Morphine-3-glucuronide - a potent antagonist of morphine analgesia

Smith, Maree T.; Watt, J. A.; Cramond, Tess

doi:10.1016/0024-3205(90)90619-3

Cited by 310 publications

(56 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Morphine-induced analgesia did not differ between Mrp3 (Ϫ/Ϫ) and WT mice (not shown), despite the fact that M3G has been reported to antagonize morphine-induced analgesia (7,47) and the lower levels of M3G found in brain tissue of Mrp3 (Ϫ/Ϫ) mice (Fig. 3G).…”

Section: Discussionmentioning

confidence: 83%

Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception

Zelcer

Wetering

Hillebrand

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

191

141

View full text Add to dashboard Cite

Glucuronidation is a major detoxification pathway for endogenous and exogenous compounds in mammals that results in the intracellular formation of polar metabolites, requiring specialized transporters to cross biological membranes. By using morphine as a model aglycone, we demonstrate that multidrug resistance protein 3 (MRP3͞ABCC3), a protein present in the basolateral membrane of polarized cells, transports morphine-3-glucuronide (M3G) and morphine-6-glucuronide in vitro. Mrp3 (؊/؊) mice are unable to excrete M3G from the liver into the bloodstream, the major hepatic elimination route for this drug. This results in increased levels of M3G in liver and bile, a 50-fold reduction in the plasma levels of M3G, and in a major shift in the main disposition route for morphine and M3G, predominantly via the urine in WT mice but via the feces in Mrp3 (؊/؊) mice. The pharamacokinetics of injected morphine-glucuronides are altered as well in the absence of Mrp3, and this results in a decreased antinociceptive potency of injected morphine-6-glucuronide.analgesia ͉ glucuronides ͉ morphine-3-glucuronide ͉ transport

show abstract

Section: Discussionmentioning

confidence: 83%

Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception

Zelcer

Wetering

Hillebrand

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

191

141

View full text Add to dashboard Cite

show abstract

“…Two of these are the active metabolites of morphine, morphine-6-glucuronide, a potent analgesic, and morphine-3-glucuronide (M3G), an antianalgesic (268). M3G has been shown to cause excitatory behavioral effects in animals and to directly modulate neurotransmitter release (269).…”

Section: Endogenous Antiopioid System(s)mentioning

confidence: 99%

Opioid Receptors

Waldhoer

Bartlett

Whistler

2004

Annu. Rev. Biochem.

709

589

View full text Add to dashboard Cite

Opioid receptors belong to the large superfamily of seven transmembrane-spanning (7TM) G protein-coupled receptors (GPCRs). As a class, GPCRs are of fundamental physiological importance mediating the actions of the majority of known neurotransmitters and hormones. Opioid receptors are particularly intriguing members of this receptor family. They are activated both by endogenously produced opioid peptides and by exogenously administered opiate compounds, some of which are not only among the most effective analgesics known but also highly addictive drugs of abuse. A fundamental question in addiction biology is why exogenous opioid drugs, such as morphine and heroin, have a high liability for inducing tolerance, dependence, and addiction. This review focuses on many aspects of opioid receptors with the aim of gaining a greater insight into mechanisms of opioid tolerance and dependence.

show abstract

“…Both metabolites are active, but with opposite pharmacological actions. M6G is a more potent analgesic than morphine [5], whereas M3G antagonizes both the pharmacological action and the respiratory depression side effects of morphine [6,7]. However, in rats, M6G is formed in negligible amounts and therefore M3G is considered the only glucuronide metabolite of morphine [8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 96%

Influence of Phenobarbital on Morphine Metabolism and Disposition:LC-MS/MS Determination of Morphine (M) and Morphine-3-Glucuronide (M3G) in Wistar-Kyoto Rat Serum, Bile, and Urine

Alnouti¹,

Shelby²,

Chen³

et al. 2007

CDM

View full text Add to dashboard Cite

A simple LC-MS/MS method has been developed and validated for the simultaneous determination of morphine (M) and morphine-3-glucuronide (M3G) in rat serum, bile, and urine. Deuterated D3-M and D3-M3G were used as internal standards (IS) for M and M3G, respectively. Serum samples were processed by acetonitrile precipitation. Bile samples were prepared by solid-phase extraction (SPE) using Oasis MCX cartridges. Urine samples were directly analyzed after dilution with mobile phase. Chromatography was performed using a Luna C18 column (5 microm, 150x2.1 mm I.D.). The mobile phase consisted of acetonitrile (ACN) and 7.5 mM ammonium formate (pH 9.3) delivered from separate pumps with a simple gradient. The method was validated to quantify M in the range of 1-1000 ng/ml in bile and serum, and 0.025-25 microg/ml in urine. M3G was quantified in the range of 1-1000 ng/ml in serum, 0.1-100 microg/ml in bile, and 0.05-25 microg/ml in urine. The method was applied to study the pharmacokinetics and disposition of M and M3G in Wistar-Kyoto (WKY) rats, and the effect of phenobarbital (PB) on M and M3G disposition. M is metabolized to M3G at a lower rate in male than female rats leading to higher M levels and lower M3G levels in serum, urine, and bile of male than female rats. PB administration induces M glucuronidation to M3G in male, but not female WKY rats, and abolishes the gender differences in M and M3G pharmacokinetics.

show abstract

Morphine-3-glucuronide - a potent antagonist of morphine analgesia

Cited by 310 publications

References 8 publications

Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception

Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception

Opioid Receptors

Influence of Phenobarbital on Morphine Metabolism and Disposition:LC-MS/MS Determination of Morphine (M) and Morphine-3-Glucuronide (M3G) in Wistar-Kyoto Rat Serum, Bile, and Urine

Contact Info

Product

Resources

About