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| morphine |
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| CHEBI:17303 |
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| A morphinane alkaloid that is a highly potent opiate analgesic psychoactive drug. Morphine acts directly on the central nervous system (CNS) to relieve pain but has a high potential for addiction, with tolerance and both physical and psychological dependence developing rapidly. Morphine is the most abundant opiate found in Papaver somniferum (the opium poppy). |
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This entity has been manually annotated by the ChEBI Team.
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CHEBI:44202, CHEBI:7001, CHEBI:14622, CHEBI:25419
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| ZINC000001530031 |
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Molfile
XML
SDF
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more structures >>
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36 1 0 0 0 0 21 37 1 0 0 0 0 21 38 1 0 0 0 0 22 39 1 0 0 0 0 22 40 1 0 0 0 0 M END): 18 ms reading 40 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. 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| Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as mevalonate and is of major pharmaceutical importance. Drugs like statins (which lower levels of cholesterol) stop the production of mevalonate by inhibiting HMG-CoA reductase. |
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Read full article at Wikipedia
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InChI=1S/C17H19NO3/c1- 18-7-6-17-10-3-5-13(20)16(17)21-15-12(19)4-2-9(14(15)17)8-11(10)18/h2-5,10-11,13,16,19-20H,6-8H2,1H3/t10-,11+,13-,16-,17-/m0/s1 |
| BQJCRHHNABKAKU-KBQPJGBKSA-N |
| [H][C@]12C=C[C@H](O)[C@@H]3Oc4c(O)ccc5C[C@H]1N(C)CC[C@@]23c45 |
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Papaver somniferum
(NCBI:txid3469)
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See:
PubMed
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environmental contaminant
Any minor or unwanted substance introduced into the environment that can have undesired effects.
Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
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mu-opioid receptor agonist
A compound that exhibits agonist activity at the mu-opioid receptor.
plant metabolite
Any eukaryotic metabolite produced during a metabolic reaction in plants, the kingdom that include flowering plants, conifers and other gymnosperms.
opioid analgesic
A narcotic or opioid substance, synthetic or semisynthetic agent producing profound analgesia, drowsiness, and changes in mood.
xenobiotic
A xenobiotic (Greek, xenos "foreign"; bios "life") is a compound that is foreign to a living organism. Principal xenobiotics include: drugs, carcinogens and various compounds that have been introduced into the environment by artificial means.
drug allergen
Any drug which causes the onset of an allergic reaction.
metabolite
Any intermediate or product resulting from metabolism. The term 'metabolite' subsumes the classes commonly known as primary and secondary metabolites.
(via alkaloid )
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mu-opioid receptor agonist
A compound that exhibits agonist activity at the mu-opioid receptor.
vasodilator agent
A drug used to cause dilation of the blood vessels.
anaesthetic
Substance which produces loss of feeling or sensation.
opioid analgesic
A narcotic or opioid substance, synthetic or semisynthetic agent producing profound analgesia, drowsiness, and changes in mood.
drug allergen
Any drug which causes the onset of an allergic reaction.
geroprotector
Any compound that supports healthy aging, slows the biological aging process, or extends lifespan.
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View more via ChEBI Ontology
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17-methyl-7,8-didehydro-4,5α-epoxymorphinan-3,6α-diol
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(−)-morphine
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ChemIDplus
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(5α,6α)-17-methyl-7,8-didehydro-4,5-epoxymorphinan-3,6-diol
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ChEBI
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(5α,6α)-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol
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NIST Chemistry WebBook
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(5R,6S,9R,13S,14R)-4,5-epoxy-N-methyl-7-morphinen-3,6-diol
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ChemIDplus
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(7R,7AS,12BS)-3-METHYL-2,3,4,4A,7,7A-HEXAHYDRO-1H-4,12-METHANO[1]BENZOFURO[3,2-E]ISOQUINOLINE-7,9-DIOL
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PDBeChem
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morfina
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ChEBI
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Morphia
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ChemIDplus
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Morphin
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ChemIDplus
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Morphine
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KEGG COMPOUND
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morphinum
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ChemIDplus
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morphium
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ChemIDplus
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1845
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DrugCentral
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1Q0Y
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PDB
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2982
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VSDB
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C00001889
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KNApSAcK
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C01516
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KEGG COMPOUND
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D08233
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KEGG DRUG
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DB00295
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DrugBank
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MOI
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PDBeChem
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Morphine
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Wikipedia
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MORPHINE
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MetaCyc
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| View more database links |
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57-27-2
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CAS Registry Number
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ChemIDplus
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57-27-2
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CAS Registry Number
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NIST Chemistry WebBook
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93704
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Reaxys Registry Number
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Reaxys
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Rose MA, Anderson J, Green SL, Yun J, Fernando SL (2018)
Morphine and pholcodine-specific IgE have limited utility in the diagnosis of anaphylaxis to benzylisoquinolines.
Acta anaesthesiologica Scandinavica 62, 628-634 [PubMed:29368335]
[show Abstract]
BackgroundInvestigation of immediate hypersensitivity reactions in the perioperative setting involves skin testing and measurement of specific IgE (sIgE) as standard practice. In the case of the neuromuscular blocking agents (NMBAs), the main allergenic epitopes have been shown to be substituted ammonium groups. Commercial assays are available for detection of sIgE to these epitopes using morphine and pholcodine substrates but questions have been raised about the effectiveness of these assays in the diagnosis of benzylisoquinoline anaphylaxis. This study was therefore undertaken to assess the effectiveness of these assays in the diagnosis of hypersensitivity reactions to this group of NMBAs.MethodsAnalysis was carried out on all available results for patients assessed at the Royal North Shore Hospital Anaesthetic Allergy Clinic during the period June 2009 to June 2016. Standardised intradermal skin tests were performed with a panel of NMBAs. Measurement of sIgE to morphine and pholcodine was performed via the Phadia ImmunoCAP® system.ResultsFor all patients with positive skin test results to NMBAs which included a benzylisoquinoline NMBA (n = 24), 75% exhibited negative sIgE to both morphine and pholcodine. Where patients were reactive to benzylisoquinoline NMBAs alone (n = 12), 100% exhibited negative sIgE results, indicating 0% sensitivity of the assays relative to skin testing, in this subgroup.ConclusionUse of sIgE testing to morphine and pholcodine in the assessment of NMBA immediate hypersensitivity is a valuable tool particularly in the case of reactions to the aminosteroid NMBAs. However, these assays are unreliable in detecting sensitisation to benzylisoquinoline NMBAs. | Oosten AW, Abrantes JA, Jönsson S, Matic M, van Schaik RHN, de Bruijn P, van der Rijt CCD, Mathijssen RHJ (2017)
A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients.
Clinical pharmacokinetics 56, 733-746 [PubMed:27815868]
[show Abstract]
BackgroundOral and subcutaneous morphine is widely used for the treatment of cancer-related pain; however, solid pharmacokinetic data on this practice are lacking. Furthermore, it is largely unknown which factors contribute to the variability in clearances of morphine and its metabolites and whether morphine clearance is related to treatment outcome.MethodsBlood samples from 49 cancer patients treated with oral and/or subcutaneous morphine were prospectively collected and were used to develop a population pharmacokinetic model for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The influence of age, gender, renal function and several polymorphisms possibly related to the pharmacokinetics of the three compounds was investigated. In addition, the relation between treatment failure and morphine and metabolite clearances was explored.ResultsA one-compartment model including an extensive first-pass effect adequately described the data of morphine and its metabolites. Estimated mean area under the plasma concentration-time curve (AUC) ratios following oral versus subcutaneous administration were: M3G/morphine 29.7:1 vs. 11.1:1; M6G/morphine 5.26:1 vs. 1.95:1; and M3G/M6G 5.65:1 vs. 5.70:1. Renal function was significantly correlated with clearance of the metabolites, which increased 0.602 L/h per every 10 mL/min/1.73 m2 increase of estimated glomerular filtration rate (eGFR), reaching a plateau for eGFR >90 mL/min/1.73 m2. The clearance of morphine or its metabolites was not found to be correlated with treatment failure.ConclusionThe influence of age-, gender- and pharmacokinetic-related polymorphisms was not identified on the pharmacokinetics of morphine. Clearance of morphine or its metabolites was not found to explain treatment outcome; however, large variations in plasma concentrations of morphine, M3G and M6G support further studies on the relation between plasma concentrations and treatment outcome. Dutch Trial Register ID: NTR4369. | Ma Y, Ren Z, Ma S, Yan W, He M, Wang D, Ding P (2017)
Morphine enhances renal cell carcinoma aggressiveness through promotes survivin level.
Renal failure 39, 258-264 [PubMed:27866460]
[show Abstract]
BackgroundMorphine is an opioid analgesic drug often used for pain relief in cancer patients. However, there is growing evidence that morphine may modulate tumor growth, progression and metastasis. Unfortunately, the results obtained by these studies are still contradictory.MethodsIn this study, we investigated the effect of morphine in human clear cell renal cell carcinoma 786-O, RLC-310 cells and whether morphine affects on tumor growth in human clear cell renal cell carcinoma 786-O, RLC-310 cells. The cell proliferation was determined by MTT assay, cell proliferation, migration and invasion assays. Immunofluorescence staining and Q-PCR was used to determine the Survivin expression.ResultsIt was shown that morphine enhances proliferation of 786-O, RLC-310 cells, whereas morphine promoted the growth and aggressive phenotype of 786-O and RLC-310 cells in vitro though Survivin-dependent signaling.ConclusionsOur data showed that morphine promotes RCC growth and increases RCC progression via over-expression of Survivin. | Chu S, Münster N, Balan T, Smith MD (2016)
A Cascade Strategy Enables a Total Synthesis of (±)-Morphine.
Angewandte Chemie (International ed. in English) 55, 14306-14309 [PubMed:27735107]
[show Abstract]
Morphine has been a target for synthetic chemists since Robinson proposed its correct structure in 1925, resulting in a large number of total syntheses of morphine alkaloids. Here we report a total synthesis of (±)-morphine that employs two key strategic cyclizations: 1) a diastereoselective light-mediated cyclization of an O-arylated butyrolactone to form a tricyclic cis-fused benzofuran and 2) a cascade ene-yne-ene ring closing metathesis to forge the tetracyclic morphine core. This approach enables a short and stereoselective synthesis of morphine in an overall yield of 6.6 %. | García-Pérez D, López-Bellido R, Hidalgo JM, Rodríguez RE, Laorden ML, Núñez C, Milanés MV (2015)
Morphine regulates Argonaute 2 and TH expression and activity but not miR-133b in midbrain dopaminergic neurons.
Addiction biology 20, 104-119 [PubMed:23927484]
[show Abstract]
Epigenetic changes such as microRNAs (miRs)/Ago2-induced gene silencing represent complex molecular signature that regulate cellular plasticity. Recent studies showed involvement of miRs and Ago2 in drug addiction. In this study, we show that changes in gene expression induced by morphine and morphine withdrawal occur with concomitant epigenetic modifications in the mesolimbic dopaminergic (DA) pathway [ventral tegmental area (VTA)/nucleus accumbens (NAc) shell], which is critically involved in drug-induced dependence. We found that acute or chronic morphine administration as well as morphine withdrawal did not modify miR-133b messenger RNA (mRNA) expression in the VTA, whereas Ago2 protein levels were decreased and increased in morphine-dependent rats and after morphine withdrawal, respectively. These changes were paralleled with enhanced and decreased NAc tyrosine hydroxylase (TH) protein (an early DA marker) in morphine-dependent rats and after withdrawal, respectively. We also observed changes in TH mRNA expression in the VTA that could be related to Ago2-induced translational repression of TH mRNA during morphine withdrawal. However, the VTA number of TH-positive neurons suffered no alterations after the different treatment. Acute morphine administration produced a marked increase in TH activity and DA turnover in the NAc (shell). In contrast, precipitated morphine withdrawal decreased TH activation and did not change DA turnover. These findings provide new information into the possible correlation between Ago2/miRs complex regulation and DA neurons plasticity during opiate addiction. | Chaturvedi N, Singh M, Shukla AK, Shasany AK, Shanker K, Lal RK, Khanuja SP (2014)
Comparative analysis of Papaver somniferum genotypes having contrasting latex and alkaloid profiles.
Protoplasma 251, 857-867 [PubMed:24306419]
[show Abstract]
Papaver somniferum produces therapeutically useful benzylisoquinoline alkaloids (BIAs) like papaverine, thebaine, codeine, and morphine that accumulate in its capsular latex. Morphine is a potent analgesic but is also abused as a narcotic, which has increased the demand for non-narcotic thebaine that can be converted into various analgesics. To curtail the narcotic menace, many distinct genotypes of the plant have been developed that are deficient in morphine and/or latex. Sujata is one such latex-less low alkaloid-producing variety developed from the alkaloid-rich gum harvest variety Sampada. Its utility for gene prospecting and studying differential gene regulation responsible for its low alkaloid, nutritive seed oil, and latex-less phenotype has been exploited in this study. BIA profiling of Sujata and Sampada capsules at the early and late stages indicated that except for thebaine, Sujata had a depressed alkaloid phenotype as compared to Sampada. Comparative transcript-based analysis of the two genotypes was carried out in the early stage capsule (higher thebaine) using subtractive hybridization and microarray. Interrogation of a P. somniferum array yielded many differentially expressing transcripts. Their homology-based annotation classified them into categories--latex related, oil/lipid related, alkaloid related, cell wall related, and others. These leads will be useful to characterize the highly sought after Sujata phenotype. | Koek W (2014)
Effects of repeated exposure to morphine in adolescent and adult male C57BL/6J mice: age-dependent differences in locomotor stimulation, sensitization, and body weight loss.
Psychopharmacology 231, 1517-1529 [PubMed:24096538]
[show Abstract]
RationaleGiven evidence for age-related differences in the effects of drugs of abuse, surprisingly few preclinical studies have explored effects of opioids in adolescents (versus adults).ObjectivesThis study compared the motor stimulating and ataxic effects of repeatedly administered morphine in adolescent, late adolescent, and adult mice.MethodsMice were treated with saline or morphine (10-100 mg/kg, i.p.) once per day for 4 days, and morphine (3.2-56 mg/kg)-induced locomotion was assessed 3 days or 5 weeks later. Different mice were treated repeatedly with morphine and ataxia was measured.ResultsAcute administration of morphine increased locomotion more in adolescents than in adults. Repeated morphine enhanced morphine-induced locomotion, assessed 3 days later, to a similar extent in each age group (minimum effective dose 17.8 mg/kg). This sensitization was still evident 5 weeks later when the adolescents had become adult, but was smaller and occurred at a higher dose (56 mg/kg). In animals treated repeatedly with morphine as adults, sensitization was no longer apparent 5 weeks later. Intermittent morphine was at least 10-fold less potent to produce body weight loss in adolescents than in adults. Repeated morphine did not alter morphine-induced ataxia at any age.ConclusionsCompared with adults, adolescents were more sensitive to the acute locomotor stimulating effects of morphine and to its long-lasting locomotor sensitizing effects, consistent with overactivity of dopamine systems during adolescence. In contrast, adolescents were less sensitive than adults to body weight loss induced by intermittent morphine, an effect indicative of morphine withdrawal in adult rodents. | Fakurazi S, Rahman SA, Hidayat MT, Ithnin H, Moklas MA, Arulselvan P (2013)
The combination of mitragynine and morphine prevents the development of morphine tolerance in mice.
Molecules (Basel, Switzerland) 18, 666-681 [PubMed:23292329]
[show Abstract]
Mitragynine (MG) is the major active alkaloid found in Mitragyna speciosa Korth. In the present study, we investigated the enhancement of analgesic action of MG when combined with morphine and the effect of the combination on the development of tolerance towards morphine. Mice were administered intraperitoneally with a dose of MG (15 and 25 mg/kg b.wt) combined with morphine (5 mg/kg b.wt) respectively for 9 days. The antinociceptive effect was evaluated by a hot plate test. The protein expression of cyclic adenosine monophosphate (cAMP) and cAMP response element binding (CREB) was analyzed by immunoblot. Toxicological parameters especially liver and kidney function tests were assessed after the combination treatment with MG and morphine. The concurrent administration of MG and morphine showed significant (p < 0.05) increase in latency time when compared to morphine alone group and the outstanding analgesic effects in the combination regimens were maintained until day 9. For the protein expression, there was a significant increment of cAMP and CREB levels (p < 0.05) in group treated with 5 mg/kg morphine but there was no significant change of these protein expressions when MG was combined with morphine. There was a significant changes in toxicological parameters of various treated groups. The combination treatment of MG and morphine effectively reduce the tolerance due to the chronic administration of morphine. | Togna AR, Antonilli L, Dovizio M, Salemme A, De Carolis L, Togna GI, Patrignani P, Nencini P (2013)
In vitro morphine metabolism by rat microglia.
Neuropharmacology 75, 391-398 [PubMed:23988259]
[show Abstract]
Morphine is mainly transformed to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in the liver. Glucuronidation is also performed by rat brain homogenates and UDP-glucuronosyltransferases (UGTs) are present in the brain. Here we investigated the possibility that microglia transforms morphine into its metabolites M3G and M6G. Primary cultures of neonatal rat microglia were incubated for different intervals of time in basal conditions or with different concentrations of morphine. The following measures were performed on these cultures and/or in the medium: (i) morphine as well as M3G and M6G concentrations; (ii) levels of mRNA coding for UGT1A1, UGT1A6, UGT1A7, and UGT2B1 as well as their protein levels; (iii) released prostaglandin (PG)E2 and nitrite concentrations. Results show that in basal conditions morphine and M3G are produced by microglia; accordingly, these cells expressed UGT1A1, UGT1A6 and UGT1A7, but not UGT2B1. When cultures were exposed to different concentrations of exogenous morphine, M6G was also synthesized. This shift in the glucuronidation was associated with variations in the expression of UGT isozymes. In particular, UGT1A7 expression was rapidly upregulated and this event was translated into enhanced protein levels of UGT1A7; lesser effects were exerted on UGT1A1 and UGT1A6. Upon prolonged exposure to morphine, microglial cell UGT expression returned to baseline conditions or even to reduced levels of expression. Morphine exposure did not affect the synthesis of both PGE2 and nitrites, ruling out a generalized priming of microglia by morphine. In conclusion, this study suggests that morphine glucuronides found in the cerebrospinal liquor upon peripheral morphine administration may at least in part be brain-born, reconciling the conceptual gap between the high hydrophilic features of morphine glucuronides and their presence beyond the blood-brain barrier. | Lan X, Rai P, Chandel N, Cheng K, Lederman R, Saleem MA, Mathieson PW, Husain M, Crosson JT, Gupta K, Malhotra A, Singhal PC (2013)
Morphine induces albuminuria by compromising podocyte integrity.
PloS one 8, e55748 [PubMed:23555556]
[show Abstract]
Morphine has been reported to accelerate the progression of chronic kidney disease. However, whether morphine affects slit diaphragm (SD), the major constituent of glomerular filtration barrier, is still unclear. In the present study, we examined the effect of morphine on glomerular filtration barrier in general and podocyte integrity in particular. Mice were administered either normal saline or morphine for 72 h, then urine samples were collected and kidneys were subsequently isolated for immunohistochemical studies and Western blot. For in vitro studies, human podocytes were treated with morphine and then probed for the molecular markers of slit diaphragm. Morphine-receiving mice displayed a significant increase in albuminuria and showed effacement of podocyte foot processes. In both in vivo and in vitro studies, the expression of synaptopodin, a molecular marker for podocyte integrity, and the slit diaphragm constituting molecules (SDCM), such as nephrin, podocin, and CD2-associated protein (CD2AP), were decreased in morphine-treated podocytes. In vitro studies indicated that morphine modulated podocyte expression of SDCM through opiate mu (MOR) and kappa (KOR) receptors. Since morphine also enhanced podocyte oxidative stress, the latter seems to contribute to decreased SDCM expression. In addition, AKT, p38, and JNK pathways were involved in morphine-induced down regulation of SDCM in human podocytes. These findings demonstrate that morphine has the potential to alter the glomerular filtration barrier by compromising the integrity of podocytes. | Schwarz JM, Bilbo SD (2013)
Adolescent morphine exposure affects long-term microglial function and later-life relapse liability in a model of addiction.
The Journal of neuroscience : the official journal of the Society for Neuroscience 33, 961-971 [PubMed:23325235]
[show Abstract]
Adolescence in humans represents a unique developmental time point associated with increased risk-taking behavior and experimentation with drugs of abuse. We hypothesized that exposure to drugs of abuse during adolescence may increase the risk of addiction in adulthood. To test this, rats were treated with a subchronic regimen of morphine or saline in adolescence, and their preference for morphine was examined using conditioned place preference (CPP) and drug-induced reinstatement in adulthood. The initial preference for morphine did not differ between groups; however, rats treated with morphine during adolescence showed robust reinstatement of morphine CPP after drug re-exposure in adulthood. This effect was not seen in rats pretreated with a subchronic regimen of morphine as adults, suggesting that exposure to morphine specifically during adolescence increases the risk of relapse to drug-seeking behavior in adulthood. We have previously established a role for microglia, the immune cells of the brain, and immune molecules in the risk of drug-induced reinstatement of morphine CPP. Thus, we examined the role of microglia within the nucleus accumbens of these rats and determined that rats exposed to morphine during adolescence had a significant increase in Toll-like receptor 4 (TLR4) mRNA and protein expression specifically on microglia. Morphine binds to TLR4 directly, and this increase in TLR4 was associated with exaggerated morphine-induced TLR4 signaling and microglial activation in rats previously exposed to morphine during adolescence. These data suggest that long-term changes in microglial function, caused by adolescent morphine exposure, alter the risk of drug-induced reinstatement in adulthood. | Dubiley TA, Rushkevich YE, Koshel NM, Voitenko VP, Vaiserman AM (2011)
Life span extension in Drosophila melanogaster induced by morphine.
Biogerontology 12, 179-184 [PubMed:21061062]
[show Abstract]
The influence of morphine on the life span of Drosophila melanogaster fruit flies has been investigated. Morphine hydrochloride (MH) at concentrations of 0.01, 0.05 and 0.25 mg/ml was added to a medium starting from day 5 or 54 of imaginal life. Supplementation with MH starting from day 5 of imaginal life has resulted in significant increases in the mean life span of males at all concentrations studied. In females, a significant increase in life span compared with control was obtained only for those treated with 0.25 mg/ml MH. In flies with MH feeding from day 54, residual life span was significantly increased in both males and females after treatment with 0.05 mg/ml MH. The present data, together with those of our earlier study in mice (Dubiley et al. Probl Aging Longvity 9:331–332, 2000) suggest that morphine supplementation can result in life extension in both vertebrate and invertebrate animal species. | Abildskov K, Weldy P, Garland M (2010)
Molecular cloning of the baboon UDP-glucuronosyltransferase 2B gene family and their activity in conjugating morphine.
Drug metabolism and disposition: the biological fate of chemicals 38, 545-553 [PubMed:20071451]
[show Abstract]
Glucuronidation by UDP-glucuronyltransferase 2B enzymes (UGT2Bs) is a major pathway for the elimination of endobiotics and xenobiotics, including therapeutic drugs. Morphine, a probe drug for UGT2B7, is metabolized to morphine-3-beta-glucuronide (M3G) and morphine-6-beta-glucuronide (M6G) in humans. Morphine has been used in a series of experiments in the baboon to characterize developmental changes in fetal glucuronidation. This study identifies the baboon UGT2B family of enzymes, compares them with that of the human and the monkey (Macaca fascicularis), and measures the activity of the individual baboon UGT2Bs toward morphine. UGT2B cDNAs were cloned from the liver of adult and newborn baboons and expressed in human embryonic kidney 293 cells. The UGT activity toward morphine was assessed by the rate of formation of M3G and M6G by high-performance liquid chromatography. Eight baboon UGT2Bs were cloned and identified: UGT2B41 and UGT2B42, which are 90% homologous to human UGT2B4; UGT2B43, which is 93% homologous to human UGT2B15; and UGT2B39, UGT2B40, UGT2B44, UGT2B45, and UGT2B46, which are 89 to 91% homologous to human UGT2B7. Homology between baboon and monkey UGT2B ranged from 92.6 to 99.1%, with the primary protein structure of UGT2B43 being 99.1% identical to monkey UGT2B20, including a unique R96I substitution. Gene conversion interfered with the phylogenetic signal in the baboon UGT2B7-like and the monkey UGT2B4-like groups and led to concerted evolution of these enzymes. All of the baboon UGT2Bs metabolized morphine to both M3G and M6G. This study lays the foundation for investigating the regulation of UGT2B enzymes during fetal and neonatal development in the baboon. | Afshari R, Maxwell SR, Webb DJ, Bateman DN (2009)
Morphine is an arteriolar vasodilator in man.
British journal of clinical pharmacology 67, 386-393 [PubMed:19371311]
[show Abstract]
AimThe mechanisms of action of morphine on the arterial system are not well understood. The aim was to report forearm vascular responses, and their mediation, to intra-arterial morphine in healthy subjects.MethodsThree separate protocols were performed: (i) dose ranging; (ii) acute tolerance; (iii) randomized crossover mechanistic study on forearm blood flow (FBF) responses to intrabrachial infusion of morphine using venous occlusion plethysmography. Morphine was infused either alone (study 1 and 2), or with an antagonist: naloxone, combined histamine-1 and histamine-2 receptor blockade or during a nitric oxide clamp.ResultsMorphine caused an increase in FBF at doses of 30 microg min(-1)[3.25 (0.26) ml min(-1) 100 ml(-1)][mean (SEM)] doubling at 100 microg min(-1) to 5.23 (0.53) ml min(-1) 100 ml(-1). Acute tolerance was not seen to 50 microg min(-1) morphine, with increased FBF [3.96 (0.35) ml min(-1) 100 ml(-1)] (P = 0.003), throughout the 30-min infusion period. Vasodilatation was abolished by pretreatment with antihistamines (P = 0.008) and the nitric oxide clamp (P < 0.001), but not affected by naloxone. The maximum FBF with pretreatment with combined H1/H2 blockade was 3.06 (0.48) and 2.90 (0.17) ml min(-1) 100 ml(-1) after 30 min, whereas with morphine alone it reached 4.3 (0.89) ml min(-1) 100 ml(-1).ConclusionsIntra-arterial infusion of morphine into the forearm circulation causes vasodilatation through local histamine-modulated nitric oxide release. Opioid receptor mechanisms need further exploration. | Ebo DG, Venemalm L, Bridts CH, Degerbeck F, Hagberg H, De Clerck LS, Stevens WJ (2007)
Immunoglobulin E antibodies to rocuronium: a new diagnostic tool.
Anesthesiology 107, 253-259 [PubMed:17667569]
[show Abstract]
BackgroundDiagnosis of allergy from neuromuscular blocking agents is not always straightforward. The objectives of the current study were to investigate the value of quantification of immunoglobulin E (IgE) by ImmunoCAP (Phadia AB, Uppsala, Sweden) in the diagnosis of rocuronium allergy and to study whether IgE inhibition tests can predict clinical cross-reactivity between neuromuscular blocking agents.MethodsTwenty-five rocuronium-allergic patients and 30 control individuals exposed to rocuronium during uneventful anesthesia were included. Thirty-two sera (total IgE > 1,500 kU/l) were analyzed for potential interference of elevated total IgE titers. Results were compared with quantification of IgE for suxamethonium, morphine, and pholcodine. Cross-reactivity between drugs was assessed by IgE inhibition and skin tests.ResultsSensitivity of IgE for rocuronium, suxamethonium, morphine, and pholcodine was 68, 60, 88, and 86%, respectively. Specificity was 100% for suxamethonium, morphine, and pholcodine IgE and 93% for rocuronium IgE. ROC analysis between patients and control individuals changed the threshold to 0.13 kUa/l for rocuronium, 0.11 kUa/l for suxamethonium, 0.36 kUa/l for morphine, and 0.43 kUa/l for pholcodine. Corresponding sensitivity was 92, 72, 88, and 86%, respectively. Specificity was unaltered. Interference of elevated total IgE with quantification of IgE was demonstrated by the analysis in sera with a total IgE greater than 1,500 kU/l. IgE inhibition did not predict clinical relevant cross-reactivity.ConclusionsThe rocuronium ImmunoCAP constitutes a reliable technique to diagnose rocuronium allergy, provided an assay-specific decision threshold is applied. IgE assays based on compounds bearing ammonium epitopes are confirmed to represent reliable tools to diagnose rocuronium allergy. High total IgE titers were observed to affect specificity of the assays. | Pozharski E, Wilson MA, Hewagama A, Shanafelt AB, Petsko G, Ringe D (2004)
Anchoring a cationic ligand: the structure of the Fab fragment of the anti-morphine antibody 9B1 and its complex with morphine.
Journal of molecular biology 337, 691-697 [PubMed:15019787]
[show Abstract]
The crystal structures of an anti-morphine antibody 9B1 (to 1.6A resolution) and its complex with morphine (to 2.0 A resolution) are reported. The morphine-binding site is described as a shallow depression on the protein surface, an unusual topology for a high-affinity ( Ka approximately 10(9) M(-1)) antibody against a small antigen. The polar part of the ligand is exposed to solvent, and the cationic nitrogen atom of the morphine molecule is anchored at the bottom of the binding site by a salt-bridge to a glutamate side-chain. Additional affinity is provided by a double cation-pi interaction with two tryptophan residues. Comparison of the morphine complex with the structure of the free Fab shows that a domain closure occurs upon binding of the ligand. | Jairaj M, Watson DG, Grant MH, Gray AI, Skellern GG (2002)
Comparative biotransformation of morphine, codeine and pholcodine in rat hepatocytes: identification of a novel metabolite of pholcodine.
Xenobiotica; the fate of foreign compounds in biological systems 32, 1093-1107 [PubMed:12593758]
[show Abstract]
1. Pholcodine (3-morpholinoethylmorphine), a semi-synthetic alkaloid, is widely used as an antitussive agent. 2. Norpholcodine [7,8-didehydro-4,5alpha-epoxy-3-(2-morpholinoethoxy)morphinan-6alpha-ol] (NP) and pholcodine-N-oxide [1(9a)-dehydro-(4aR,5S,7aR,9cS,12S)-4a,5,7a,8,9,9a-hexahydro-5-hydroxy-12-methyl-3-morpholinoethoxy-1H-8,9,c-(iminoethano)phenanthro[4,5-bcd] furan-12-oxide] (PNOX) were identified in incubations of pholcodine with freshly isolated rat hepatocytes by liquid chromatography/electrospray-mass spectrometry (LC/ESI-MS). 3. Synthesized NP and PNOX were characterized by mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. 4. N-oxidation was the major metabolic pathway for pholcodine, producing a previously unreported metabolite. 5. The metabolism of morphine and codeine was also determined using freshly isolated hepatocytes. 6. For morphine, 3-glucuronidation was the major metabolic pathway, whilst for codeine it was dealkylation (O- and N-). 7. Neither morphine nor its metabolites were metabolites of pholcodine. 8. This observation supports the hypothesis that the absence of analgesic activity with pholcodine may be due to less O-dealkylation in vivo. 9. Together with the slow biotransformation of pholcodine (k(met) = 0.021 microM min(-1)) in comparison with morphine (k(met) = 0.057 microM min(-1)) and codeine (k(met) = 0.112 microM min(-1)), the results obtained were consistent with its low addiction potential and suggest that its antitussive efficacy is mediated by the parent drug or one of its metabolites other than morphine. | Tempe DK, Joshi N, Mehta N, Khanna SK, Banerjee A, Tyagi S (1997)
Anaesthetic management of patients undergoing surgery for tachyarrhythmias. Initial experience with 16 patients.
Indian heart journal 49, 173-178 [PubMed:9231550]
[show Abstract]
Sixteen patients suffering from various cardiac arrhythmias were treated surgically. Intraoperative computerised electrophysiologic mapping was used in 14. Thirteen patients were suffering from Wolff-Parkinson-White syndrome. They underwent surgical division or cryoablation of accessory pathways. Two patients who had rheumatic mitral stenosis with left atrial clot underwent "Maze III" procedure with open mitral commissurotomy and clot removal. One patient with paroxysmal refractory ventricular tachycardia and a left ventricular aneurysm had an aneurysmectomy with subendocardial resection of the arrhythmic focus. All antiarrhythmic medications were discontinued preoperatively. Morphine was the principal anaesthetic agent, supplemented with halothane. Muscle relaxation was provided with pancuronium bromide. The various problems encountered included hypotension and arrhythmia during placement of epicardial band array for mapping (4 patients), ventricular tachycardia during internal jugular vein cannulation (1 patient) and continuance of delta wave after cryoablation in 2 patients. Halothane may have interfered with electrophysiologic mapping and accurate localization of accessory pathway leading to persistence of delta wave. The choice of anaesthetic agents should be guided by the electrophysiologic effects and potential influence of these agents on the accessory pathways. | Benthuysen JL, Foltz BD, Smith NT, Sanford TJ, Dec-Silver H, Westover CJ (1988)
Prebypass hemodynamic stability of sufentanil-O2, fentanyl-O2, and morphine-O2 anesthesia during cardiac surgery: a comparison of cardiovascular profiles.
Journal of cardiothoracic anesthesia 2, 749-757 [PubMed:17171884]
[show Abstract]
Cardiovascular responses and the need for intervention with vasoactive agents were measured prospectively in a randomized study of 50 adult patients receiving sufentanil (n = 20), fentanyl (n = 20), or morphine (n = 10) anesthesia for cardiac surgery. Measurements were recorded and compared during induction and prebypass at intervals during which airway or surgically induced stress responses were likely to be greatest. Randomized, double-blinded doses of opioids were administered slowly and titrated according to clinical responses (hemodynamics) and the electroencephalogram. Mean doses were as follows: from induction until time of incision, sufentanil, 9.1 microg/kg; fentanyl, 58 microg/kg; and morphine, 2.5 mg/kg; and total dose for surgery; sufentanil, 18.9 microg/kg; fentanyl, 95.4 microg/kg; and morphine, 4.4 mg/kg. Equi-anesthetic depth in patients receiving sufentanil or fentanyl was confirmed by continuous electroencephalographic monitoring. Patients anesthetized with sufentanil and fentanyl showed marked cardiovascular stability and rarely responded to stimuli. Systolic arterial pressure, mean arterial pressure, heart rate, cardiac index, systemic vascular resistance index, pulmonary vascular resistance index, stroke volume index, and stroke work index values were similar in the two groups. Patients receiving morphine experienced large changes in several variables. Pharmacologic intervention was made when systolic arterial pressure deviated more than 30% from pre-event values and was uncontrolled by additional opioids. Interventions were necessary more often in patients receiving morphine (nine of ten) or fentanyl (12 of 20) than in patients receiving sufentanil (six of 20), P < 0.05. Results from this study suggest that morphine is a relatively unsatisfactory anesthetic, while sufentanil and fentanyl, at equi-anesthetic depths, provide stable and satisfactory hemodynamics. |
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2014-10-29
