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Journal of Neuroscience Research Jan 2022Tolerance and hyperalgesia associated with chronic exposure to morphine are major limitations in the clinical management of chronic pain. At a cellular level, neuronal...
Tolerance and hyperalgesia associated with chronic exposure to morphine are major limitations in the clinical management of chronic pain. At a cellular level, neuronal signaling can in part account for these undesired side effects, but unknown mechanisms mediated by central nervous system glial cells are likely also involved. Here we applied data-independent acquisition mass spectrometry to perform a deep proteome and phosphoproteome analysis of how human astrocytes responds to opioid stimulation. We unveil time- and dose-dependent effects induced by morphine and its major active metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide that converging on activation of mitogen-activated protein kinase and mammalian target of rapamycin signaling pathways. We also find that especially longer exposure to M3G leads to significant dysregulation of biological pathways linked to extracellular matrix organization, antigen presentation, cell adhesion, and glutamate homeostasis, which are crucial for neuron- and leukocyte-astrocyte interactions.
Topics: Astrocytes; Humans; Morphine; Morphine Derivatives; Proteomics
PubMed: 32954564
DOI: 10.1002/jnr.24731 -
Deutsche Medizinische Wochenschrift... Jul 1999A 57-year-old woman with metastasizing ovarian cancer and chronic renal failure was admitted for morphine treatment of an acute lumbospinal pain syndrome, ambulant... (Review)
Review
HISTORY AND ADMISSION FINDINGS
A 57-year-old woman with metastasizing ovarian cancer and chronic renal failure was admitted for morphine treatment of an acute lumbospinal pain syndrome, ambulant treatment with analgesics having failed provide adequate pain relief. On admission due to pain the conscious patient presented with reduced general condition and lumbal pain sensitive to tapping. Lasègue's sign was positive on both sides, no other disturbed neurological functions were found.
TREATMENT AND COURSE
On the 7th day of morphine administration she became somnolent and breathing became markedly depressed, indicating overdosage, metabolic and intracranial causes having been excluded. Naloxone, an opioid antagonist, was given i.v. and the breathing pattern improved. But drowsiness continued for another 48 hours and only regressed after repeated doses of naloxone.
CONCLUSIONS
Morphine-6-glucuronide (M6G), formed from morphine in the liver, accumulates in blood and penetrates the blood-brain barrier, binding with strong affinity to opiate receptors and exerts a strong analgesic effect. As M6G is excreted by the kidney, its concentration rises in renal failure and can lead to severe intoxication. Morphine dosage must therefore be carefully controlled in patients with renal failure.
Topics: Analgesics, Opioid; Diagnosis, Differential; Female; Humans; Kidney Failure, Chronic; Middle Aged; Morphine; Morphine Derivatives; Naloxone; Narcotic Antagonists; Ovarian Neoplasms; Pain, Intractable; Poisoning
PubMed: 10464491
DOI: 10.1055/s-2007-1024449 -
Anesthesia and Analgesia Jul 2007There is great variability in the need for morphine in the postoperative period. We performed a pharmacokinetic-pharmacodynamic study considering the potential effect of... (Comparative Study)
Comparative Study
BACKGROUND
There is great variability in the need for morphine in the postoperative period. We performed a pharmacokinetic-pharmacodynamic study considering the potential effect of the two main metabolites of morphine.
METHODS
Fifty patients with moderate to severe pain received morphine as an IV titration, followed by IM administration postoperatively. The plasma concentration of morphine, morphine-6-glucuronide (M-6-G), morphine-3-glucuronide (M-3-G), and pain intensity were measured at frequent intervals. Pharmacokinetic and pharmacodynamic fitting was performed with the software NONMEM.
RESULTS
The pharmacokinetics were largely predictable. M-6-G and M-3-G clearances were markedly decreased in patients with renal failure. The pharmacodynamics was less predictable, with an important interindividual variability. M-6-G was 7.8 times more potent than morphine, but the average time to peak concentration in the effect compartment after a bolus injection of morphine was 4.25 h for M-6-G, when compared to 0.33 h for morphine. M-3-G showed mild inhibition of the analgesic properties of morphine and of M-6-G. The time to M-3-G peak concentration in the effect compartment after a bolus injection of morphine was 10 h.
CONCLUSIONS
M-6-G is a potent opioid agonist and M-3-G a mild opioid antagonist. Both are poorly excreted in patients with renal failure. However, the metabolism of morphine was rapid when compared to the transfer of metabolites through the blood-brain barrier, which appears to be the limiting process. Because poor analgesia due to M-3-G's effect may occur in some patients after 1 or 2 days, a switch to other molecules should be considered.
Topics: Adult; Aged; Female; Humans; Male; Metabolic Networks and Pathways; Middle Aged; Morphine; Morphine Derivatives; Pain, Postoperative; Postoperative Period
PubMed: 17578959
DOI: 10.1213/01.ane.0000265557.73688.32 -
Life Sciences 1991It was recently confirmed that a metabolite of morphine, morphine-6-glucuronide (M6G), is a long lasting, powerful analgesic in humans and animals and may account for a... (Comparative Study)
Comparative Study
It was recently confirmed that a metabolite of morphine, morphine-6-glucuronide (M6G), is a long lasting, powerful analgesic in humans and animals and may account for a major component of clinical opiate analgesia. It is reported here that M6G is also a powerful behavioral reinforcer in the conditioned place preference test in rats, indicating that it has rewarding properties, and is therefore likely to have abuse potential. The induction of a place preference by M6G is blocked by naltrexone, indicating that the rewarding effect of M6G is mediated by opioid receptors. Given systemically M6G is approximately equipotent with morphine. When given intracerebroventricularly to bypass the blood-brain barrier, M6G is 146 times more potent than morphine in the place preference test. Thus 6-substituted metabolites of opiates may play a more significant role in the effects of opiates than has been previously assumed.
Topics: Animals; Behavior, Animal; Blood-Brain Barrier; Dose-Response Relationship, Drug; Injections, Intravenous; Learning; Morphine; Morphine Derivatives; Narcotics; Rats
PubMed: 2002747
DOI: 10.1016/0024-3205(91)90453-i -
Journal of Analytical Toxicology May 2020The USA and numerous other countries worldwide are currently experiencing a public health crisis due to the abuse of heroin and illicitly manufactured fentanyl. We have...
The USA and numerous other countries worldwide are currently experiencing a public health crisis due to the abuse of heroin and illicitly manufactured fentanyl. We have developed a liquid chromatography tandem mass spectrometry (LC-MS-MS)-based method for the detection of morphine, fentanyl and their metabolites, including morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), normorphine, norfentanyl and deuterated internal standards in limited sample volumes with the limit of detection of 5.0/0.5 ng/mL (morphine, M3G, M6G, normorphine/fentanyl, norfentanyl). The inter-assay precision (%CV) was less than 12% for all assays, and the inter-assay bias (%) was less than 5%. The ruggedness of the method, dilution effect and carryover were also investigated as part of the study. The simultaneous quantification of morphine, fentanyl and its metabolites via this simple and time- and cost-efficient method could be successfully applied to samples taken for pharmacokinetic evaluation (antemortem and postmortem) after a single dose of morphine or co-administration of morphine with other drugs (e.g., fentanyl) in rats.
Topics: Animals; Chromatography, Liquid; Fentanyl; Heroin; Morphine; Morphine Derivatives; Rats; Reproducibility of Results; Substance Abuse Detection; Tandem Mass Spectrometry
PubMed: 31897488
DOI: 10.1093/jat/bkz104 -
Biochemical Pharmacology Oct 1986Isolated rat hepatocytes metabolized morphine to its glucuronide conjugate, morphinone-glutathione conjugate, normorphine and morphinone. Addition of morphine to the...
Isolated rat hepatocytes metabolized morphine to its glucuronide conjugate, morphinone-glutathione conjugate, normorphine and morphinone. Addition of morphine to the isolated hepatocytes induced a marked decrease in the level of glutathione in the cells and resulted in cell death. The formation of glutathione conjugate was correlated well with the loss of intracellular glutathione. The cytotoxicity of morphinone was higher than that of morphine. Naloxone and normorphine showed no cytotoxic effect on the cells. Naloxone inhibited the formation of morphinone-glutathione conjugate and prevented the morphine-induced cytotoxicity. Naloxone also blocked morphine-induced liver damage in vivo. In contrast, the morphinone-induced hepatotoxicity was not prevented by naloxone. It is concluded that morphine has a hepatotoxic effect, that the morphine-induced hepatotoxicity is due to its metabolic activation, and that naloxone acts as an inhibitor of an enzyme converting morphine to morphinone.
Topics: Animals; Cell Survival; Glutathione; Hydromorphone; Isoenzymes; L-Lactate Dehydrogenase; Liver; Male; Morphine; Morphine Derivatives; Naloxone; Perfusion; Rats; Rats, Inbred Strains
PubMed: 2429666
DOI: 10.1016/0006-2952(86)90624-6 -
The American Journal of Forensic... Dec 2000Medical examiners frequently rely on the finding of free morphine present in postmortem specimens to assist in certifying deaths associated with narcotics. In vitro...
Medical examiners frequently rely on the finding of free morphine present in postmortem specimens to assist in certifying deaths associated with narcotics. In vitro hydrolysis of morphine-3-D glucuronide (M3DG) to free morphine was studied using variable specimen pH, initial degree of specimen putrefaction, storage temperature and time, and the effectiveness of sodium fluoride (NaF) preservation. Reagent M3DG was added to opiate-free fresh blood and urine and to autopsy-derived blood specimens. Reagent bovine glucuronidase was also added to certain specimens. Freshly collected and refrigerated NaF-preserved blood produced minimal free morphine, whereas four of five autopsy blood specimens produced free morphine from M3DG. Increased storage time, temperature, and initial degree of putrefaction resulted in greater free morphine generation despite the absence of viable bacteria. Hydrolysis occurring during specimen storage can generate free morphine from M3DG and may result in erroneous conclusions in certifying narcotic deaths.
Topics: Adolescent; Aged; Animals; Bacteria; Cattle; Female; Forensic Medicine; Gas Chromatography-Mass Spectrometry; Glucuronidase; Humans; Hydrogen-Ion Concentration; Hydrolysis; In Vitro Techniques; Indicators and Reagents; Intestines; Male; Middle Aged; Morphine; Morphine Derivatives; Postmortem Changes; Preservatives, Pharmaceutical; Sodium Fluoride; Specimen Handling; Temperature; Time Factors
PubMed: 11111790
DOI: 10.1097/00000433-200012000-00005 -
Physical Chemistry Chemical Physics :... Nov 2023A toll-like receptor 4/myeloid differentiation factor 2 complex (TLR4/MD2) has been identified as a non-classical opioid receptor capable of recognizing morphine isomers...
A toll-like receptor 4/myeloid differentiation factor 2 complex (TLR4/MD2) has been identified as a non-classical opioid receptor capable of recognizing morphine isomers and activating microglia in a non-enantioselective manner. Additionally, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), the major metabolites of morphine, possess similar chemical structures but exhibit distinct effects on TLR4 signaling. However, the specific mechanisms by which morphine isomers and morphine metabolites are recognized by the innate immune receptor TLR4/MD2 are not well understood. Herein, molecular dynamics simulations were performed to dissect the molecular recognition of TLR4/MD2 with morphine isomers, M3G and M6G. Morphine and its (+)-enantiomer, dextro-morphine ((+)-morphine), were found to have comparable binding free energies as well as similar interaction modes when interacting with (TLR4/MD2). Binding with morphine and (+)-morphine caused the motion of the F126 loop towards the inside of the MD2 cavity, which stabilizes (TLR4/MD2) with similar dimerization interfaces. The binding free energies of M3G and M6G with (TLR4/MD2), while lower than those of morphine isomers, were comparable to each other. However, the binding behaviors of M3G and M6G exhibited contrasting patterns when interacting with (TLR4/MD2). The glucuronide group of M3G bound to the gating loop of MD2 and formed strong interactions with TLR4*, which stabilizes the active heterotetrameric complex. In contrast, M6G was situated in cavity A of MD2, where the critical interactions between M6G and the residues of TLR4* were lost, resulting in fluctuation of (TLR4/MD2) away from the active conformation. These results indicate that the pivotal interactions at the dimerization interface between MD2 and TLR4* in M6G-bound (TLR4/MD2) were considerably weaker than those in M3G-bound (TLR4/MD2), which partially explains why M6G fails to activate TLR4 signaling. The discoveries from this study will offer valuable insights for the advancement of next-generation TLR4 small molecule modulators based on opioids.
Topics: Morphine; Toll-Like Receptor 4; Morphine Derivatives; Computer Simulation; Immunity, Innate
PubMed: 37882236
DOI: 10.1039/d3cp03715k -
Annales Pharmaceutiques Francaises Nov 2019In the field of doping, a great interest is carried for the analysis of morphine, a powerful narcotic analgesic opiate which use is prohibited during competitions. In...
In the field of doping, a great interest is carried for the analysis of morphine, a powerful narcotic analgesic opiate which use is prohibited during competitions. In order to confirm the abnormal analytical result in our anti-doping laboratory, a sensitive and selective gas chromatography-mass spectrometry (GC-MS) method was performed for the quantification of urinary morphine. As sample preparation is a key step for the determination of drugs in biological samples, the aim of this work consists of the optimization of the urinary human sample pretreatment conditions before quantification by GC/MS. Enzymatic hydrolysis associated with liquid-liquid extraction constitute the major pre-treatment steps. Our study has first focused on the optimization of the extraction solvents then to enzymatic hydrolysis which morphine is released from its glucuronide conjugated form. Onboard premiums, a study involving the effect of "amount of enzyme", "incubation temperature" and "duration of hydrolysis" was conducted. This univariate study has enabled us to evaluate the influence of each of these operating variables on the area ratio of morphine to the internal standard (A/A) response and to set the experimental fields for each one of them. Based on these results, an experimental design was established using the Box-Behnken model to determine, by multivariate analysis, the optimal operating conditions maximizing the "A/A response. After validation, the analysis of response surface makes it possible to set the optimum operating conditions, which the ratio "A/A is maximized. The retained conditions for enzymatic hydrolysis are 160μl of Escherichia coli glucuronidase enzyme during 6hours of incubation at a temperature of 36°C. The solvent mixture Methyl-t-Butyl Ether/isopropanol (4:1, v/v) was selected since it has improved morphine extraction from the urinary matrix allowing a gain of 50% when compared to that used in our routine laboratory. Our developed extraction method can be successfully applied for our forensic anti-doping analysis of morphin in human sample urine.
Topics: 2-Propanol; Acetamides; Centrifugation; Doping in Sports; Escherichia coli Proteins; Fluoroacetates; Gas Chromatography-Mass Spectrometry; Glucuronidase; Humans; Hydrogen-Ion Concentration; Hydrolysis; Methyl Ethers; Models, Chemical; Morphine; Morphine Derivatives; Solubility; Solvents; Temperature; Trimethylsilyl Compounds; Urinalysis
PubMed: 31564417
DOI: 10.1016/j.pharma.2019.07.004 -
Ugeskrift For Laeger Apr 1997
Topics: Analgesics, Opioid; Denmark; Drug Prescriptions; Humans; Morphine; Morphine Derivatives
PubMed: 9163107
DOI: No ID Found