LeVier D G, Brown R D, Musgrove D L, Butterworth L F, McCay J A, White K L, Fuchs B A, Harris L S, Munson A E
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298-0613, USA.
Fundam Appl Toxicol. 1995 Feb;24(2):275-84. doi: 10.1006/faat.1995.1030.
Previously, morphine has been shown to elevate corticosterone via the hypothalamic-pituitary-adrenal axis and to suppress the immune system. The present investigation sought to determine if the mu-opiate receptor agonist methadone incurred a similar immune suppression in B6C3F1 mice. Serum methadone and corticosterone levels peaked 1 hr following a single subcutaneous injection of 20 mg/kg methadone HCl. Indeed, the rise in corticosterone levels paralleled that of methadone. After a single injection with 20 mg/kg methadone a pharmacokinetic analysis revealed a serum half-life of approximately 2 hr. Following five injections of methadone over a 24-hr period (every 6 hr), methadone levels were elevated as would be expected; however, corticosterone levels did not become elevated. This suggests that the ability of methadone to elevate corticosterone becomes uncoupled following repeated dosing, indicative of either a tolerance or an increased catabolic mechanism. Moreover, dosing every 6 hr for 5 days induced an increase in the catabolism of methadone itself. Therefore, all assays were begun 1 hr after subcutaneous administration of methadone HCl, a time at which both methadone and corticosterone serum levels were elevated. The primary IgM antibody response to sheep red blood cells (sRBC) was suppressed when splenocytes were immunized in vitro. In contrast, animals immunized with sRBC and assayed for the primary IgM antibody response 4 days later were not suppressed. The activity of the resident macrophages of the liver and spleen as measured by the uptake of 51Cr-sRBC was suppressed in a dose-dependent manner. Previously, it has been demonstrated that morphine suppresses hepatic and splenic phagocytic activity through an opiate receptor-mediated pathway that involves the release of corticosterone. It would appear that methadone plays a similar role in the suppression of hepatic and splenic phagocytosis.
此前已表明，吗啡可通过下丘脑 - 垂体 - 肾上腺轴升高皮质酮水平，并抑制免疫系统。本研究旨在确定μ - 阿片受体激动剂美沙酮是否会在B6C3F1小鼠中引起类似的免疫抑制作用。单次皮下注射20 mg/kg盐酸美沙酮后1小时，血清美沙酮和皮质酮水平达到峰值。实际上，皮质酮水平的升高与美沙酮平行。单次注射20 mg/kg美沙酮后，药代动力学分析显示血清半衰期约为2小时。在24小时内（每6小时一次）注射五次美沙酮后，美沙酮水平如预期升高；然而，皮质酮水平并未升高。这表明重复给药后，美沙酮升高皮质酮的能力出现解偶联，这表明存在耐受性或分解代谢机制增强。此外，每6小时给药一次，持续5天会导致美沙酮自身分解代谢增加。因此，所有检测均在皮下注射盐酸美沙酮1小时后开始，此时美沙酮和皮质酮血清水平均升高。当脾细胞在体外免疫时，对绵羊红细胞（sRBC）的主要IgM抗体反应受到抑制。相比之下，用sRBC免疫并在4天后检测主要IgM抗体反应的动物未受到抑制。通过51Cr - sRBC摄取测量的肝脏和脾脏驻留巨噬细胞活性以剂量依赖性方式受到抑制。此前已证明，吗啡通过涉及皮质酮释放的阿片受体介导途径抑制肝脏和脾脏的吞噬活性。看来美沙酮在抑制肝脏和脾脏吞噬作用中起类似作用。
