Morphine-6-glucuronide: Analgesic effects and receptor binding profile in rats

Abbott, Frances V.; Palmour, Roberta M.

doi:10.1016/0024-3205(88)90479-1

Cited by 183 publications

(89 citation statements)

References 32 publications

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“…M6G is also more potent than morphine (146 : 1) at producing rewarding e ects measured with place preference testing following intracerebral administration (Abbott & Franklin, 1991). Binding studies show that M6G has an equal or lower a nity for the muopioid receptor than morphine (Abbott & Palmour, 1988;Chen et al, 1991;Hucks et al, 1992;Lambert et al, 1993;Mignat et al, 1995;LoÈ ser et al 1996;Brown et al, 1997b;Pan et al, 1999). In order to explain these di erences in the potencies of M6G and morphine, it has recently been hypothesized that M6G has selective antinociceptive and other behavioural agonist e ects at a receptor that is not activated by morphine (reviewed by Pasternak & Standifer, 1995).…”

Section: Introductionmentioning

confidence: 96%

Morphine‐6β‐glucuronide has a higher efficacy than morphine as a mu‐opioid receptor agonist in the rat locus coeruleus

Osborne

Chieng

Christie

2000

British J Pharmacology

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1 The pharmacological properties of the active morphine metabolite, morphine-6b-D-glucuronide (M6G), and the parent compound were compared in rat locus coeruleus neurons by electrophysiological recording in brain slices. 2 M6G and morphine activated potassium currents in voltage clamped neurons, which were blocked by the opioid receptor antagonist naloxone. 3 Both M6G and morphine behaved as partial agonists that produced maximal responses smaller than the system maximum, which was measured using [Met 5 ]-enkephalin. M6G produced a larger maximal response (78%) than morphine (62%), which we estimated was due to a 2 ± 4 fold di erence in the relative e cacy of the agonists. 4 3-O-methoxynaltrexone, which has been reported to behave as a selective antagonist of a M6G preferring receptor, was equally e ective at blocking currents produced by M6G and the selective mu-opioid receptor agonist DAMGO. 5 M6G currents were occluded by a prior application of morphine, and were reduced when muopioid receptors were desensitized by using [Met 5 ]-enkephalin. 6 Morphine-3b-D-glucuronide did not a ect action potential ®ring or membrane currents in locus coeruleus neurons and had no e ect on currents produced by M6G. 7 These results show that the relative e cacy of M6G is higher than morphine in locus coeruleus neurons, contrary to what has been shown using mu-opioid receptors expressed in cell clones.

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Section: Introductionmentioning

confidence: 96%

Morphine‐6β‐glucuronide has a higher efficacy than morphine as a mu‐opioid receptor agonist in the rat locus coeruleus

Osborne

Chieng

Christie

2000

British J Pharmacology

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“…In general, glucuronidation is thought to serve as an inactivating or protective function by terminating or attenuating the activity of many endogenous, dietary and clinically administered drugs as well as environmental chemicals that have been shown to result in toxicity or carcinogenesis [2]. However, glucuronidation also can result in the generation of bioactive or even toxic compounds, including those of estrogens, morphine, retinoids, bile acids, and heterocyclic aromatic amines [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Identification of UDP-glucuronosyltransferase 1A10 in non-malignant and malignant human breast tissues

2008

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UGT1A10 was recently identified as the major isoform that conjugates estrogens. In this study, realtime PCR revealed high levels of UGT1A10 and UGT2B7 in human breast tissues. The expression of UGT1A10 in breast was a novel finding. UGT1A10 and UGT2B7 mRNAs were differentially expressed among normal and malignant specimens. Their overall expression was significantly decreased in breast carcinomas as compared to normal breast specimens (UGT1A10: 68 ± 26 vs. 252 ± 86, respectively; p < 0.05) and (UGT2B7: 1.4 ± 0.7 vs. 12 ± 4, respectively; p < 0.05). Interestingly, in African American women, UGT1A10 expression was significantly decreased in breast carcinomas in comparison to normals (57 ± 35 vs. 397 ± 152, respectively; p < 0.05). Among Caucasian women, UGT2B7 was significantly decreased in breast carcinomas in comparison to normals (1.1 ± 0.5 vs. 13.5 ± 6, respectively; p < 0.05). Glucuronidation of 4-OHE 1 was significantly reduced in breast carcinomas compared to normals (30 ± 15 vs. 106 ± 31, respectively; p < 0.05). Differential downregulation of UGT1A10 and UGT2B7 mRNA, protein, and activity in breast carcinomas compared to the adjacent normal breast specimens from the same donor were also found. These data illustrate the novel finding of UGT1A10 in human breast and confirm the expression of UGT2B7. Significant individual variation and down-regulation of expression in breast carcinomas of both isoforms was also demonstrated. These findings provide evidence that decreased UGT expression and activity could result in the promotion of carcinogenesis.

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“…Although M3G is devoid of analgesic activity, M6G is now thought to play a major role in mediating the analgesic effect of morphine (Osborne et al, 1986;Hanks et al, 1987; Hanks, 1990). When given directly M6G has been demonstrated to have more potent antinociceptive activity than morphine in animals (Shimomura et al, 1971;Pasternak et al, 1987;Abbott & Palmour, 1988;Paul et al, 1989). It is tempting to presume the receptor binding profile of morphine and M6G is similar with M6G purely binding more avidly to the same receptors as morphine.…”

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confidence: 99%

Explanation at the opioid receptor level for differing toxicity of morphine and morphine 6-glucuronide

Hucks

Thompson²,

McLoughlin³

et al. 1992

Br J Cancer

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Summary The radiolabelled opioid receptor binding affinities of morphine and its active metabolite morphine 6-glucuronide at the total mu, mu 1, mu 2 and delta receptors were determined. Morphine 6-glucuronide was found to have a 4-fold lower affinity for the mu 2 receptor (IC50 17 nm and 82 nm for morphine and morphine 6-glucuronide respectively, P = 0.01), the receptor postulated to be responsible for mediating the respiratory depression and gastrointestinal effects after morphine. This provides a possible explanation for the reduced respiratory depression and vomiting seen following morphine 6-glucuronide in man. A similar reduction in affinity of morphine 6-glucuronide was seen at the total mu receptor whilst there was no significant difference seen at the mu or delta receptor. Hence the increased analgesic potency of morphine 6-glucuronide over morphine remains unexplained.Morphine is one of the commonest drugs prescribed by cancer physicians and is an effective potent analgesic. However one or more of the side effects of constipation, nausea and vomiting, and sedation are encountered frequently (Jaffe & Martin, 1991). Respiratory depression is a less common problem but is the most potentially dangerous toxicity. An analgesic with equivalent potency but lower toxicity would therefore be of particular use.The major metabolic products of morphine are morphine 3-glucuronide (M3G) and morphine 6-glucuronide (M6G). Although M3G is devoid of analgesic activity, M6G is now thought to play a major role in mediating the analgesic effect of morphine (Osborne et al., 1986;Hanks et al., 1987;Hoskin & Hanks, 1990 Pasternak, 1981). This model suggests there is a common receptor labelled by either a prototypic delta agonist such as DADLE (D-Ala2, D-Leu5-enkephalin) or with a mu agonist such as morphine which has high affinity for morphine. This they termed the mu 1 receptor. The receptor labelled with a mu agonist which possessed a lower affinity they termed the mu 2 receptor. Similarly the receptor labelled with a delta agonist possessing lower affinity for morphine they termed the true delta receptor.It has been postulated that several of the adverse affects including respiratory depression of morphine are due to activation of the mu 2 or lower affinity mu opioid receptor (Pasternak & Wood, 1986). Using this classification it was therefore hypothesised that M6G has a lower affinity for the mu 2 receptor than morphine at least partially explaining the lower apparent toxicity seen in man. The aim of the current study was

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Morphine-6-glucuronide: Analgesic effects and receptor binding profile in rats

Cited by 183 publications

References 32 publications

Morphine‐6β‐glucuronide has a higher efficacy than morphine as a mu‐opioid receptor agonist in the rat locus coeruleus

Morphine‐6β‐glucuronide has a higher efficacy than morphine as a mu‐opioid receptor agonist in the rat locus coeruleus

Identification of UDP-glucuronosyltransferase 1A10 in non-malignant and malignant human breast tissues

Explanation at the opioid receptor level for differing toxicity of morphine and morphine 6-glucuronide

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