Department of Physiology and Pharmacology Vittorio Erspamer, Sapienza University of Rome, Rome, Italy.
Psychopharmacology (Berl). 2012 May;221(2):195-203. doi: 10.1007/s00213-011-2534-7. Epub 2011 Oct 21.
Heroin is rapidly metabolized to morphine that in turn is transformed into morphine-3-glucuronide (M3G), an inactive metabolite at mu-opioid receptor (MOR), and morphine-6-glucuronide (M6G), a potent MOR agonist. We have found that rats that had received repeated intraperitoneal injections of heroin exhibit measurable levels of M6G (which is usually undetectable in this species).
The goal of the present study was to investigate whether M6G synthesis can be induced by intravenous (i.v.) heroin self-administration (SA).
Rats were trained to self-administer either heroin (50 μg/kg per infusion) or saline for 20 consecutive 6-h sessions and then challenged with an intraperitoneal challenge of 10 mg/kg of heroin. Plasma levels of heroin, morphine, 6-mono-acetyl morphine, M3G, and M6G were quantified 2 h after the challenge. In vitro morphine glucuronidation was studied in microsomal preparations obtained from the liver of the same rats.
Heroin SA induced the synthesis of M6G, as indicated by detectable plasma levels of M6G (89.7 ± 37.0 ng/ml vs. 7.35 ± 7.35 ng/ml after saline SA). Most important, the in vitro V (max) for M6G synthesis was correlated with plasma levels of M6G (r (2) = 0.78). Microsomal preparations from saline SA rats produced negligible amounts of M6G.
Both in vivo and in vitro data indicate that i.v. heroin SA induces the synthesis of M6G. These data are discussed in the light of previous studies conducted in heroin addicts indicating that in humans heroin enhances the synthesis of the active metabolite of heroin and morphine.
海洛因迅速代谢为吗啡，吗啡继而转化为吗啡-3-葡萄糖醛酸苷（M3G），这是一种在μ-阿片受体（MOR）上无活性的代谢物，以及吗啡-6-葡萄糖醛酸苷（M6G），一种有效的 MOR 激动剂。我们发现，接受过多次腹腔内注射海洛因的大鼠会产生可测量水平的 M6G（在该物种中通常无法检测到）。
本研究的目的是研究静脉内（i.v.）海洛因自我给药（SA）是否可以诱导 M6G 的合成。
大鼠接受海洛因（50μg/kg 每剂量）或生理盐水的连续 20 次 6 小时 SA 训练，然后接受 10mg/kg 海洛因的腹腔挑战。挑战后 2 小时定量检测海洛因、吗啡、6-单乙酰吗啡、M3G 和 M6G 的血浆水平。还在来自同一大鼠肝脏的微粒体制剂中研究了吗啡的葡萄糖醛酸化。
海洛因 SA 诱导了 M6G 的合成，表现为可检测到的 M6G 血浆水平（89.7±37.0ng/ml 与生理盐水 SA 后 7.35±7.35ng/ml）。最重要的是，M6G 合成的 V（max）与 M6G 的血浆水平相关（r²=0.78）。来自生理盐水 SA 大鼠的微粒体制剂几乎不产生 M6G。
体内和体外数据均表明，静脉内海洛因 SA 诱导了 M6G 的合成。这些数据是在先前对海洛因成瘾者进行的研究的基础上讨论的，这些研究表明在人类中，海洛因增强了海洛因和吗啡的活性代谢物的合成。
