Disposition of morphine in chronically infused rats: relationship to antinociception and tolerance.
Disposition of morphine in chronically infused rats: relationship to antinociception and tolerance.
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长期输注大鼠中吗啡的处置：与镇痛和耐受性的关系。
DOI：
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发表时间：
1978
影响因子：
3.5
通讯作者：
L. Harris
中科院分区：
文献类型：
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作者：
G. Patrick;W. Dewey;F. Huger;E. Daves;L. Harris
用荧光法测量大脑和其他生物材料中吗啡的水平，并绘制出与甩尾活动和通过腹膜内输注长期接受麻醉剂治疗的大鼠的耐受性发展的关系。在6天输注方案的前3天，脑吗啡浓度和甩尾潜伏期均随剂量增加而增加。在输注开始后24至48小时内存在细胞耐受性的证据，到第6天具有显著耐受性。在第3天和第6天之间，一种倾向性的耐受性，证明了大脑吗啡浓度的急剧下降，也变得明显。停止输注后，脑吗啡在24小时降至极低水平，但对镇痛作用的显著耐受性保持了72小时。血浆、尿液、腹膜组织和粪便中吗啡的估计值为观察到的倾向性耐受提出了几种可能的解释。这些包括增加吗啡的结合，增加粪便消除和增加在肌肉或腹膜组织中的定位与相对高剂量的慢性输注。因此，目前的工作研究吗啡在大鼠中的药代动力学的慢性治疗模型，目前正在使用的一些实验室的快速诱导药物耐受性和依赖性。
Levels of morphine in brain and other biological materials were measured fluorometrically, and relationships were drawn to tail-flick activity and to tolerance development in rats treated chronically with the narcotic by i.p. infusion. Brain morphine concentration and tail-flick latency both increased with increasing dosage over the first 3 days of the 6-day infusion regimen. There was evidence of cellular tolerance within 24 to 48 hours after the beginning of infusion, with marked tolerance by day 6. Between days 3 and 6 a dispositional tolerance, evidenced by a dramatic fall in brain morphine concentration, also became apparent. After discontinuation of the infusion, the brain morphine dropped to extremely low levels by 24 hours, but significant tolerance to antinociceptive effects remained for 72 hours. Estimation of morphine in plasma, urine, peritoneal tissues and feces suggested several possible explanations for the dispositional tolerance observed. These include increased conjugation of morphine, increased fecal elimination and increased localization in muscle or peritoneal tissues with chronic infusion at relatively high doses. The present work thus examines the pharmacokinetics of morphine in the rat in a chronic treatment model that is currently being used in a number of laboratories for the rapid induction of drug tolerance and dependence.