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  • 1
    Electronic Resource
    Electronic Resource
    Increased CNS uptake and enhanced antinociception of morphine-6-glucuronide in rats after inhibition of P-glycoprotein (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 83 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Morphine-6-glucuronide (M6G) is a substrate of P-glycoprotein (P-gp), which forms an outward transporter at the blood–brain barrier. Inhibition of P-gp may therefore be expected to cause increased CNS uptake of M6G. We directly assessed the spinal concentrations of M6G and its antinociceptive effects in rats following pharmacological inhibition of P-gp. Spinal cord tissue concentrations of M6G were assessed by microdialysis with probes transversally implanted through the dorsal horns of the spinal cord at level L4. Ten rats received M6G intravenously (0.018 mg/kg loading dose plus 0.00115 mg/kg/min for an 8-h infusion), five of them together with PSC833 to inhibit P-gp (32-h infusion, starting 24 h before the addition of M6G). Antinociceptive effects were explored by means of formalin tests. After having obtained evidence for enhanced CNS uptake and antinociception of M6G in the presence of PSC833, additional behavioural experiments were performed in another 32 rats to assess the dose dependency of the antinociceptive effects of M6G either with or without PSC833 in comparison with both PSC833 alone and placebo. Inhibition of P-gp increased the M6G concentrations in the spinal cord approximately three-fold whereas the plasma concentrations were increased only by a factor of 1.4, which resulted in a more than doubled spinal cord/plasma concentration ratio (from 0.08 ± 0.03 for M6G alone to 0.17 ± 0.08 for M6G plus PSC833). Antinociceptive effects of M6G were significantly enhanced by inhibition of P-gp. Inhibition of P-gp alters the transport of M6G across the blood–brain barrier, resulting in enhanced spinal cord uptake and enhanced antinociception.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.01177.x
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  • 2
    Electronic Resource
    Electronic Resource
    Circadian rhythm and desensitization in chemosensory event-related potentials in response to odorous and painful stimuli (2003)
    Oxford, UK : Blackwell Publishing
    Psychophysiology 40 (2003), S. 0 
    Details
    ISSN: 1469-8986
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine , Psychology
    Notes: Olfactory (H2S) and trigeminal (CO2) event-related potentials (ERPs) were studied with respect to circadian rhythm and desensitization. ERPs, perceived odor and pain intensity, oral temperature, blood pressure, heart rate, nasal volume, and sleepiness were assessed four times at 04:00, 08:00, 12:00, 16:00, 20:00, and 24:00 hr in five young men. For each of these 24 sessions per participant, H2S and CO2 were each presented in 15 series of five stimuli with a 5-s ISI within and 30-s ISI between series. ERP amplitudes, but not latencies, followed a circadian rhythm (largest at 16:00 and smallest at 04:00) similar to oral temperature and opposite to sleepiness. Amplitudes decreased (most pronounced at 16:00 and 20:00) and latencies increased with repeated stimulation, suggesting desensitization, in accordance with odor and pain intensity. These findings imply that circadian rhythm and desensitization should be considered in chemosensory ERP studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/1469-8986.00062
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  • 3
    Electronic Resource
    Electronic Resource
    GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence (2006)
    [s.l.] : Nature Publishing Group
    Nature medicine 12 (2006), S. 1269-1277 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] We report that GTP cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, is a key modulator of peripheral neuropathic and inflammatory pain. BH4 is an essential cofactor for catecholamine, serotonin and nitric oxide production. After axonal injury, concentrations ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/nm1490
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  • 4
    Electronic Resource
    Electronic Resource
    Population Pharmacokinetics of Fast Release Oral Diclofenac in Healthy Volunteers: Relation to Pharmacodynamics in an Experimental Pain Model (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 77-84 
    Details
    ISSN: 1573-904X
    Keywords: population pharmacokinetics ; pharmacodynamics ; drug absorption ; double-blind four-way crossover study ; diclofenac tablets ; diclofenac-Na effervescent
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Population pharmacokinetics of a fast release diclofenac wereassessed with special focus on pharmacodynamic implications. Methods In a double blind four-way crossover study, 20 healthyvolunteers received orally 50 and 100 mg diclofenac-Na effervescent(“fast-release NSAID”), 50 mg diclofenac tablets (“control”), or placebo.Population pharmacokinetics of the fast release diclofenac wereassessed using a nonlinear mixed effects modeling approach(NON-MEM). Analgesic effects were investigated by means of anexperimental pain model based on both pain-ratings and cortical evoked potentialsafter specific stimulation of nasal nociceptors with short pulses ofgaseous CO2. Results. Pharmacokinetics of fast release diclofenac were bestdescribed by a two-compartment population model, with an estimatedterminal half-life of 1.2 hours. Pharmacokinetics of diclofenac tabletswere highly variable and a population pharmacokinetic model couldnot be obtained. As an indication of an early onset of analgesic effects,100 mg fast release diclofenac but not the tablets significantly reducedthe amplitudes of pain-related evoked potentials at 30 min afteradministration. Conclusions. Earlier drug absorption and lower pharmacokineticvariability of the fast-release formulation are likely to be preserved ina population.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007574710140
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