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The Journal of Comparative Neurology May 2012Morphine, codeine, morphine-6-glucuronide, and morphine-3-glucuronide are synthesized de novo in mammalian cells and in the central nervous system. Knowledge on...
Morphine, codeine, morphine-6-glucuronide, and morphine-3-glucuronide are synthesized de novo in mammalian cells and in the central nervous system. Knowledge on endogenous morphine-like compound distribution in the adult mouse brain has been recently improved, and new hypotheses have been suggested about the potential implications in brain physiology. Endogenous morphine-like compounds have been shown to be synthesized in the spinal cord, but their localization is unknown. Here we describe the distribution of endogenous morphine-like compounds (morphine and/or its glucuronides and/or codeine) in the adult mouse spinal cord using a well-validated antibody. By using different microscopy approaches, we found the presence of morphine, codeine, or morphine glucuronides in γ-aminobutyric acid (GABA)-ergic neurons and astrocytes of the spinal cord. Whereas GABAergic neurons containing endogenous morphine-like compounds were located primarily in the ventral horn, astrocytes that were labeled for morphine-like compounds were found throughout the gray matter and the white matter. Our study demonstrates the possibility that endogenous morphine-like compounds in the central nervous system have other functions beyond their analgesic functions.
Topics: Animals; Astrocytes; Codeine; GABAergic Neurons; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Microscopy, Electron, Transmission; Morphine; Morphine Derivatives; Spinal Cord
PubMed: 22102217
DOI: 10.1002/cne.22811 -
Paediatric Anaesthesia Oct 2019While respiratory depression is a known complication of morphine overdose, the neuro-excitatory side effect of the morphine metabolite morphine-3-glucuronide is less...
While respiratory depression is a known complication of morphine overdose, the neuro-excitatory side effect of the morphine metabolite morphine-3-glucuronide is less widely known. Here, we report the case of an infant with neurological excitation after morphine overdose. The neuro-excitation in this infant was probably induced by an elevated morphine-3-glucuronide concentration.
Topics: Analgesics, Opioid; Drug Overdose; Humans; Infant; Male; Morphine; Morphine Derivatives; Respiratory Insufficiency
PubMed: 31433900
DOI: 10.1111/pan.13723 -
Life Sciences Dec 1987The 3- and the 6-glucuronides of morphine have been examined in binding studies and in vivo. The 3-glucuronide had poor affinity in all binding studies whereas the...
The 3- and the 6-glucuronides of morphine have been examined in binding studies and in vivo. The 3-glucuronide had poor affinity in all binding studies whereas the 6-glucuronide potently labeled mu, but not delta or kappa receptors with affinities similar to morphine. Microinjections of the 3-glucuronide directly into the periaqueductal gray were without effect. The 6-glucuronide, on the other hand, was up to 20-fold more potent than morphine following microinjections in the same region. High doses of the 6-glucuronide produced profound seizure activity. All 6-glucuronide actions were sensitive to the opiate antagonist naloxone.
Topics: Animals; Biotransformation; Male; Microinjections; Morphine; Morphine Derivatives; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu
PubMed: 2826951
DOI: 10.1016/0024-3205(87)90431-0 -
Life Sciences 1994The present study tested the hypothesis that morphine glucuronides have stimulant properties by studying their effects on locomotor activity in mice. Drug-naive C57BL/6J...
The present study tested the hypothesis that morphine glucuronides have stimulant properties by studying their effects on locomotor activity in mice. Drug-naive C57BL/6J male mice were injected with saline, morphine, morphine-6-glucuronide (M6G) or morphine-3-glucuronide (M3G). In some experiments, mice were injected with saline or naloxone 5 min prior to drug treatment. Injection of 40 mg/kg morphine or M6G, but not M3G, significantly increased activity versus saline. The extent of activation induced by M6G was markedly higher than for morphine. Subsequent dose-response studies across a somewhat lower dose range using equimolar doses of morphine and M6G (3-80 mumoles/kg) found that both drugs significantly increased locomotor activity beginning at 20 mumoles/kg. M6G increased locomotor activity from 1.3 to 2.1 times more than for equimolar doses of morphine. Pretreatment with naloxone (10 mg/kg) completely abolished the locomotor stimulation induced by 32 mumoles/kg morphine and M6G. These findings present evidence that M6G is an active metabolite of morphine which has behaviorally stimulating effects and may play an important role in mediating the reinforcing properties of morphine in humans.
Topics: Animals; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Morphine; Morphine Derivatives; Motor Activity
PubMed: 8046991
DOI: 10.1016/0024-3205(94)00493-5 -
Biomedical Chromatography : BMC Sep 2014Morphine is one of the most effective agents for the control of significant pain, primarily metabolized to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G)....
Morphine is one of the most effective agents for the control of significant pain, primarily metabolized to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). While M6G is a potent opioid agonist, M3G has no opioid action and seems to have a role in side-effects caused by morphine. In this study, a reversed-phase high-performance liquid chromatographic method with diode-array and electrochemical detection was developed for the simultaneous determination of morphine, M3G and M6G in antemortem and postmortem samples (plasma, whole blood, urine, liver, kidney and brain). Morphine, glucuronides and internal standard were extracted by double solid-phase extraction and the separation was carried out with a Waters Spherisorb® ODS2 reversed-phase column and potassium phosphate buffer (pH = 2.2)–acetonitrile containing sodium dodecyl sulfate as the mobile phase. The method proved to be specific with good linearity for all analytes in a calibration range from 1 to 600 ng/mL and proved to be accurate and have adequate precision and recovery. Limits of detection in the studied matrices were 0.4–4.5 ng/mL for morphine, 2.7–6.1 ng/mL for M3G and 0.8–4.4 ng/mL for M6G. The proposed method can be successfully applied to quantify morphine and its metabolites in several biological samples, covering the major routes of distribution, metabolism and elimination of morphine.
Topics: Chromatography, High Pressure Liquid; Humans; Limit of Detection; Linear Models; Morphine; Morphine Derivatives; Postmortem Changes; Reproducibility of Results; Tissue Distribution
PubMed: 25237710
DOI: 10.1002/bmc.3158 -
British Journal of Clinical Pharmacology Nov 1992The metabolism of morphine was studied in seven fullterm neonates and five infants receiving a continuous infusion of morphine. All the patients had detectable plasma...
The metabolism of morphine was studied in seven fullterm neonates and five infants receiving a continuous infusion of morphine. All the patients had detectable plasma concentrations of morphine 3-glucuronide (M3G) and 10 had detectable concentrations of morphine 6-glucuronide (M6G). The mean plasma clearance of morphine was 20.1 ml min-1 kg-1 in neonates and 23.4 ml min-1 kg-1 in the group as a whole. The M3G/morphine ratio (7.3) was higher than that previously reported for preterm neonates (5.0) but lower than that reported for children (23.9).
Topics: Chromatography, High Pressure Liquid; Humans; Infant; Infant, Newborn; Infant, Premature; Morphine; Morphine Derivatives; Spectrometry, Fluorescence
PubMed: 1467140
DOI: 10.1111/j.1365-2125.1992.tb05652.x -
BMC Palliative Care Oct 2015The feasibility and clinical implication of drug monitoring of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) need further investigation. This... (Observational Study)
Observational Study
BACKGROUND
The feasibility and clinical implication of drug monitoring of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) need further investigation. This study aimed to determine what predicts serum concentrations of morphine in cancer patients receiving continuously intravenous morphine, the relationships between serum concentration of morphine/its metabolites and urinary concentrations, and the relation between morphine concentrations and with clinical outcomes.
METHODS
We collected serum and urine samples from 24 patients with advanced cancer undergoing continuously intravenous morphine therapy. Serum samples were obtained at day one. Spot urine samples were collected once daily on three consecutive days. Pain and adverse drug events were assessed using the Korean version of MD Anderson Symptom Inventory.
RESULTS
A total of 96 samples (72 urine and 24 serum samples) were collected. Median dose of morphine was 82.0 mg/24 h. In a multivariate analysis, total daily morphine dose was the most significant predictors of both serum and urine concentration of morphine. Morphine, M6G, and M3G in serum and urine were statistical significantly correlated (correlation coefficient = 0.81, 0.44, 0.56; p values < 0.01, 0.03, 0.01, respectively).
CONCLUSION
Spot urine concentrations of morphine and its metabolites were highly correlated to those of serum. Total dose of daily morphine was related to both serum and urine concentration of morphine and its metabolites.
Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Republic of Korea
PubMed: 26507979
DOI: 10.1186/s12904-015-0052-9 -
Journal of Chromatography. A Jul 1994An overview of the analysis of opiates by gas chromatography-mass spectrometry (GC-MS) is presented. The review is focused on the hydrolysis, extraction and... (Review)
Review
An overview of the analysis of opiates by gas chromatography-mass spectrometry (GC-MS) is presented. The review is focused on the hydrolysis, extraction and derivatization procedures most widely used for the identification and determination by GC-MS of legal and illegal opiates in various biological fluids.
Topics: Codeine; Gas Chromatography-Mass Spectrometry; Heroin; Humans; Hydrolysis; Morphine; Morphine Derivatives; Narcotics; Specimen Handling
PubMed: 8075772
DOI: 10.1016/0021-9673(94)85227-8 -
Clinical Pharmacology and Therapeutics Sep 1993Morphine-6-glucuronide is a metabolite of morphine that shows significant analgesic effects in animals and humans. To evaluate route-specific differences in the... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Morphine-6-glucuronide is a metabolite of morphine that shows significant analgesic effects in animals and humans. To evaluate route-specific differences in the potential contribution of morphine-6-glucuronide to morphine analgesia, we studied the pharmacokinetics of morphine, morphine-6-glucuronide, and morphine-3-glucuronide after oral and rectal administration of morphine sulfate in a six-subject randomized, single-dose, two-way crossover evaluation. The mean area under the plasma concentration-time curve (AUC) molar ratios of morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) to morphine (M) were greater after oral morphine administration compared with rectal morphine administration (M6G/M ratio, 2.7:1 versus 1.3:1, p = 0.025; M3G/M ratio, 18.3:1 versus 9.3:1, p = 0.002). Systemic bioavailability and peak plasma concentrations of morphine-6-glucuronide and morphine-3-glucuronide were significantly greater after oral morphine administration compared with the rectal route (AUC: M6G, 377.1 +/- 124.2 versus 236.2 +/- 133.7 nmol.hr/L, p = 0.05; M3G, 2610.1 +/- 446.4 versus 1650.2 +/- 309.0 nmol.hr/L, p = 0.004; maximum concentrations: M6G, 110.9 +/- 37.5 versus 64.6 +/- 28.8 nmol/L, p = 0.002; M3G, 576.9 +/- 155.8 versus 266.8 +/- 110.5 nmol/L, p = 0.007). Conversely, the systemic availability of morphine was lower after oral administration, although this difference failed to achieve statistical significance (142.3 +/- 17.1 versus 176.6 +/- 69.4 nmol.hr/L, p = 0.14). These data suggest that rectal administration of morphine is associated with significant avoidance of hepatic biotransformation, and they provide a convincing argument for the evaluation of morphine-6-glucuronide concentrations in pharmacokinetic and pharmacodynamic comparisons involving different routes of morphine administration.
Topics: Administration, Oral; Administration, Rectal; Adult; Biological Availability; Humans; Male; Morphine; Morphine Derivatives
PubMed: 8375123
DOI: 10.1038/clpt.1993.149 -
Archives of Disease in Childhood Jul 1993Morphine pharmacokinetics were studied in 17 premature neonates (26-34 weeks' gestation) after intravenous infusion during the first 24 hours of life. Infants received...
Morphine pharmacokinetics were studied in 17 premature neonates (26-34 weeks' gestation) after intravenous infusion during the first 24 hours of life. Infants received either standard dose morphine that comprised of a 100 micrograms/kg/hour loading infusion for 2 hours followed by a maintenance infusion of 12.5 micrograms/kg/hour, or a high dose of 200 micrograms/kg/hour for 2 hours followed by 50 micrograms/kg/hour. Mean plasma concentrations of morphine (SD) after 2 and 24 hours were 99 (12.9) and 96.4 (3.2) ng/ml, and 184.2 (37.7) and 319 (71.2) ng/ml for the standard and high dose regimens, respectively. Morphine-3-glucuronide plasma concentrations achieved about 20% and 80% of morphine values at 2 and 24 hours respectively. Morphine-6-glucuronide could not be detected at 2 hours, but attained 20-25% of morphine plasma concentrations by 24 hours. The population mean morphine clearance was 2.4 ml/min/kg, the elimination half life was 8.75 hours and the volume of distribution was 1.82 1/kg. High plasma concentrations of morphine appeared to be well tolerated. Although mean arterial blood pressure decreased during the first six hours of treatment, this was not statistically significant; two infants experienced transient muscle rigidity, but no evidence of seizures was noted. There appears to be no clinical advantage in using the high dose regimen.
Topics: Blood Pressure; Drug Administration Schedule; Female; Half-Life; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infusions, Intravenous; Male; Metabolic Clearance Rate; Morphine; Morphine Derivatives; Respiration, Artificial
PubMed: 8346956
DOI: 10.1136/adc.69.1_spec_no.55