Stasiak A, Fogel W A
Department of Hormone Biochemistry, Medical University of Lodz, Lodz, Poland.
J Physiol Pharmacol. 2008 Mar;59(1):101-14.
Rats with liver cirrhosis, evoked by chronic administration of thioacetamide (TAA), consumed voluntarily more alcohol than their healthy counterparts. Seeking the mechanisms underlying this phenomenon, the opioid system was screened for involvement and alterations. In vivo, the influence of chronically administered Naloxone and Naltrexone, non-specific opioid receptor antagonists, on alcohol intake was examined in free choice tests between 10% alcohol and tap water and ex vivo receptor binding studies were performed on cerebral membrane preparations.
TAA rats, selected for the study, had confirmed liver insufficiency: their plasma bilirubin concentrations were about 3 times higher, the prothrombin time was 50% longer and they consumed voluntarily 3 times more alcohol than the control animals. The drugs were given s.c. for five days, at the beginning of the dark phase of a 24h cycle, in a daily dose of 10 mg per kg body mass. Throughout the treatment, the rats were kept individually in metabolic cages with a free access to water, alcohol solution and food. Feed and fluid consumption, as well as the urine outputs, were recorded on the 2h, 4h, 6h and 24h after the drug administration. The mu opioid ligand - [(3)H]-(D-Ala(2), -N-MePhe(4), Glyol(5)) Enkephalin was used to obtain binding characteristics of the control and TAA rat brain membranes.
The drugs, if modified drinking behaviours, they did it transiently; alcohol, water and thus the total fluid intake by the cirrhotic and control rats was significantly less after 2h - 6h from either naloxone or naltrexone administration. Both drugs decreased general fluid consumption as such rather than the consumption of alcohol only, as observed from the recordings related to TAA rats. The binding data: K(d) of 2.62 +/- 0.98 nM and B(max) of 43.71 +/- 6.12 fmol/mg protein for cirrhotic rats, versus K(d) of 4.63 +/- 1.98 nM and B(max) 95.61 +/- 18.33 fmol/mg protein for the control ones, suggest that while the affinity of radioligand to cerebral mu receptors was similar for the two groups, there was a lower density of those receptors in the cirrhotic rats.
The results indicate some disturbances in the opioid system in cirrhotic rats. However, the low response to opioid therapy suggests that the opioid system may have only be partly involved in the development of the observed increased alcohol drinking in the rats with liver cirrhosis.
通过长期给予硫代乙酰胺（TAA）诱发肝硬化的大鼠，自愿摄入的酒精比健康大鼠更多。为探究这一现象背后的机制，对阿片系统是否参与及发生改变进行了筛查。在体内，通过在10%酒精和自来水之间的自由选择试验，研究了长期给予非特异性阿片受体拮抗剂纳洛酮和纳曲酮对酒精摄入的影响，并对脑膜制剂进行了体外受体结合研究。
入选本研究的TAA大鼠已确诊肝功能不全：其血浆胆红素浓度约高3倍，凝血酶原时间长50%，且自愿摄入的酒精量是对照动物的3倍。在24小时周期的黑暗期开始时，将药物皮下注射，连续五天，每日剂量为每千克体重10毫克。在整个治疗过程中，将大鼠单独饲养在代谢笼中，可自由获取水、酒精溶液和食物。在给药后2小时、4小时、6小时和24小时记录饲料和液体摄入量以及尿量。使用μ阿片配体 - [（3）H] - （D - Ala（2）， - N - MePhe（4），Glyol（5））脑啡肽来获得对照大鼠和TAA大鼠脑膜的结合特性。
如果药物改变了饮水行为，也是短暂的；在给予纳洛酮或纳曲酮后2小时至6小时，肝硬化大鼠和对照大鼠的酒精、水以及总液体摄入量均显著减少。从与TAA大鼠相关的记录中可以看出，两种药物均降低了总体液体摄入量，而非仅降低酒精摄入量。结合数据显示：肝硬化大鼠的解离常数（K（d））为2.62±0.98 nM，最大结合容量（B（max））为43.71±6.
