Morphine-6-glucuronide: effects on ventilation in normal volunteers

Peat, S.J.; Hanna, Magdi; Woodham, M.; Knibb, Aston; Ponte, J

doi:10.1016/0304-3959(91)90170-3

Cited by 69 publications

(48 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…doses of M6G (1, 3.3, 5.0 mg/70 kg) caused significantly less respiratory depression than morphine (10 mg/70 kg i.v.) and Peat et al, 48 showed that i.v. M6G (0.03 and 0.06 mg/kg) had no detectable effect on respiration when the volunteers were breathing air, whilst morphine (0.12 mg/kg) induced a significant decrease in respiratory response.…”

Section: R E S P I R a T O R Y D E P R E S S I O Nmentioning

confidence: 97%

Morphine‐6‐glucuronide: Actions and mechanisms

Kilpatrick¹,

Smith²

2005

Medicinal Research Reviews

131

View full text Add to dashboard Cite

Morphine-6-glucuronide (M6G) appears to show equivalent analgesia to morphine but to have a superior side-effect profile in terms of reduced liability to induce nausea and vomiting and respiratory depression. The purpose of this review is to examine the evidence behind this statement and to identify the possible reasons that may contribute to the profile of M6G. The vast majority of available data supports the notion that both M6G and morphine mediate their effects by activating the micro-opioid receptor. The differences for which there is a reasonable consensus in the literature can be summarized as: (1) Morphine has a slightly higher affinity for the micro-opioid receptor than M6G, (2) M6G shows a slightly higher efficacy at the micro-opioid receptor, (3) M6G has a lower affinity for the kappa-opioid receptor than morphine, and (4) M6G has a very different absorption, distribution, metabolism, and excretion (ADME) profile from morphine. However, none of these are adequate alone to explain the clinical differences between M6G and morphine. The ADME differences are perhaps most likely to explain some of the differences but seem unlikely to be the whole story. Further work is required to examine further the profile of M6G, notably whether M6G penetrates differentially to areas of the brain involved in pain and those involved in nausea, vomiting, and respiratory control or whether micro-opioid receptors in these brain areas differ in either their regulation or pharmacology.

show abstract

Section: R E S P I R a T O R Y D E P R E S S I O Nmentioning

confidence: 97%

Morphine‐6‐glucuronide: Actions and mechanisms

Kilpatrick¹,

Smith²

2005

Medicinal Research Reviews

131

View full text Add to dashboard Cite

show abstract

“…This is of particular importance since both M3G and M6G are pharmacologically active. M6G is a potent respiratory depres sant [10,16,17] and interacts with opioid receptors in the guinea pig brain stem [18], On the other hand. M3G may antagonize ven tilatory depression induced by M6G [19], The guinea pig also has a hemomonochorial pla centa which has similar permeability charac teristics to the human placenta [20][21][22], In addition, the guinea pig is more neurological ly mature at birth than the rat, mouse, rabbit, cat.…”

Section: Discussionmentioning

confidence: 99%

Chronic Intermittent in utero Exposure to Morphine: Effects on Respiratory Control in the Neonatal Guinea Pig

Hunter¹,

Vangelisti²,

Olsen³

1997

Neonatology

View full text Add to dashboard Cite

This study was done to determine if chronic intermittent in utero exposure to morphine (MOR) during the last half of gestation results in hypoventilation and decreased ventilatory sensitivity to CO₂ in the neonate. Pregnant guinea pigs were randomly assigned to once-daily treatment with saline and 1.5, 5.0, or 15.0mg/kg MOR. Neonates were studied for 3 weeks. Prenatal exposure to 5.0 and 15.0 mg/kg MOR significantly increased neonatal minute ventilation and central inspiratory drive on day 7 while breathing room air or 5% CO₂. The increase in minute ventilation was part of a withdrawal syndrome that included increased locomotor activity, but was not due to an increase in metabolic rate or sensitivity to CO₂. We conclude that neonatal guinea pigs exposed once daily to MOR during the last half of gestation hyperventilate during the 1 st week after birth. These changes are neither permanent nor followed by hypoventilation or depressed sensitivity to CO₂.

show abstract

“…Case reports have implicated M6G in respiratory depression (Osborne et al, 1986) and have reported on the respiratory depressant properties of M6G after cerebroventricular administration to dogs (Pelligrino et al, 1989) and rats (Gong et al, 1991). In one study in humans, M6G was shown to produce fewer respiratory effects than morphine (Peat et al, 1991;Thompson et al, 1995). However, this study was not compatible with the other observations where respiratory depression was observed after intrathecal administration of M6G in human subjects (Grace and Fee, 1996).…”

Section: Discussionmentioning

confidence: 99%

Improved Brain Uptake and Pharmacological Activity Profile of Morphine-6-Glucuronide Using a Peptide Vector-Mediated Strategy

Temsamani¹,

Bonnafous²,

Rousselle³

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Morphine-6-glucuronide (M6G), an active metabolite of morphine, has been shown to have significantly attenuated brain penetration relative to that of morphine. Recently, we have demonstrated that conjugation of various drugs to peptide vectors significantly enhances their brain uptake. In this study, we have conjugated morphine-6-glucuronide to a peptide vector SynB3 to enhance its brain uptake and its analgesic potency after systemic administration. We show by in situ brain perfusion that vectorization of M6G (Syn1001) markedly enhances the brain uptake of M6G. This enhancement results in a significant improvement in the pharmacological activity of M6G in several models of nociception. Syn1001 was about 4 times more potent than free M6G (ED 50 of 1.87 versus 8.74 mol/kg). Syn1001 showed also a prolonged duration of action compared with free M6G (300 and 120 min, respectively). Furthermore, the conjugation of M6G results in a lowered respiratory depression, as measured in a rat model. Taken together, these data strongly support the utility of peptide-mediated strategies for improving the efficacy of drugs such as M6G for the treatment of pain.The main metabolism pathway of morphine includes liver glucuronidation to morphine-6-glucuronide (M6G) and morphine-3-glucuronide. M6G is thought to contribute to the pharmacological effects of the parent drug (Abbott and Palmour, 1988;Paul et al., 1989;Frances et al., 1992), and various clinical trials have used M6G as the therapeutic drug in preference to morphine (Hanna et al., 1990;Thompson et al., 1995;Grace and Fee, 1996;Lötsch et al., 1997;Motamed et al., 2000;Penson et al., 2000). Antinociception studies in experimental animals have demonstrated that, although M6G and morphine are almost equally potent after systemic administration, the analgesic potency of M6G is more than 100-fold higher than morphine after intracerebroventricular injection, a route of administration that bypasses the bloodbrain barrier (BBB) in vivo (Abbott and Palmour, 1988;Paul et al., 1989;Frances et al., 1992). These pharmacological data suggest that the brain penetration of M6G is significantly attenuated relative to that of morphine, probably due to the presence of the glucuronide moiety of M6G, conferring a higher hydrophilic character. Recently, a weak capacity and bidirectional transport by GLUT-1 and by a digoxin-sensitive transporter, which could be oatp2, was reported to be involved in the transport of M6G through the mouse BBB (Bourasset et al., 2003). However, several studies have shown that morphine has a better BBB permeability than M6G after i.v. injection (Bickel et al., 1996;Wu et al., 1997). Thus, enhancing the brain uptake of M6G would be expected to result in an improvement in its analgesic activity.Brain delivery is still one of the major challenges for the pharmaceutical industry since many therapeutic drugs are unable to penetrate the BBB, a complex endothelial interface in vertebrates that separates the blood compartment from the extracellular fluid compartment o...

show abstract

Morphine-6-glucuronide: effects on ventilation in normal volunteers

Cited by 69 publications

References 13 publications

Morphine‐6‐glucuronide: Actions and mechanisms

Morphine‐6‐glucuronide: Actions and mechanisms

Chronic Intermittent in utero Exposure to Morphine: Effects on Respiratory Control in the Neonatal Guinea Pig

Improved Brain Uptake and Pharmacological Activity Profile of Morphine-6-Glucuronide Using a Peptide Vector-Mediated Strategy

Contact Info

Product

Resources

About