antagonist There is evidence to suggest that the endogenous opioid naloxone in rats following PCA. system of the brain is implicated in the mediation of the effects of chronic liver disease on central nervous system MATERIALS AND METHODS function. For example, patients with chronic liver disease are hypersensitive to morphine, 1 and experimental portacaval PCA Surgery. Male Sprague-Dawley rats, weighing 150-200 g, were purchased from Charles River Breeding Laboratories (St. Con-anastomosis (PCA) in the rat results in increased pain sensistant, Que ยดbec, Canada). The animals were divided into two groups; tivity, 2 a phenomenon with which the endogenous opioid syshalf of them, PCA rats, underwent a laparotomy, under halothane tem is known to be implicated. 3 Furthermore, increased volanesthesia, and an end-to-side PCA was performed as previously described. 22 Surgery time was less than 15 minutes. Sham-operated rats were anesthetized, laparotomized, and the inferior vena cava and portal vein were clamped for 15 minutes. The animals were Abbreviations: PCA, portacaval anastomosis; b-EP, b-endorphin; b-EPlir, b-endorphinthen housed individually and fed with Purina Lab Chow (Woodstock, like immunoreactivity; FK, 33-824 [D-Ala 2 , MePhe 4 , Met(o)ol 5 ]-enkephalin; DPDPE, [2-D-Ontario, Canada) and water ad libitum for a period of 1 month. To penicillamine, 5-D-penicillamine]-enkephalin. minimize the effects of handling stress on b-EP release, the animals