Time Course of the Distribution of Morphine in Brain Regions, Spinal Cord and Serum following Intravenous Injection to Rats of Differing Ages

Hn, Bhargava; Villar, Vincent M.; Nh, Rahmani; Larsen, AK

doi:10.1159/000139073

Cited by 13 publications

(7 citation statements)

References 13 publications

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“…By comparing the AUC ratios of cortex to plasma of unbound morphine and M6G (Table 2), we found dramatic differences in the brain ECF to ICS partitioning of the two compounds. By considering the whole brain or cortex tissue to plasma ratios, we found relatively high ratios for morphine, quite similar to those described by Bhargava et al . (1993), but much lower values for M6G, about 21 times lower than those of morphine (cortex).…”

Section: Discussionsupporting

confidence: 90%

“…Our results, obtained in brain homogenates, indicate that pharmacokinetic parameters are similar for cortex and whole brain. Measurements of homogenates from several regions of the rat brain after intravenous administration of morphine had already demonstrated that the morphine level in the cortex is representative of the rest of the brain (Bhargava et al ., 1993). This has been confirmed by microdialysis following the administration of morphine (10 mg kg −1 , i.p.…”

Section: Discussionmentioning

confidence: 99%

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Elevated concentrations of morphine 6‐beta‐D‐glucuronide in brain extracellular fluid despite low blood–brain barrier permeability

Stain-Texier

Boschi

Sandouk

et al. 1999

British J Pharmacology

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1 This study was done to ®nd out how morphine 6-beta-D-glucuronide (M6G) induces more potent central analgesia than morphine, despite its poor blood ± brain barrier (BBB) permeability. The brain uptake and disposition of these compounds were investigated in plasma and in various brain compartments: extracellular¯uid (ECF), intracellular space (ICS) and cerebrospinal¯uid (CSF). 2 Morphine or M6G was given to rats at 10 mg kg 71 s.c. Transcortical microdialysis was used to assess their distributions in the brain ECF. Conventional tissue homogenization was used to determine the distribution in the cortex and whole brain. These two procedures were combined to estimate drug distribution in the brain ICS. The blood and CSF pharmacokinetics were also determined. 3 Plasma concentration data for M6G were much higher than those of morphine, with C max and AUC 4 ± 5 times more higher, T max shorter, and V Z f 71 (volume of distribution) and CL f 71 (clearance) 4 ± 6 times lower. The concentrations of the compounds in various brain compartments also di ered: AUC values for M6G were lower than those of morphine in tissue and CSF and higher in brain ECF. AUC values in brain show that morphine levels were four times higher in ICS than in ECF, whereas M6G levels were 125 higher in ECF than in ICS. 4 Morphine entered brain cells, whereas M6G was almost exclusively extracellular. This high extracellular concentration, coupled with extremely slow di usion into the CSF, indicates that M6G was predominantly trapped in the extracellular¯uid and therefore durably available to bind at opioid receptors.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Elevated concentrations of morphine 6‐beta‐D‐glucuronide in brain extracellular fluid despite low blood–brain barrier permeability

Stain-Texier

Boschi

Sandouk

et al. 1999

British J Pharmacology

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“…Once absorbed and distributed in blood flow, morphine is efficiently transferred across the BBB of rodent brain (Kalvass et al, 2007 ; Boström et al, 2008 ). The diffusion process varies according to the age or to the injected morphine dose (Bhargava et al, 1993 ). Interestingly, morphine can also be produced in situ in several tissues, including brain, from endogenous precursors such as tyramine and DA, (Laux-Biehlmann et al, 2013 ).…”

Section: Role Of Ugt In the Glucuronidation Of Xenobiotics In Brainmentioning

confidence: 99%

The UDP-glucuronosyltransferases of the blood-brain barrier: their role in drug metabolism and detoxication

Ouzzine

Gulberti

Ramalanjaona

et al. 2014

Front. Cell. Neurosci.

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UDP-glucuronosyltransferases (UGTs) form a multigenic family of membrane-bound enzymes expressed in various tissues, including brain. They catalyze the formation of β-D-glucuronides from structurally unrelated substances (drugs, other xenobiotics, as well as endogenous compounds) by the linkage of glucuronic acid from the high energy donor, UDP-α-D-glucuronic acid. In brain, UGTs actively participate to the overall protection of the tissue against the intrusion of potentially harmful lipophilic substances that are metabolized as hydrophilic glucuronides. These metabolites are generally inactive, except for important pharmacologically glucuronides such as morphine-6-glucuronide. UGTs are mainly expressed in endothelial cells and astrocytes of the blood brain barrier (BBB). They are also associated to brain interfaces devoid of BBB, such as circumventricular organ, pineal gland, pituitary gland and neuro-olfactory tissues. Beside their key-role as a detoxication barrier, UGTs play a role in the steady-state of endogenous compounds, like steroids or dopamine (DA) that participate to the function of the brain. UGT isoforms of family 1A, 2A, 2B and 3A are expressed in brain tissues to various levels and are known to present distinct but overlapping substrate specificity. The importance of these enzyme species with regard to the formation of toxic, pharmacologically or physiologically relevant glucuronides in the brain will be discussed.

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“…32 In rats, morphine concentrations in the nervous system can transiently approach 1.5μg/g tissue weight following a 10-mg/kg intravenous dose. 11 Thus, the morphine concentrations used that increase Tat toxicity in the present study are likely to mimic those seen with chronic drug abuse, but importantly are less likely to be realized at therapeutic dosages for pain management.…”

Section: Morphine and Hiv-1 Tat (1-72) Concentrationsmentioning

confidence: 99%

Synergistic neurotoxicity of opioids and human immunodeficiency virus-1 Tat protein in striatal neurons in vitro

et al. 2001

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Human immunodeficiency virus (HIV) infection selectively targets the striatum, a region rich in opioid receptor-expressing neural cells, resulting in gliosis and neuronal losses. Opioids can be neuroprotective or can promote neurodegeneration. To determine whether opioids modify the response of neurons to human immunodeficiency virus type 1 (HIV-1) Tat protein-induced neurotoxicity, neural cell cultures from mouse striatum were initially characterized for mu and/or kappa opioid receptor immunoreactivity. These cultures were continuously treated with morphine, the opioid antagonist naloxone, and/or HIV-1 Tat (1-72) protein, a non-neurotoxic HIV-1 Tat deletion mutant (TatDelta31-61) protein, or immunoneutralized HIV-1 Tat (1-72) protein. Neuronal and astrocyte viability was examined by ethidium monoazide exclusion, and by apoptotic changes in nuclear heterochromatin using Hoechst 33342. Morphine (10nM, 100nM or 1microM) significantly increased Tat-induced (100 or 200nM) neuronal losses by about two-fold at 24h following exposure. The synergistic effects of morphine and Tat were prevented by naloxone (3microM), indicating the involvement of opioid receptors. Furthermore, morphine was not toxic when combined with mutant Tat or immunoneutralized Tat. Neuronal losses were accompanied by chromatin condensation and pyknosis. Astrocyte viability was unaffected. These findings demonstrate that acute opioid exposure can exacerbate the neurodegenerative effect of HIV-1 Tat protein in striatal neurons, and infer a means by which opioids may hasten the progression of HIV-associated dementia.

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Time Course of the Distribution of Morphine in Brain Regions, Spinal Cord and Serum following Intravenous Injection to Rats of Differing Ages

Cited by 13 publications

References 13 publications

Elevated concentrations of morphine 6‐beta‐D‐glucuronide in brain extracellular fluid despite low blood–brain barrier permeability

Elevated concentrations of morphine 6‐beta‐D‐glucuronide in brain extracellular fluid despite low blood–brain barrier permeability

The UDP-glucuronosyltransferases of the blood-brain barrier: their role in drug metabolism and detoxication

Synergistic neurotoxicity of opioids and human immunodeficiency virus-1 Tat protein in striatal neurons in vitro

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