Morphine-3-glucuronide: Silent regulator of morphine actions

Lipkowski, Andrzej W.; Carr, Daniel B.; Langlade, A.; Osgood, Patricia F.; Szyfelbein, S.K.

doi:10.1016/0024-3205(94)90106-6

Cited by 45 publications

(12 citation statements)

References 13 publications

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“…A large fraction of morphine absorbed into the body is removed by this first-pass metabolism. Morphine 6b-glucuronide, but not morphine 3b-glucuronide is reported to stimulate locomotor activity in mice [31] and show analgesic activity in rats [32]. In contrast to metabolism of morphine, various cytochrome P450 enzymes, especially P450 2B1, are involved in metabolism of clorgyline.…”

Section: Discussionmentioning

confidence: 98%

Modification of Morphine-induced Hyperlocomotion and Antinociception in Mice by Clorgyline, a Monoamine Oxidase-A Inhibitor

Kitanaka

Takemura

2006

Neurochem Res

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We evaluated the effects of pretreatment with clorgyline, an irreversible monoamine oxidase (MAO)-A inhibitor, on morphine-induced hyperlocomotion and antinociception. A single administration of morphine (30 mg/kg, i.p.) to male ICR mice induced a hyperlocomotion. ANOVA analysis revealed the statistical significance of the morphine effect on horizontal locomotion and of the clorgyline pretreatment x morphine interaction effect, but not of the effect of clorgyline pretreatment. The initial (5 min after challenge) phase of morphine actions vs. saline challenge appeared as if morphine had a strong inhibitory effect on locomotor activity in combination with different doses of clorgyline. The mice administered with morphine in combination of clorgyline (1 and 10 mg/kg) did not show any stereotypic behaviors. Clorgyline at a dose of 0.1 mg/kg but not other doses tested significantly potentiated morphine-induced antinociception evaluated by tail flick but not hot plate test. During the measurements of locomotor activity and antinociception, clorgyline at doses of 1 and 10 mg/kg significantly inhibited monoamine metabolism through MAO. These results suggest that clorgyline showed an inhibitory effect on morphine-induced hyperlocomotion, but not antinociception, through MAO inhibition. There is not a possibility that clorgyline pretreatment enhanced morphine action on motor activity, resulting in the abnormal behavior from hyperlocomotion to stereotypic movements.

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Section: Discussionmentioning

confidence: 98%

Modification of Morphine-induced Hyperlocomotion and Antinociception in Mice by Clorgyline, a Monoamine Oxidase-A Inhibitor

Kitanaka

Takemura

2006

Neurochem Res

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“…5–7,23–25 Although the mechanisms by which morphine causes hyperalgesia independently of opioid receptor activity are not yet known, we have previously speculated on the possible contribution of M3G. M3G has no detectable opioid receptor affinity, 26,27 is pronociceptive in rats and mice, 5,28 and is believed to underlie hyperalgesia in humans during chronic morphine treatment. 1,2 However, there are inconsistencies.…”

Section: Discussionmentioning

confidence: 99%

Sex-specific Mediation of Opioid-induced Hyperalgesia by the Melanocortin-1 Receptor

et al. 2010

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Background N-Methyl-d-aspartate receptor antagonists reverse hyperalgesia during morphine infusion in male mice only. Because the melanocortin-1 receptor can act as a female-specific counterpart to N-methyl-d-aspartate receptors in κ-opioid analgesic mechanisms, the authors assessed the contribution of melanocortin-1 receptors to the sex-specific mechanisms underlying morphine hyperalgesia. Methods The tail-withdrawal test was used to compare the nociceptive responses of male and female C57BL/6J (B6) mice with those of C57BL/6J-Mc1re/e (e/e) mice, spontaneous mutants of the B6 background lacking functional melanocortin-1 receptors, during continuous morphine infusion (1.6 and 40.0 mg kg−1 · 24 h−1). Separate groups of hyperalgesic B6 and outbred CD-1 mice were injected with MK-801 or MSG606, selective N-methyl-d-aspartate and melanocortin-1 receptor antagonists, respectively. Results Morphine infusion (40.0 mg · kg−1 · 24 h−1) reduced baseline withdrawal latencies by 45–55% in B6 mice of both sexes, indicating hyperalgesia; this increased nociception was manifest in male e/e mice only. Although MK-801 reversed hyperalgesia in male mice only, increasing latencies by 72%, MSG606 increased latencies by approximately 60% exclusively in females. A lower morphine infusion dose (1.6 mg · kg−1 · 24 h−1) reduced baseline withdrawal latencies by 45–52% in B6 and e/e mice of both sexes, which was reversed by MK-801, but not MSG606, in both male and female B6 mice. Conclusions The data indicate the sex-specific mediation of highdose morphine-induced hyperalgesia by N-methyl-d-aspartate and melanocortin-1 receptors in male and female mice, respectively, suggesting a broader relevance of this known sexual dimorphism. The data further indicate that the neural substrates contributing to hyperalgesia are morphine dose-dependent.

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“…Lipkowski et al reached a quite different conclusion. After coadministration of morphine and M3G in rats a prolonged and increased analgesic action was obtained compared to administration of morphine alone (74).…”

Section: Morphine-3-glucuronidementioning

confidence: 97%

Morphine metabolites

Christrup

1997

Acta Anaesthesiol Scand

235

144

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Morphine is a potent opioid analgesic widely used for the treatment of acute pain and for long-term treatment of severe pain. Morphine is a member of the morphinan-framed alkaloids, which are present in the poppy plant. The drug is soluble in water, but its solubility in lipids is poor. In man, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are the major metabolites of morphine. The metabolism of morphine occurs not only in the liver, but may also take place in the brain and the kidneys. The glucuronides are mainly eliminated via bile and urine. Glucuronides as a rule are considered as highly polar metabolites unable to cross the blood-brain barrier. Although morphine glucuronidation has been demonstrated in human brain tissue, the capacity is very low compared to that of the liver, indicating that the M3G and M6G concentrations observed in the cerebrospinal fluid (CSF) after systemic administration reflect hepatic metabolism of morphine and that the morphine glucuronides, despite their high polarity, can penetrate into the brain. Like morphine, M6G has been shown to be relatively more selective for mu-receptors than for delta- and kappa-receptors while M3G does not appear to compete for opioid receptor binding. The analgesic properties of M6G were recognised in the early 1970s and more recent work suggests that M6G might significantly contribute to the opioid analgesia after administration of morphine. The analgesic potency of M6G after intracerebroventricular (ICV) or intrathecal (IT) administration in rats is from 45-800 timer greater than that of morphine, depending on the animal species and the experimental antinociceptive test used. Furthermore, the development of a sensitive high-performance liquid chromatography (HPLC) assay for the quantitative determination of morphine, M6G and M3G has revealed that M6G and M3G were present in abundance after chronic oral morphine administration and that the area under the plasma concentration-time curve exceeded that of morphine. M3G has been found to antagonise morphine and M6G induced analgesia and ventilatory depression in the rat, which has led to the hypothesis that M3G may influence the development of morphine tolerance. M3G exhibits no analgesic effect after ICV or IT administration. Some studies do, however, indicate that M3G may cause non-opioid mediated hyperalgesia/allodynia and convulsions after IT administration in rats. These observations led to the hypothesis that M3G might be responsible for side-effects, hyperalgesia/allodynia and myoclonus seen after high-dose morphine treatment.

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Morphine-3-glucuronide: Silent regulator of morphine actions

Cited by 45 publications

References 13 publications

Modification of Morphine-induced Hyperlocomotion and Antinociception in Mice by Clorgyline, a Monoamine Oxidase-A Inhibitor

Modification of Morphine-induced Hyperlocomotion and Antinociception in Mice by Clorgyline, a Monoamine Oxidase-A Inhibitor

Sex-specific Mediation of Opioid-induced Hyperalgesia by the Melanocortin-1 Receptor

Morphine metabolites

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