Repeated Exposures to Heroin and/or Cadmium Alter the Rate of Formation of Morphine Glucuronides in the Rat

Abstract

After absorption, heroin is transformed into mono-acetyl-morphine and then into morphine. Morphine, in turn, is metabolized to morphine-3-glucuronide (M3G), an inactive compound, and morphine-6-glucuronide (M6G), a potent opioid agonist. Thus, changes in the rate of formation of M6G may alter the pharmacological consequences of a treatment with heroin or morphine. In this study, we investigate the effect of repeated exposures (10 daily i.p. injections) to heroin, morphine, cadmium (which has been previously shown to inhibit M3G formation in vitro), or heroin ϩ cadmium on morphine glucuronidation both in vivo and ex vivo (i.e., microsomal preparation obtained from rats treated in vivo). Repeated heroin (2.5, 5.0, and 10 mg/kg) increased plasma levels of M6G (which was undetectable in all other groups) and reduced those of M3G. Also, the microsomal preparations obtained from the liver of repeated heroin rats, when incubated with morphine, yielded significant amounts of M6G (which was undetectable in all other groups) and decreased levels of M3G relative to the control groups. These effects were reversible upon discontinuation of heroin administration. In contrast, repeated morphine (10, 20, and 40 mg/kg) only slightly reduced M3G formation at the dose of 40 mg/kg. Repeated cadmium (5, 15, and 45 g/kg) reduced the rate of M3G formation without inducing M6G synthesis. The effects of the repeated coadministration of heroin (10 mg/kg) and cadmium (15 g/kg) were virtually identical to those of repeated heroin alone. In summary, repeated exposure of rats to heroin can shift morphine glucuronidation toward the formation of the active metabolite M6G.

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

“…(as done in previous studies; Antonilli et al 2003bAntonilli et al , 2005 and after 2 h were sacrificed to obtain blood samples for the quantification of heroin, 6-monoacetylmorphine (6-MAM), morphine, M3G, and M6G (see "Microsomal preparations"), and their livers were excised to obtain microsomal preparations (see "Microsomal preparations").…”

“…Most important, we have shown that repeated non-contingent intraperitoneal (i.p.) injections of high doses of heroin (but not of morphine) can induce the synthesis M6G in the rat (Antonilli et al 2003b(Antonilli et al , 2005. Furthermore, microsomal preparations obtained from the livers of herointreated rats yielded, when incubated with morphine, measurable quantities of M6G, which was not detectable in microsomal preparations from rats treated with saline (Antonilli et al 2003b(Antonilli et al , 2005.…”

Evaluation of Oxidative Markers, Apoptosis and Reproductive Efficiency in Heroin Addicted Rats

“…(3) the rats of third group were injected daily intraperitoneally with daily (5mg Heroin/kg b.w.) (15) .…”

Inhibition of Udp-Glucuronosyltransferase 2b7-Catalyzed Morphine Glucuronidation by Ketoconazole: Dual Mechanisms Involving a Novel Noncompetitive Mode

“…To date, UGT2B7 is the sole enzyme reported capable of forming morphine-6-glucuronide (M-6-G) (Coffman et al, 1997), a metabolite having more potent analgesic activity than morphine. Although increasing evidence suggests that there are a number of factors that affect morphine UGT activity (Narayan et al, 1991;Ishii et al, 2001Ishii et al, , 2004Ishii et al, , 2005Antonilli et al, 2003;Takeda et al, 2005a,b), little is known about inhibitors of UGT2B7.…”