Comparison of the discriminative and antinociceptive effects of morphine and its glucuronide metabolites after central or systemic administration in the rat

Easterling, Keith W; Holtzman, Stephen G.

doi:10.1007/s002130050743

Cited by 12 publications

(5 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additional support for this conclusion includes the finding that M6G, like morphine, fully reproduced the DS effects of heroin in monkeys trained to discriminate heroin from vehicle (present study; Platt et al, 2001). M6G also has been found to reproduce the DS effects of morphine in rats trained to discriminate morphine from vehicle (Easterling and Holtzman, 1998). Shared DS effects may indicate pharmacological effects at a common site of action, implying that similar receptor populations mediate the DS effects of heroin, morphine, and M6G.…”

Section: Discussionmentioning

confidence: 88%

Opioid Partial Agonist Effects of 3-O-Methylnaltrexone in Rhesus Monkeys

Platt¹,

Rowlett²,

Izenwasser³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

3-O-Methylnaltrexone (3-MNTX), a putative antagonist of morphine-6-␤-D-glucuronide (M6G) receptors, has been reported to block the behavioral effects of heroin at doses that do not block those of morphine, suggesting that M6G receptors may play a unique role in the addictive properties of heroin. This study investigated the effects of 3-MNTX in monkeys trained to discriminate i.v. heroin from vehicle or to self-administer i.v. heroin under a progressive-ratio schedule. Additional in vitro studies determined the effects of 3-MNTX and reference drugs on adenylyl cyclase activity in caudate-putamen membranes of monkeys and rats. In drug discrimination experiments, heroin, morphine, and M6G substituted for heroin in all subjects, whereas 3-MNTX substituted for heroin in one-half the monkeys tested. In these latter monkeys, the effects of 3-MNTX were antagonized by naltrexone, and pretreatment with 3-MNTX enhanced the effects of heroin, M6G, and morphine, indicative of -agonist activity. In monkeys showing no substitution of 3-MNTX for heroin, 3-MNTX antagonized the effects of heroin, M6G, and morphine. In self-administration experiments, heroin and 3-MNTX maintained injections per session significantly above those maintained by vehicle when the initial response requirement (IRR) was low; only heroin maintained significant self-administration when the IRR was high. In vitro, 3-MNTX inhibited adenylyl cyclase activity in both monkey and rat brain membranes. The degree of inhibition produced by 3-MNTX was less than that produced by the full agonist [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin (DAMGO). The results suggest that 3-MNTX functions primarily as a partial agonist at -receptors in monkeys and do not support a singular role for M6G receptors in the abuse-related effects of heroin.

show abstract

Section: Discussionmentioning

confidence: 88%

Opioid Partial Agonist Effects of 3-O-Methylnaltrexone in Rhesus Monkeys

Platt¹,

Rowlett²,

Izenwasser³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…It is reported that these metabolites are similarly produced in iv and sc administration and hepatic microsomes in rats (Kuo et al, 1991;Wu et al, 1997;Van Crugten et al, 1997;Ogura, 2000). In rats, M6G generalized to the discriminative stimulus effects of morphine, but not M3G (Easterling and Holtzman, 1998). This fact suggests that the morphine metabolite M6G is also related to the discriminative stimulus effects of morphine.…”

Section: Discussionmentioning

confidence: 95%

“…The sc morphine generalized to the training dose of morphine at 3 mg/kg, and the po morphine generalized at 10-fold this dose level (30 mg/kg). In discrimination training, sc morphine at 3 mg/kg is a commonly used route and dose combination, as is ip administration at this dose (Nishida et al, 1989;Easterling and Holtzman, 1998;Li et al, 2013). This means that sc morphine at 3 mg/kg induces sufficient discrimination stimulus effects.…”

Section: Discussionmentioning

confidence: 99%

Generalization tests using different dosing routes from those of drug discrimination training in rats

Fujiwara¹,

Shimosawa²,

Iino³

et al. 2018

J. Toxicol. Sci.

View full text Add to dashboard Cite

The purpose of this study was to investigate the discriminative stimulus properties of morphine and codeine using different administration routes to that used at drug discrimination training. Rats were trained to discriminate morphine at 3 mg/kg from saline by the intraperitoneal route in a standard two-lever drug discrimination paradigm. Generalization of morphine by the subcutaneous and the oral routes, and codeine by the intraperitoneal and the oral routes to the discriminative stimulus properties of the morphine training dose were investigated. Morphine at 3 mg/kg by the subcutaneous route generalized to the morphine training dose and 10 of 12 rats showed 80% or more morphine-lever responses. In the administration of morphine by the oral route, morphine at 30 mg/kg generalized to the morphine training dose and all rats showed 80% or more morphine-lever responses within the range of 3 to 30 mg/kg. In the administration of codeine by the intraperitoneal route, codeine at 20 mg/kg generalized to the morphine training dose and 14 of the 15 animals showed 80% or more morphine-lever responses within the range of 3 to 20 mg/kg. In the administration of codeine by the oral route, codeine at 60 mg/kg generalized to the morphine training dose and 14 of the 15 animals showed 80% or more morphine-lever responses within the range of 10 to 60 mg/kg. Thus, the discriminative stimulus properties of morphine and codeine were comparable when using different administration routes to those at discrimination training.

show abstract

“…In a drug discrimination procedure, M6G was fully substituted for heroin in rhesus monkeys [ 184 ] and for morphine in rats [ 185 ]. In the latter study, M6G was 17 times more potent than morphine when these drugs were administered in the cerebral ventricles, but less potent when injected subcutaneously.…”

Section: Neurobehavioral Effects Of Heroin and Its Metabolitesmentioning

confidence: 99%

Heroin and its metabolites: relevance to heroin use disorder

et al. 2023

View full text Add to dashboard Cite

Heroin is an opioid agonist commonly abused for its rewarding effects. Since its synthesis at the end of the nineteenth century, its popularity as a recreational drug has ebbed and flowed. In the last three decades, heroin use has increased again, and yet the pharmacology of heroin is still poorly understood. After entering the body, heroin is rapidly deacetylated to 6-monoacetylmorphine (6-MAM), which is then deacetylated to morphine. Thus, drug addiction literature has long settled on the notion that heroin is little more than a pro-drug. In contrast to these former views, we will argue for a more complex interplay among heroin and its active metabolites: 6-MAM, morphine, and morphine-6-glucuronide (M6G). In particular, we propose that the complex temporal pattern of heroin effects results from the sequential, only partially overlapping, actions not only of 6-MAM, morphine, and M6G, but also of heroin per se, which, therefore, should not be seen as a mere brain-delivery system for its active metabolites. We will first review the literature concerning the pharmacokinetics and pharmacodynamics of heroin and its metabolites, then examine their neural and behavioral effects, and finally discuss the possible implications of these data for a better understanding of opioid reward and heroin addiction. By so doing we hope to highlight research topics to be investigated by future clinical and pre-clinical studies.

show abstract

Comparison of the discriminative and antinociceptive effects of morphine and its glucuronide metabolites after central or systemic administration in the rat

Cited by 12 publications

References 17 publications

Opioid Partial Agonist Effects of 3-O-Methylnaltrexone in Rhesus Monkeys

Opioid Partial Agonist Effects of 3-O-Methylnaltrexone in Rhesus Monkeys

Generalization tests using different dosing routes from those of drug discrimination training in rats

Heroin and its metabolites: relevance to heroin use disorder

Contact Info

Product

Resources

About