Induction of morphine-6-glucuronide synthesis by heroin self-administration in the rat.
BACKGROUND
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).


OBJECTIVE
The goal of the present study was to investigate whether M6G synthesis can be induced by intravenous (i.v.) heroin self-administration (SA).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Physiology and Pharmacology Vittorio Erspamer, Sapienza University of Rome, Rome, Italy.
Maria
M
Meringolo
Valentina
V
Brusadin
Maria T
MT
De Luca
Christian
C
Montanari
Christian L
CL
Montanari
Letizia
L
Antonilli
Paolo
P
Nencini
Aldo
A
Badiani
D000818:Animals; D003932:Heroin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009022:Morphine Derivatives / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration
D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D003932:Heroin; C018108:morphine-3-glucuronide