Antinociceptive and ventilatory effects of the morphine metabolites: morphine-6-glucuronide and morphine-3-glucuronide

Gong, Qiyong; Hedner, Thomas; Hedner, Jan; Björkman, R.; Nordberg, Gunnar F.

doi:10.1016/0014-2999(91)90199-z

Cited by 167 publications

(93 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…M3G has also .The dialysate was been shown to be a potent antagonist of morphine-induced morphine by use of analgesia in rats (Smith et al, 1990 (Gong et al, 1991). Although M3G has been demonstrated to be antagonistic to morphine-or M6G-induced analgesic and ventilatory effect in the rat (Gong et al, 1992), the exact mechanisms of action remain obscure.…”

Section: Discussionmentioning

confidence: 99%

“…M6G appears to be active and more potent than morphine in several systems. Thus, it has been shown to produce analgesia in man (Osborne et al, 1988;Hanna et al, 1990) and in rodent (Shimomura et al, 1971;Yoshimura et al, 1973;Pasternak et al, 1987;Abbott & Palmour et al, 1988;Paul et al, 1989;Sullivan et al, 1989;Gong et al, 1991;1992;Frances et al, 1992). It also possesses a respiratory depressant action in guinea-pigs (Murphey & Olsen, 1994).…”

Section: Introductionmentioning

confidence: 99%

“…It antagonizes the analgesic (Smith et al, 1990) and ventilatory (Gong et al, 1991;1992) effects of morphine as well as of M6G, and appears to have long biological half-life (Ekblom et al, 1993). Because of these observations, it has been suggested that the ratio M6G/M3G in serum and/or CSF may be important in the overall analgesic activity of morphine (Bowsher, 1993).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study

Barjavel

Scherrmann

Bhargava

1995

British J Pharmacology

View full text Add to dashboard Cite

1 The effect of morphine (10 mg kg-', s.c.) on the analgesic response measured by the tail-flick method was determined in male Sprague-Dawley rats. The analgesic response to morphine was correlated with the levels of morphine and its metabolites collected by microdialysis from the cortical extracellular fluid (ECF).2 The analgesic response to morphine lasted for 4 h. The concentration of morphine during a 4 h collection period was significantly higher than the metabolites concentration. The relative concentration of morphine and its metabolites during the 4 h period was 70 and 30% respectively. 3 The analgesic response during the first 2.25 h period accounted for more than 82% of the total analgesia as determined by the area under the time-response curve (AUC). The concentration of morphine and its metabolites during the same period were 78 and 22%, respectively, but they did not differ during the 2.25-4.0 h period (52 and 48%). 4 The half-life for morphine and its metabolites were similar, the maximal achievable concentration Cma, and AUCO4 h were lower for metabolites but the time to reach maximum concentration was higher for morphine metabolites than for morphine. The ratio of the concentration of metabolites to the concentration of morphine in the cortical ECF increased with time whereas the analgesic response to morphine decreased with time. 5 At several time points following morphine injection even though the levels of morphine were the same, the concentration of metabolites (mainly M3G) differed and thus the ratio [metabolite/morphine]. A plot of [metabolite]/[morphine] vs. analgesia gave a high correlation coefficient. Since M3G has been shown to be antianalgesic and is the only metabolite of morphine in the rat, it is concluded that the levels of this metabolite may regulate the analgesic effect of morphine in the rat.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study

Barjavel

Scherrmann

Bhargava

1995

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…M6G binds to y and 6 receptors with apparent affinities similar to those of morphine (Christensen & Jorgensen, 1987;Pasternak et al, 1987;Frances et al, 1990). After administration of M6G into the central nervous system, it has been reported to have a 9 to 650 fold greater analgesic effect than morphine administered via the same route (Pasternak et al, 1987;Abbott & Palmour, 1988;Sullivan et al, 1989;Paul et al, 1989;Gong et al, 1991;Frances et al, 1990;. In contrast, M3G does not bind to any opioid receptor subtype (Pasternak et al, 1987), and is devoid of analgesic activity (Shimomura et al, 1971;Yoshimura et al, 1973;Pasternak et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

“…; Labella et al, 1979). It may antagonize some pharmacological effects of morphine (Smith et al, 1990) and M6G (Gong et al, 1991;.…”

Section: Introductionmentioning

confidence: 99%

Effects of morphine metabolites on micturition in normal, unanaesthetized rats

Igawa

Westerling

Mattiasson

et al. 1993

British J Pharmacology

View full text Add to dashboard Cite

1 By means of continuous cystometry in normal, unanaesthetized rats, the effects on micturition of intrathecally (i.t.) administered morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), the two main metabolites of morphine, were studied and compared with those of i.t. morphine.2 Both M6G (0.01, 0.1, and 0.5 lg) and M3G (5 pg) were found to have significant effects on micturition. Like morphine (0.1, 0.5, and 10pg), M6G was able to inhibit the micturition reflex, and produce urinary retention and dribbling incontinence in a dose-dependent manner. The potency of M6G for inhibiting micturition was approximately 10 times higher than that of morphine, and the duration of its effect was longer. All effects of M6G could be reversed by naloxone.3 M3G (5 jig) facilitated the micturition reflex, resulting in decreases in bladder capacity and micturition volume, and an increase in spontaneous contractile activity. Pretreatment with naloxone (10 fig), which by itself had no effect on micturition, enhanced the facilitatory effects of M3G. In addition, M3G tended to counteract the inhibitory effects of both morphine and M6G on micturition. M3G (5 jg) also produced an excitatory behavioural syndrome. 4 It is concluded that in rats, i.t. M3G has excitatory effects on micturition and behaviour, probably not mediated via opioid receptors. I.t M6G has a potent inhibitory effect on micturition mediated by stimulation of opioid receptors. It may have effects on somatosensory afferent input in lower doses than those required for effects on micturition.

show abstract

Pharmacokinetic and pharmacodynamic study of morphine and morphine 6‐glucuronide after oral and intravenous administration of morphine in children with cancer

Mashayekhi

Ghandforoush-Sattari

Routledge

et al. 2009

Biopharm & Drug Disp

View full text Add to dashboard Cite

The aim of this study was to characterize the pharmacokinetics and pharmacodynamics of morphine and morphine 6-glucuronide (M6G) in children with cancer. Serum concentrations of morphine and M6G in children who received single oral or short term continuous intravenous morphine were determined by HPLC and ELISA assays, respectively. The serum C(max) of morphine and M6G after i.v. morphine administration was 560.5 and 309.0 nM and the T(max) was 61 and 65 min, respectively. The elimination half-life was 140.0 and 328.7 min, respectively. After oral administration of morphine, the serum C(max) of morphine and M6G was 408.34 and 256.3 nM and the T(max) was 40.0 and 60 min, respectively. The half-life was 131.0 and 325.8 min, respectively. The side effects were: drowsiness (100%), nausea and/or vomiting (57%), pruritus (28%) and urinary retention (14%). There were no reports of respiratory complications. This study showed that pharmacokinetics factors of morphine and M6G in children were significantly different from adults. Therefore the required dose for children should be different from that of adults and should be based on studies performed on children rather than on studies on adults. Some adverse effects, particularly nausea and pruritus, may be commoner than is usually thought, while others, particularly respiratory problems did not occur.

show abstract

Antinociceptive and ventilatory effects of the morphine metabolites: morphine-6-glucuronide and morphine-3-glucuronide

Cited by 167 publications

References 33 publications

Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study

Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study

Effects of morphine metabolites on micturition in normal, unanaesthetized rats

Pharmacokinetic and pharmacodynamic study of morphine and morphine 6‐glucuronide after oral and intravenous administration of morphine in children with cancer

Contact Info

Product

Resources

About