Effect of repeated administrations of heroin, naltrexone, methadone, and alcohol on morphine glucuronidation in the rat

Abstract

The effects of heroin on morphine glucuronidation are not shared by methadone or alcohol (two drugs that figure prominently in the natural history of heroin addiction) and do not appear to depend on the activation of MOR.

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

“…However, we have previously shown that M6G can be induced by repeated noncontingent i.p. administrations of heroin (Antonilli et al 2003b(Antonilli et al , 2005, and there is evidence that adult rats can synthesize M6G even under basal conditions (Wang et al 2005). Microsomal preparations, obtained from the livers of these rats, yielded, when incubated with morphine, significant concentration of M6G (which was absent in the microsomal preparations obtained from saline-treated rats).…”

“…(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.…”

Selective Effects of a Morphine Conjugate Vaccine on Heroin and Metabolite Distribution and Heroin-Induced Behaviors in Rats

“…The assay measures total (bound and unbound) drug. M-6-G was not measured because it is not appreciably formed in rats (Antonilli et al, 2005). Morphine-3-glucuronide was not measured because it lacks reinforcing effects (Vindenes et al, 2009), and appreciable levels were not expected in plasma and brain shortly after heroin or 6-MAM administration.…”

“…In contrast, heroin is sequentially metabolized both peripherally and in the central nervous system (Fig. 1A) as: heroin → 6-monoacetylmorphine (6-MAM) → morphine → morphine-6-glucuronide (M-6-G) (Antonilli et al, 2005), which are all active in humans. Heroin enters brain but is presumed to be a pro-drug because it is rapidly metabolized, has considerably lower affinity for opioid receptors than 6-MAM or morphine (Inturrisi et al, 1983), and is generally found at low concentrations in brain (Andersen et al, 2009).…”