Patrick G A, Dewey W L, Huger F P, Daves E D, Harris L S
J Pharmacol Exp Ther. 1978 Jun;205(3):556-62.
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.
采用荧光法测定了大脑及其他生物材料中的吗啡水平，并将其与甩尾活动以及通过腹腔注射长期给予麻醉剂的大鼠的耐受性发展建立联系。在为期6天的注射方案的前3天，随着剂量增加，大脑吗啡浓度和甩尾潜伏期均增加。在开始注射后的24至48小时内有细胞耐受性的证据，到第6天出现明显耐受性。在第3天至第6天之间，大脑吗啡浓度急剧下降所证明的处置耐受性也变得明显。停止注射后，大脑吗啡在24小时内降至极低水平，但对镇痛作用的显著耐受性持续72小时。血浆、尿液、腹膜组织和粪便中吗啡的测定为观察到的处置耐受性提出了几种可能的解释。这些包括吗啡结合增加、粪便排泄增加以及在相对高剂量长期注射时在肌肉或腹膜组织中的定位增加。因此，本研究在一个慢性治疗模型中研究了大鼠体内吗啡的药代动力学，该模型目前正在许多实验室中用于快速诱导药物耐受性和依赖性。
