243 results on '"Colpaert FC"'
Search Results
2. Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1Areceptor agonist
- Author
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Newman-Tancredi, A, primary, Martel, J-C, additional, Assié, M-B, additional, Buritova, J, additional, Lauressergues, E, additional, Cosi, C, additional, Heusler, P, additional, Bruins Slot, L, additional, Colpaert, FC, additional, Vacher, B, additional, and Cussac, D, additional
- Published
- 2009
- Full Text
- View/download PDF
3. EVIDENCE THAT TOLERANCE DOES NOT DEVELOP TO OPIATE DRUGS
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Colpaert Fc
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Pharmacology ,Psychiatry and Mental health ,business.industry ,Anesthesia ,Medicine ,Opiate ,business - Published
- 1993
4. The discriminative response
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Colpaert Fc
- Subjects
Pharmacology ,Psychiatry and Mental health ,Stimulus generalization ,Discriminative model ,Speech recognition ,Elementary particle ,Psychology ,Drug discrimination ,Social psychology - Published
- 1991
5. Effects of Dorsal Raphe Stimulation On Escape Induced By Medial Hypothalamic Or Central Gray Stimulation
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UCL, Schmitt, P., Sandner, G., Colpaert, FC., De Witte, Philippe, UCL, Schmitt, P., Sandner, G., Colpaert, FC., and De Witte, Philippe
- Published
- 1983
6. Further Evidence Validating Adjuvant Arthritis As An Experimental-model of Chronic Pain in the Rat
- Author
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UCL, Colpaert, FC., Meert, T., De Witte, Philippe, Schmitt, P., UCL, Colpaert, FC., Meert, T., De Witte, Philippe, and Schmitt, P.
- Published
- 1982
7. Self-administration of the Analgesic Suprofen in Arthritic Rats - Evidence of Mycobacterium-butyricum-induced Arthritis As An Experimental-model of Chronic Pain
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UCL, Colpaert, FC., De Witte, Philippe, Maroli, AN., Awouters, F., Niemegeers, CJE., Janssen, PAJ., UCL, Colpaert, FC., De Witte, Philippe, Maroli, AN., Awouters, F., Niemegeers, CJE., and Janssen, PAJ.
- Published
- 1980
8. Interactions Between Centrally-induced Appetitive Effects and Centrally Or Peripherally-induced Aversive Effects
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UCL, Bada, MF., De Witte, Philippe, Colpaert, FC., Moreau, JL., Schmitt, P., UCL, Bada, MF., De Witte, Philippe, Colpaert, FC., Moreau, JL., and Schmitt, P.
- Published
- 1982
9. A model of chronic pain in the rat: functional correlates of alterations in the activity of opioid systems
- Author
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Millan, MJ, primary, Czlonkowski, A, additional, Pilcher, CW, additional, Almeida, OF, additional, Millan, MH, additional, Colpaert, FC, additional, and Herz, A, additional
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- 1987
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10. A model of chronic pain in the rat: response of multiple opioid systems to adjuvant-induced arthritis
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Millan, MJ, primary, Millan, MH, additional, Czlonkowski, A, additional, Hollt, V, additional, Pilcher, CW, additional, Herz, A, additional, and Colpaert, FC, additional
- Published
- 1986
- Full Text
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11. [(3)H]-F13640, a novel, selective and high-efficacy serotonin 5-HT(1A) receptor agonist radioligand.
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Heusler P, Palmier C, Tardif S, Bernois S, Colpaert FC, and Cussac D
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- Animals, Binding, Competitive, CHO Cells, Cell Culture Techniques, Cell Membrane drug effects, Cell Membrane metabolism, Cricetinae, Cricetulus, Humans, Protein Binding, Radioligand Assay, Receptor, Serotonin, 5-HT1A biosynthesis, Tritium, Piperidines pharmacology, Pyridines pharmacology, Receptor, Serotonin, 5-HT1A metabolism, Serotonin 5-HT1 Receptor Agonists pharmacology
- Abstract
F13640 is a selective and high-efficacy serotonin 5-HT(1A) receptor agonist that demonstrates outstanding analgesic potential in different animal models. Here, we use the radiolabelled compound to further characterise its binding properties at 5-HT(1A) receptors. F13640 was tritium-labelled to 47 and 64 Ci/mmol specific activity and used as radioligand at membrane preparations of CHO cells expressing human (h) 5-HT(1A) receptors. The K (d) of [(3)H]-F13640 was 1.8 nM at h5-HT(1A) receptors as determined from saturation binding experiments. In association time-course experiments, k (obs) of [(3)H]-F13640 was 0.06 min(-1). Dissociation experiments performed in the presence of unlabelled F13640 as competing ligand yielded a k (off) value of 0.05 min(-1), resulting in a calculated K (d) of 1.4 nM. In comparison, [(3)H]-8-OH-DPAT had a k (obs) of 0.50 min(-1), a k (off) of 0.25 min(-1) and a calculated K (d) of 0.37 nM. Surprisingly, [(3)H]-F13640 dissociation kinetics were distinctly slower in the presence of WAY-100635 and spiperone as competing ligands when compared with the agonist competitors, F13640 and (+)8-OH-DPAT. The competitive binding profile of [(3)H]-F13640 with eight chemically diverse 5-HT(1A) receptor agonists and antagonists correlated highly (r = 0.996) with that of [(3)H]-8-OH-DPAT. In conclusion, [(3)H]-F13640 is a potent agonist radioligand at 5-HT(1A) receptors and may be a useful tool in pharmacological studies at native and recombinant 5-HT(1A) receptors. In addition, [(3)H]-F13640 dissociates more slowly from h5-HT(1A) receptors than [(3)H]-8-OH-DPAT, a kinetic property that might be related to its powerful analgesic effects as observed in vivo.
- Published
- 2010
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12. F15599, a preferential post-synaptic 5-HT1A receptor agonist: activity in models of cognition in comparison with reference 5-HT1A receptor agonists.
- Author
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Depoortère R, Auclair AL, Bardin L, Colpaert FC, Vacher B, and Newman-Tancredi A
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- 8-Hydroxy-2-(di-n-propylamino)tetralin metabolism, 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Aminopyridines metabolism, Aminopyridines pharmacology, Animals, Disease Models, Animal, Enzyme Inhibitors pharmacology, Male, Memory, Short-Term drug effects, Phencyclidine pharmacology, Piperidines metabolism, Rats, Rats, Sprague-Dawley, Reflex, Startle drug effects, Signal Transduction, Cognition drug effects, Piperidines pharmacology, Pyrimidines pharmacology, Receptor, Serotonin, 5-HT1A metabolism, Serotonin 5-HT1 Receptor Agonists pharmacology
- Abstract
We assessed the activity of F15599, a selective and high efficacy 5-HT(1A) agonist that preferentially activates post- versus pre-synaptic receptors, in rat cognition/memory models. F15599 (0.16 mg/kg i.p.) partially alleviated detrimental effects of phencyclidine on working and reference memory deficit in a hole-board model. It also attenuated phencyclidine-induced deficit of cognitive flexibility in a reversal learning task, without effects of its own. F13714 (0.04 mg/kg) a chemical congener of F15599, and 8-OH-DPAT (0.01 or 0.16), were inactive against these phencyclidine-induced deficits, and/or even worsened basal performances. F15599 (0.04-2.5) was less disruptive than F13714 (0.005-0.16) or 8-OH-DPAT (0.01-0.63), on basal performance in models of attention (5-choice serial reaction time task) and working memory (delayed non-matching to position). Finally, unlike either comparator, F15599 reduced PPI with modest potency and only partially. To conclude, F15599, in models of memory/cognition, has a more favourable profile than F13714 and 8-OH-DPAT. This suggests that preferential activation of post-synaptic 5-HT(1A) receptors could prove useful in pathologies characterized by cognitive/memory deficiencies, such as schizophrenia and depression., (Copyright 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
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13. Recall of learned information may rely on taking drug again.
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Young AM and Colpaert FC
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- Amphetamines adverse effects, Animals, Cognition physiology, Humans, Amphetamines administration & dosage, Amphetamines pharmacology, Biomedical Enhancement, Cognition drug effects, Health, Mental Recall drug effects, Mental Recall physiology
- Published
- 2009
- Full Text
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14. Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist.
- Author
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Newman-Tancredi A, Martel JC, Assié MB, Buritova J, Lauressergues E, Cosi C, Heusler P, Bruins Slot L, Colpaert FC, Vacher B, and Cussac D
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Aminopyridines, Animals, Autoradiography, Binding, Competitive, CHO Cells, Cricetinae, Cricetulus, Extracellular Signal-Regulated MAP Kinases metabolism, In Vitro Techniques, Male, Phosphorylation, Prefrontal Cortex metabolism, Proto-Oncogene Proteins c-fos metabolism, Pyridines pharmacology, Rats, Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT1A physiology, Signal Transduction, Piperidines pharmacology, Pyrimidines pharmacology, Serotonin 5-HT1 Receptor Agonists
- Abstract
Background and Purpose: Activation of post-synaptic 5-HT(1A) receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5-HT(1A) receptor agonist., Experimental Approach: F15599 was compared with a chemical congener, F13714, and with (+)8-OH-DPAT in models of signal transduction in vitro and ex vivo., Key Results: F15599 was highly selective for 5-HT(1A) receptors in binding experiments and in [(35)S]-GTPgammaS autoradiography of rat brain, where F15599 increased labelling in regions expressing 5-HT(1A) receptors. In cell lines expressing h5-HT(1A) receptors, F15599 more potently stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, compared with G-protein activation, internalization of h5-HT(1A) receptors or inhibition of cAMP accumulation. F13714, (+)8-OH-DPAT and 5-HT displayed a different rank order of potency for these responses. F15599 stimulated [(35)S]-GTPgammaS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated G(alphai) than G(alphao) activation. In rat prefrontal cortex (a region expressing post-synaptic 5-HT(1A) receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c-fos mRNA expression. In contrast, in raphe regions (expressing pre-synaptic 5-HT(1A) receptors) F15599 only weakly or did not induce c-fos mRNA expression. Finally, despite its more modest affinity in vitro, F15599 bound to 5-HT(1A) receptors in vivo almost as potently as F13714., Conclusions and Implications: F15599 showed a distinctive activation profiles for 5-HT(1A) receptor-mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5-HT(1A) receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition.
- Published
- 2009
- Full Text
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15. Long-lasting descending and transitory short-term spinal controls on deep spinal dorsal horn nociceptive-specific neurons in response to persistent nociception.
- Author
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You HJ, Colpaert FC, and Arendt-Nielsen L
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- Action Potentials drug effects, Afferent Pathways drug effects, Afferent Pathways physiology, Animals, Bee Venoms pharmacology, Dose-Response Relationship, Drug, Drug Interactions, Laminectomy methods, Male, Neurokinin-1 Receptor Antagonists, Nociceptors drug effects, Pain chemically induced, Posterior Horn Cells drug effects, Quinuclidines pharmacology, Rats, Rats, Wistar, Spinal Cord cytology, Time Factors, Nociceptors physiology, Pain physiopathology, Posterior Horn Cells physiology
- Abstract
Under intact and spinalized conditions, we compared the responses of deep spinal dorsal horn (DH) nociceptive-specific (NS) and wide-dynamic range (WDR) neurons to subcutaneous bee venom (BV, 0.2 mg/50 microl)-induced persistent nociception. In contrast to the monophasic, long-lasting (34-81 min) WDR neuron responses in both intact and spinalized conditions, BV in NS neurons elicited short-term (<10 min) firing in intact, and long-term (>1 h) biphasic firing in spinalized rats. The BV-induced long-term biphasic NS neuron activities in spinalized condition consisted of a first, early phase (4-13 min) of firing occurred immediately after the BV injection, and a second phase of tonic firing that lasted for 28-74 min. The two phases were separated by a period that lasted 4-11 min during which there was very little neuronal activity. The data suggest that in the presence of peripheral nociception, a transitory (about 5-13 min) spinal segmental inhibitory control and a long-lasting descending inhibitory control govern deep spinal NS neuron but not WDR neuron activity. Previous reports assessing spinally organized motor activities showed a spinal WDR neuron well-controlled monophasic long-lasting withdrawal reflex in response to BV injection in both intact and spinalized conditions. In contrast, the current data suggest that unlike spinal WDR neurons, deep spinal DH NS neurons do not modulate spinal motor output during the persistent nociception. Using the neurokinin-1 (NK-1) receptor antagonist, L-703,606 we further found that only early (within 15 min) treatment with L-703,606 produced a significant inhibition of the enhanced mechanically evoked NS neuron responses in BV-induced nociception, suggesting a dynamic function of NK-1 receptor involvement for deep spinal NS neuron mediated central sensitisation. We conclude that deep spinal DH NS neurons are strictly governed by tonic inhibitory descending controls. As this descending inhibitory control either is absent or decays, deep spinal NS neurons may play a crucial role in the development of central sensitisation in pathological nociception, for instance in spinal cord injury-induced pathological pain.
- Published
- 2008
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16. Curative-like analgesia in a neuropathic pain model: parametric analysis of the dose and the duration of treatment with a high-efficacy 5-HT(1A) receptor agonist.
- Author
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Deseure K, Bréand S, and Colpaert FC
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- Analgesia, Animals, Cranial Nerve Injuries physiopathology, Disease Models, Animal, Dose-Response Relationship, Drug, Male, Pain physiopathology, Rats, Rats, Sprague-Dawley, Serotonin 5-HT1 Receptor Agonists, Analgesics therapeutic use, Cranial Nerve Injuries drug therapy, Orbit innervation, Pain drug therapy, Piperidines therapeutic use, Pyridines therapeutic use, Serotonin Receptor Agonists therapeutic use
- Abstract
High-efficacy activation of central 5-HT(1A) receptors by means of the recently discovered, selective 5-HT(1A) receptor ligand, F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]methyl}piperidin-1-yl]methanone, fumaric acid salt] causes an unprecedented, broad-spectrum analgesia in rat models of acute and chronic pain of nociceptive and neuropathic origin; it also is effective in conditions where opioids either are ineffective, induce analgesic tolerance, or elicit persistent hyperalgesia/allodynia. Inversely mirroring morphine's actions, F 13640's ("curative-like") analgesic effects persist after the discontinuation of treatment. Here, we examined the relationships, if any, between the dose and the duration of F 13640 treatment on the one hand, and the duration of persistent analgesia on the other. Rats received unilateral infraorbital nerve injury and developed allodynia - as assessed by an increased response to von Frey filament stimulation - within 24 days; thereafter, using osmotic pumps, rats were subcutaneously infused with F 13640 in two experiments. In one, a one-week infusion was instituted at 0.04-10-mg/day doses; in a second experiment, a 0.63-mg/day dose was implemented for a duration ranging from 1 to 56 days. These 250- and 56-fold variations of the dose and duration of treatment caused post-treatment, persistent analgesia for about 10 and 40 days, respectively. At least as much as dose, the duration of F 13640 treatment determines F 13640-induced persistent analgesia. Neuroadaptive modulations at pre- and postsynaptic, brain and spinal cord 5-HT(1A) receptors may be involved in the dynamical, dose- and time-dependent, pre-treatment rise and post-treatment decay of the analgesia induced by high-efficacy 5-HT(1A) receptor activation.
- Published
- 2007
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17. High-efficacy 5-hydroxytryptamine 1A receptor activation counteracts opioid hyperallodynia and affective conditioning.
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Colpaert FC, Deseure K, Stinus L, and Adriaensen H
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- Analgesics, Opioid adverse effects, Animals, Behavior, Animal drug effects, Cranial Nerve Injuries complications, Dose-Response Relationship, Drug, Drug Tolerance, Hyperalgesia chemically induced, Male, Orbit innervation, Pain Measurement, Rats, Rats, Sprague-Dawley, Analgesics, Opioid therapeutic use, Hyperalgesia prevention & control, Pain drug therapy, Piperidines therapeutic use, Pyridines therapeutic use, Serotonin 5-HT1 Receptor Agonists, Serotonin Receptor Agonists therapeutic use
- Abstract
Pain may become intractable as tolerance develops to opioids and the opioids, paradoxically, induce pain. We examined the hypothesis that the analgesia produced by the novel analgesic and high-efficacy 5-hydroxytryptamine (5-HT)(1A) receptor agonist (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]methyl]piperidin-1-yl]methanone, fumaric acid salt (F 13640) may counteract opioid-induced pain. In studies of the somatosensory quality of pain in infraorbital nerve-injured rats, morphine infusion (5 mg/day) by means of osmotic pumps initially caused analgesia (i.e., decreased the behavioral response to von Frey filament stimulation), followed by hyperallodynia and analgesic tolerance. Infusion of F 13640 (0.63 mg/day) prevented the development of opioid hyperallodynia and reversed opioid hyperallodynia once established. In studies of the affective/motivational quality of pain, F 13640 both prevented and reversed the conditioned place aversion induced by naloxone (0.04 mg/kg i.p.) in morphine-infused rats; F 13640 also prevented and reversed the conditioned place preference induced by morphine injections (7.5 mg/kg i.p.). The data confirm that opioids produce bidirectional hypo- and proalgesic actions, and offer initial evidence that high-efficacy 5-HT(1A) receptor activation counteracts both the sensory and the affective/motivational qualities of opioid-induced pain. The data also indicate that F 13640 may be effective with opioid-resistant pain. It further is suggested that opioid addiction may represent self-therapy of opioid-induced pathological pain.
- Published
- 2006
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18. 5-HT(1A) receptor activation: new molecular and neuroadaptive mechanisms of pain relief.
- Author
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Colpaert FC
- Subjects
- Animals, Drug Tolerance, Humans, Ligands, Pain complications, Pain metabolism, Peripheral Nervous System Diseases complications, Peripheral Nervous System Diseases metabolism, Serotonin 5-HT1 Receptor Agonists, Serotonin 5-HT1 Receptor Antagonists, Signal Transduction drug effects, Analgesics administration & dosage, Analgesics pharmacology, Analgesics therapeutic use, Pain drug therapy, Peripheral Nervous System Diseases drug therapy, Piperidines administration & dosage, Piperidines pharmacology, Piperidines therapeutic use, Pyridines administration & dosage, Pyridines pharmacology, Pyridines therapeutic use, Receptor, Serotonin, 5-HT1A metabolism
- Abstract
Guided by an understanding of signal transduction in pain-processing systems, high-efficacy 5-hydroxytryptamine (5HT)1A receptor activation, by means of F-13640, has been discovered as a new molecular mechanism of pain relief in laboratory animals, inducing two neuroadaptive phenomena. Firstly, this activation cooperates with nociceptive stimulation, paradoxically causing analgesia, and secondly, inverse tolerance develops so that the resulting analgesia grows rather than decays. As an apparent result of these novel neuroadaptive mechanisms, F-13640 exerts an analgesic action in rat models of acute, tonic and chronic nociceptive pain that is rivaled only by large doses of high-efficacy mu-opioid receptor agonists. In models of neuropathic allodynia of peripheral or central origin, chronic F-13640 administration causes an analgesia that surpasses that observed with morphine or other agents exemplifying other central nervous system drug mechanisms of pain relief (e.g., ketamine, imipramine and gabapentin). Indeed, F-13640 produces long-lasting, preemptive and, most remarkably, curative-like actions in neuropathic allodynia. Although awaiting proof-of-concept evidence in humans, high-efficacy 5-HT(1A) receptor activation may uniquely challenge the opioids for pain therapy.
- Published
- 2006
19. Differential ion current activation by human 5-HT(1A) receptors in Xenopus oocytes: evidence for agonist-directed trafficking of receptor signalling.
- Author
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Heusler P, Pauwels PJ, Wurch T, Newman-Tancredi A, Tytgat J, Colpaert FC, and Cussac D
- Subjects
- Animals, Chloride Channel Agonists, Electrophysiology, Female, G Protein-Coupled Inwardly-Rectifying Potassium Channels agonists, Guanosine Diphosphate analogs & derivatives, Guanosine Diphosphate pharmacology, Humans, Ligands, Mutation, Oocytes, Patch-Clamp Techniques, Pertussis Toxin pharmacology, Plasmids genetics, RNA biosynthesis, RNA genetics, Receptor, Serotonin, 5-HT1A genetics, Serotonin pharmacology, Thionucleotides pharmacology, Xenopus laevis, Ion Channels agonists, Serotonin 5-HT1 Receptor Agonists, Serotonin Receptor Agonists pharmacology, Signal Transduction drug effects
- Abstract
The subject of the present study was the functional and pharmacological characterization of human 5-HT(1A) receptor regulation of ion channels in Xenopus oocytes. Activation of the heterologously expressed human 5-HT(1A) receptor induced two distinct currents in Xenopus oocytes, consisting of a smooth inward current (I(smooth)) and an oscillatory calcium-activated chloride current, I(Cl(Ca)). 5-HT(1A) receptor coupling to both ionic responses as well as to co-expressed inward rectifier potassium (GIRK) channels was pharmacologically characterized using 5-HT(1A) receptor agonists. The relative order of efficacy for activation of GIRK current was 5-HT approximately F 13714 approximately L 694,247 approximately LY 228,729>flesinoxan approximately (+/-)8-OH-DPAT. In contrast, flesinoxan and (+/-)8-OH-DPAT typically failed to activate I(Cl(Ca)). The other ligands behaved as full or partial agonists, exhibiting an efficacy rank order of 5-HT approximately L 694,247>F 13714 approximately LY 228,729. The pharmacological profile of I(smooth) activation was completely distinct: flesinoxan and F 13714 were inactive and rather exhibited an inhibition of this current. I(smooth) was activated by the other agonists with an efficacy order of L 694,247>5-HT approximately LY 228,729>(+/-)8-OH-DPAT. Moreover, activation of I(smooth) was not affected by application of pertussis toxin or the non-hydrolyzable GDP-analogue, guanosine-5'-O-(2-thio)-diphosphate (GDP betaS), suggesting a GTP binding protein-independent pathway. Together, these results suggest the existence of distinct and agonist-specific signalling states of this receptor.
- Published
- 2005
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20. The novel analgesic, F 13640, produces intra- and postoperative analgesia in a rat model of surgical pain.
- Author
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Kiss I, Degryse AD, Bardin L, Gomez de Segura IA, and Colpaert FC
- Subjects
- Analgesia, Analgesics, Non-Narcotic administration & dosage, Analgesics, Opioid administration & dosage, Analgesics, Opioid adverse effects, Analgesics, Opioid pharmacology, Analysis of Variance, Anesthetics, Inhalation administration & dosage, Anesthetics, Inhalation pharmacokinetics, Anesthetics, Inhalation pharmacology, Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Hyperalgesia chemically induced, Isoflurane administration & dosage, Isoflurane pharmacokinetics, Isoflurane pharmacology, Male, Monitoring, Intraoperative, Orthopedic Procedures adverse effects, Pain etiology, Pain Measurement methods, Pain Threshold drug effects, Pain, Postoperative etiology, Piperazines pharmacology, Piperidines administration & dosage, Piperidines adverse effects, Pulmonary Alveoli metabolism, Pyridines administration & dosage, Rats, Rats, Sprague-Dawley, Remifentanil, Serotonin Antagonists pharmacology, Vocalization, Animal drug effects, Analgesics, Non-Narcotic pharmacology, Pain prevention & control, Pain, Postoperative prevention & control, Piperidines pharmacology, Pyridines pharmacology
- Abstract
F 13640 is a newly discovered high-efficacy 5-HT(1A) receptor agonist that produces exceptional analgesia in animal models of tonic and chronic, nociceptive and neuropathic pains by novel molecular and neuroadaptive mechanisms. Here we examined the effects of F 13640 and remifentanil (0.63 mg/kg with either compound) when injected i.p. either before or 15 min after rats underwent orthopedic surgery. Surgery consisted of the drilling of a hole in the calcaneus bone and of an incision of the skin, fascia and plantar muscle of one foot. During surgery, the concentration of volatile isoflurane was progressively incremented depending on the animal's response to surgical maneuvers. Other experiments examined the dose-dependent effects of F 13640 (0.04 to 0.63 mg/kg) on surgical pain as well as on the Minimum Alveolar Concentration of isoflurane. Both F 13640 and remifentanil markedly reduced the intra-operative isoflurane requirement. F 13640 also reduced measures of postoperative pain (i.e., paw elevation and flexion). With these postoperative measures, remifentanil produced short-lived analgesia followed by hyperalgesia. F 13640 significantly reduced both surgical pain and the isoflurane Minimum Alveolar Concentration from 0.16 mg/kg onward. F 13640 produced powerful intra- and postoperative analgesia in rats undergoing orthopedic surgery. Unlike the opioid, remifentanil, F 13640 caused no hyperalgesia with ongoing postoperative pain, and should remain effective with protracted postoperative use.
- Published
- 2005
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21. Nociceptive spinal withdrawal reflexes but not spinal dorsal horn wide-dynamic range neuron activities are specifically inhibited by halothane anaesthesia in spinalized rats.
- Author
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You HJ, Colpaert FC, and Arendt-Nielsen L
- Subjects
- Animals, Dose-Response Relationship, Drug, Dose-Response Relationship, Radiation, Drug Interactions, Electric Stimulation methods, Electromyography methods, Evoked Potentials physiology, Evoked Potentials radiation effects, Functional Laterality physiology, Laminectomy methods, Male, Naloxone pharmacology, Narcotic Antagonists pharmacology, Neural Inhibition physiology, Posterior Horn Cells radiation effects, Rats, Rats, Wistar, Reflex physiology, Reflex radiation effects, Spinal Cord cytology, Spinal Cord physiology, Time Factors, Anesthetics, Inhalation administration & dosage, Halothane administration & dosage, Neural Inhibition drug effects, Posterior Horn Cells drug effects, Reflex drug effects, Spinal Cord drug effects
- Abstract
The aim of the present study was to investigate the spinal cord effects and sites of action of different inhaled concentrations (0.5-2%) of the anaesthetic, halothane. Simultaneous recordings were made of 3 Hz, suprathreshold (1.5 x T) electrically evoked spinal dorsal horn (DH) wide-dynamic range (WDR) neuron responses and of single motor unit (SMU) electromyographic (EMG) responses underlying the spinal withdrawal reflex in spinalized Wistar rats. Compared with the baseline responses obtained with 0.5% halothane, the electrically evoked early responses of the DH WDR neurons as well as the SMUs were only depressed by the highest, 2% concentration of halothane. In contrast, 1.5% halothane markedly inhibited the late responses of the DH WDR neurons, whereas 1% halothane started to significantly depress the late responses of the SMUs. Likewise, wind-up of the WDR neuron late responses was inhibited by 1.5-2% halothane, whereas 1-2% halothane significantly depressed wind-up of the SMU EMG late responses. The inhibitory effects of 2% halothane on the early and the late responses of the DH WDR neurons, but not of the SMUs, were completely reversed by opioid micro-receptor antagonist naloxone (0.04 mg/kg). However, no significant effects of naloxone were found on different responses of the DH WDR neurons as well as the SMUs at 0.5-1% halothane, suggesting that different concentrations of halothane may modulate different spinal receptors. We conclude that halothane at high concentrations (1.5-2%) seems to play a predominant inhibitory role via spinal multireceptors on ventral horn (VH) motor neurons, and less on DH sensory WDR neurons, of the spinal cord.
- Published
- 2005
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22. Dual, hyperalgesic, and analgesic effects of the high-efficacy 5-hydroxytryptamine 1A (5-HT1A) agonist F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, fumaric acid salt]: relationship with 5-HT1A receptor occupancy and kinetic parameters.
- Author
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Bardin L, Assié MB, Pélissou M, Royer-Urios I, Newman-Tancredi A, Ribet JP, Sautel F, Koek W, and Colpaert FC
- Subjects
- Animals, Dose-Response Relationship, Drug, Male, Microdialysis, Piperidines blood, Pyridines blood, Rats, Rats, Sprague-Dawley, Analgesics pharmacology, Hyperalgesia chemically induced, Piperidines pharmacology, Pyridines pharmacology, Serotonin 5-HT1 Receptor Agonists, Serotonin Receptor Agonists pharmacology
- Abstract
The aim of the present study was to establish the relationship between the plasma and brain concentration-time profiles of F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, fumaric acid salt] after acute administration and both its hyper- and hypoanalgesic effects in rats. The maximal plasma concentration (C(max)) of F 13640 after i.p. administration of 0.63 mg/kg was obtained at 15 min and decreased to half its maximal value after about 1 h. The amount of F 13640 collected by means of in vivo microdialysis in hippocampal dialysates could be measured reliably after 0.63 and 2.5 mg/kg, reached its maximum at about 1 h, and fell to half of its maximal value at about 3 h. 5-Hydroxytryptamine 1A (5-HT(1A)) receptor occupancy was estimated by ex vivo binding in rat brain sections. F 13640 inhibited [(3)H]8-hydroxy-2-[di-n-propylamino] tetralin binding ex vivo in rat hippocampus, entorhinal cortex, and frontal cortex (ED(50), 0.34 mg/kg i.p.). Maximal inhibition was reached at approximately 30 min after 0.63 mg/kg F 13640 and fell to half of its value after about 4 to 8 h. After injection (15 min) in the paw pressure test, F 13640 (0.63 mg/kg i.p.) induced an initial hyperalgesia that was followed 4 h later by a paradoxical analgesia that lasted until 8 h. In contrast, in the formalin test, F 13640 inhibited pain behaviors until 4 h after drug administration. F 13640 also produced elements of the 5-HT syndrome that lasted up to 4 h after administration. These results demonstrate that F 13640 induces hyperalgesia and/or analgesia with a time course that parallels the occupancy of 5-HT(1A) receptors and the presence of the compound in blood and brain.
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- 2005
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23. The novel analgesic and high-efficacy 5-HT1A receptor agonist F 13640 inhibits nociceptive responses, wind-up, and after-discharges in spinal neurons and withdrawal reflexes.
- Author
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You HJ, Colpaert FC, and Arendt-Nielsen L
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Animals, Electric Stimulation methods, Male, Pain Measurement methods, Rats, Rats, Wistar, Receptor, Serotonin, 5-HT1A physiology, Reflex drug effects, Reflex physiology, Serotonin Receptor Agonists pharmacology, Spinal Nerves physiology, Analgesics pharmacology, Pain Measurement drug effects, Piperidines pharmacology, Pyridines pharmacology, Serotonin 5-HT1 Receptor Agonists, Spinal Nerves drug effects
- Abstract
Evidence shows that serotonin (5-HT) is involved in the transmission of nociception in the central nervous system. Using a new electrophysiological method of simultaneous recordings in rats we examined the actions of the novel analgesic and high-efficacy 5-HT1A receptor agonist F 13640 as well as those of the opioid receptor agonist fentanyl on simultaneously evoked responses of spinal dorsal horn (DH) wide-dynamic range (WDR) neurons and spinal withdrawal reflexes. Spinal withdrawal reflexes were studied by assessing the activity of single motor units (SMUs) electromyographically (EMG). Like that of 0.02 mg/kg fentanyl, intraperitoneal injection of 0.31 mg/kg of F 13640 markedly inhibited nociceptive pinch-evoked responses as well as C-fiber-mediated late responses including wind-up of both DH WDR neurons and SMUs to suprathreshold (1.5 x T) repeated (3 Hz) electrical stimulation. Specifically, in contrast to no significant depressive effects by fentanyl on 20 Hz electrically evoked after-discharge of DH WDR neurons, the after-discharges of DH WDR neurons and SMUs were significantly inhibited by F 13640 (P < 0.05 and P < 0.001, respectively). The inhibitory effects of F 13640 and fentanyl on responses of DH WDR neurons and SMUs were reversed by the specific antagonists WAY 100635 and naloxone, respectively, further indicating that this 5-HT1A receptor-modulated anti-nociception is mu-opioid receptor independent. For the first time, 5-HT1A receptors are clearly proved to be involved in the progressive wind-up to 3-Hz frequency of electrical stimulation as well as after-discharges of sensory input of DH WDR neurons, and simultaneously recorded motor output of spinal reflexes to 20-Hz frequency of electrical stimulation; this suggests that serotonin, through 5-HT1A receptors, exerts an inhibitory role in the control of obstinate pathological pain.
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- 2005
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24. Effects of the combined continuous administration of morphine and the high-efficacy 5-HT1A agonist, F 13640 in a rat model of trigeminal neuropathic pain.
- Author
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Deseure KR, Adriaensen HF, and Colpaert FC
- Subjects
- Aminopyridines pharmacology, Animals, Behavior, Animal drug effects, Dose-Response Relationship, Drug, Drug Therapy, Combination, Drug Tolerance, Infusion Pumps, Implantable, Male, Pain Measurement drug effects, Physical Stimulation, Piperidines pharmacology, Rats, Rats, Sprague-Dawley, Analgesics, Opioid therapeutic use, Morphine therapeutic use, Piperidines therapeutic use, Pyridines therapeutic use, Receptor, Serotonin, 5-HT1A drug effects, Serotonin Receptor Agonists therapeutic use, Trigeminal Neuralgia drug therapy
- Abstract
F 13640 is a recently discovered high-efficacy 5-HT1A receptor agonist that has demonstrated robust anti-allodynic efficacy in a rat model of trigeminal neuropathic pain upon acute and continuous administration. In this model, continuous morphine infusion (5 mg/day) was shown to be effective during the first week of its administration but became almost completely ineffective by the end of the second week; F 13640's effectiveness (0.63 mg/day) remained unchanged during two weeks. Here, we examined the effects of combining F 13640 infusion with that of morphine. During the first week, the combination of the two agents produced a magnitude of effect that was similar to that of morphine when given alone and larger than that of F 13640 alone. During the second week, the combination produced an effect that was similar to that of F 13640 alone, and more effective than that of morphine alone. The latter data suggest that the 5-HT1A agonist, F 13640, inhibits the development of tolerance to morphine in this model. However, it is also possible that little, if any, interaction occurred between the different mechanisms initiated by opioid and 5-HT1A receptor activation, and that the anti-allodynic effect that remained by the end of the two-week treatment period is due solely to 5-HT1A receptor activation. The stable effects of F 13640 during the second week of treatment surpassed those of morphine and were not improved by the addition of morphine to F 13640.
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- 2004
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25. High-efficacy 5-HT1A receptor activation causes a curative-like action on allodynia in rats with spinal cord injury.
- Author
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Colpaert FC, Wu WP, Hao JX, Royer I, Sautel F, Wiesenfeld-Hallin Z, and Xu XJ
- Subjects
- Analgesics pharmacology, Animals, Behavior, Animal drug effects, Cold Temperature, Female, Infusions, Intravenous, Pain etiology, Pain Measurement, Pain Threshold, Piperidines pharmacology, Pyridines pharmacology, Rats, Rats, Sprague-Dawley, Touch, Vocalization, Animal drug effects, Analgesics therapeutic use, Pain drug therapy, Piperidines therapeutic use, Pyridines therapeutic use, Serotonin 5-HT1 Receptor Agonists, Spinal Cord Injuries complications
- Abstract
The selective, high-efficacy 5-HT(1A) receptor agonist, (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methanone (F 13640) has been reported to produce long-term analgesia in rodent models of chronic nociceptive and neuropathic pain; it also preempts allodynia following spinal cord injury. Here, rats underwent spinal cord injury, fully developed allodynia, and were infused with saline or 0.63 mg/day of F 13640 for 56 days. Infusion was then discontinued, and further assessments of allodynia (vocalization threshold to von Frey filament stimulation, responses to brush and cold) were conducted for another 70 days. F 13640-induced analgesia persisted during this post-treatment period. The data offer initial evidence that high-efficacy 5-HT(1A) receptor activation produces an unprecedented curative-like action on pathological pain.
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- 2004
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26. Role of spinal 5-HT(1A) receptors in morphine analgesia and tolerance in rats.
- Author
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Bardin L and Colpaert FC
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Afferent Pathways cytology, Afferent Pathways metabolism, Analgesics, Opioid pharmacology, Animals, Dose-Response Relationship, Drug, Drug Interactions physiology, Drug Tolerance physiology, Injections, Spinal, Male, Pain metabolism, Pain physiopathology, Pain Measurement drug effects, Pain Threshold drug effects, Pain Threshold physiology, Piperazines pharmacology, Pyridines pharmacology, Rats, Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT1A metabolism, Receptors, Opioid drug effects, Receptors, Opioid metabolism, Serotonin Antagonists pharmacology, Spinal Cord physiopathology, Afferent Pathways drug effects, Morphine pharmacology, Pain drug therapy, Receptor, Serotonin, 5-HT1A drug effects, Spinal Cord drug effects
- Abstract
We here studied the involvement of spinally located 5-HT(1A) and opioid receptors, in the paradoxical effects that their activation can produce on nociception. Intrathecal (i.t.) injection of the 5-HT(1A) receptor agonist 8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT) (1-10 microg) induced analgesic effects in the formalin model of tonic pain whereas in the paw pressure test, it decreased the vocalization threshold. In this latter test, i.t. 8-OH-DPAT also markedly reduced the analgesic effect of systemic morphine (5-10 mg/kg, s.c.). At 10 microg, 8-OH-DPAT totally abolished the effect of 5 mg/kg of morphine; this inhibitory effect was antagonized by pre-treatment with 0.63 mg/kg of the 5-HT(1A) antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)-cyclohexanecarboxamide-trihydrochloride). In contrast, the i.t. injection of WAY-100635 (1-10 microg) dose-dependently potentiated the antinociceptive activity of a dose of morphine (2.5 mg/kg, s.c.). Furthermore, WAY-100635 (10 microg, i.t.) potentiated morphine analgesia in morphine-tolerant rats. These findings demonstrate that 5-HT(1A) receptor agonists can act in the spinal cord to produce both hyper- and hypo-algesic effects and play a major role in the opioid analgesia and tolerance.
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- 2004
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27. Cardiovascular drugs inhibit MMP-9 activity from human THP-1 macrophages.
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Rival Y, Benéteau N, Chapuis V, Taillandier T, Lestienne F, Dupont-Passelaigue E, Patoiseau JF, Colpaert FC, and Junquéro D
- Subjects
- Acetamides, Acetates pharmacology, Anilides pharmacology, Cell Line, Enzyme Inhibitors pharmacology, Fatty Acids, Monounsaturated pharmacology, Fenofibrate pharmacology, Fluvastatin, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Indoles pharmacology, Lipoproteins, LDL pharmacology, Macrophages cytology, Matrix Metalloproteinase 9 genetics, Matrix Metalloproteinase 9 metabolism, Mevalonic Acid pharmacology, Monocytes drug effects, Monocytes metabolism, Pyrimidines pharmacology, Receptors, Cytoplasmic and Nuclear agonists, Receptors, Cytoplasmic and Nuclear antagonists & inhibitors, Receptors, Cytoplasmic and Nuclear metabolism, Rosiglitazone, Sterol O-Acyltransferase antagonists & inhibitors, Sulfonamides, Sulfonic Acids pharmacology, Tetradecanoylphorbol Acetate pharmacology, Thiazolidinediones pharmacology, Tissue Inhibitor of Metalloproteinase-1 drug effects, Tissue Inhibitor of Metalloproteinase-1 metabolism, Transcription Factors agonists, Transcription Factors antagonists & inhibitors, Cardiovascular Agents pharmacology, Fenofibrate analogs & derivatives, Macrophages drug effects, Macrophages enzymology, Matrix Metalloproteinase Inhibitors
- Abstract
It is now recognized that atherosclerosis complications are related to the unstable character of the plaque rather than its volume. Vulnerable plaques often contain a large lipid core, a reduced content of smooth muscle cells, and accumulation of inflammatory cells. Colocalization of macrophages and active matrix metalloproteinases (MMPs) is likely relevant for atherosclerotic lesion disruption. Nevertheless, MMP activity and regulation by cardiovascular drugs remains poorly defined. In this study, we evaluated the effects of avasimibe, fluvastatin, and peroxisome proliferator-activated receptor (PPAR) ligands on 92-kDa gelatinase B (MMP-9) secretion by human THP-1 macrophages. THP-1 macrophages were treated with compounds for 48 h, and secreted MMP-9 protein was quantified by immunoassay. Avasimibe, fluvastatin, and PPARalpha agonists (fenofibric acid and Wy-14643) significantly reduced, in a concentration-dependent manner, MMP-9 protein (up to 67 +/- 5% for fenofibric acid). In these assays, the PPARgamma selective agonist rosiglitazone displayed a lower efficacy than other compounds. Enzymatic activity of MMP-9 was also decreased by all cardiovascular drugs tested. MMP-9 protein/activity inhibition by cardiovascular drugs was due, at least in part, to a decrease in MMP-9 mRNA. These results show that THP-1 macrophages could be an useful cellular model to investigate effects of compounds on plaque vulnerability through MMP-9 activity.
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- 2004
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28. Ability of dopamine antagonists to inhibit the locomotor effects of cocaine in sensitized and non-sensitized C57BL/6 mice depends on the challenge dose.
- Author
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Prinssen EP, Colpaert FC, Kleven MS, and Koek W
- Subjects
- Animals, Behavior, Animal drug effects, Benzazepines pharmacology, Cocaine administration & dosage, Dopamine Uptake Inhibitors administration & dosage, Dose-Response Relationship, Drug, Male, Mice, Mice, Inbred C57BL, Raclopride pharmacology, Salicylamides pharmacology, Cocaine antagonists & inhibitors, Dopamine D2 Receptor Antagonists, Dopamine Uptake Inhibitors antagonists & inhibitors, Motor Activity drug effects
- Abstract
Rationale: Studies in rats examining the ability of selective dopamine D(2) receptor class antagonists to attenuate the effects of a cocaine challenge have suggested that these agents are less potent in attenuating sensitized as opposed to non-sensitized locomotion. A potential issue with these studies is that the same challenge dose is used in sensitized and control conditions even though that dose may occupy different positions on the respective dose-response curves., Objectives: To examine whether the ability of dopamine antagonists to attenuate cocaine-induced locomotion differs between sensitized and non-sensitized animals if they are challenged with the same dose of cocaine, and with the lowest dose to maximally increase locomotion, which is lower in sensitized than in non-sensitized animals., Methods: Mice were treated repeatedly with 20 mg/kg cocaine or saline (for 3 consecutive days) and then challenged (after an 11-day drug-free interval) with different challenge doses of cocaine after pretreatment with a dopamine antagonist or saline., Results: Using the same challenge dose of cocaine in both repeated treatment conditions (i.e. 20 mg/kg), the D(2 )class antagonists eticlopride and raclopride were less potent in attenuating the locomotor effects of cocaine in sensitized than those in non-sensitized animals. In contrast, when the lowest doses to maximally increase locomotion in each of the repeated treatment conditions were used (10 and 40 mg/kg), the D(2 )class antagonists attenuated the locomotor effects of cocaine in sensitized and non-sensitized animals with similar potencies. The ability of the D(1) class antagonist SCH23390 to attenuate the effects of cocaine demonstrated a similar dependency on the challenge dose., Conclusions: These results show that, under the present conditions, the ability of dopamine antagonists to attenuate cocaine-induced locomotion is similar in sensitized and non-sensitized animals when challenged with pharmacologically equivalent doses of cocaine, but not when challenged with the same dose.
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- 2004
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29. Noradrenergic mechanisms in neurodegenerative diseases: a theory.
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Marien MR, Colpaert FC, and Rosenquist AC
- Subjects
- Adrenergic alpha-2 Receptor Antagonists, Animals, Antioxidants therapeutic use, Body Temperature drug effects, Brain Injuries physiopathology, Dopamine metabolism, Humans, Inflammation metabolism, Nerve Growth Factors physiology, Neurodegenerative Diseases classification, Neurodegenerative Diseases drug therapy, Neurodegenerative Diseases etiology, Neuronal Plasticity physiology, Norepinephrine agonists, Norepinephrine antagonists & inhibitors, Norepinephrine therapeutic use, Recovery of Function drug effects, Recovery of Function physiology, Locus Coeruleus anatomy & histology, Locus Coeruleus physiology, Models, Neurological, Neurodegenerative Diseases metabolism, Norepinephrine physiology
- Abstract
A deficiency in the noradrenergic system of the brain, originating largely from cells in the locus coeruleus (LC), is theorized to play a critical role in the progression of a family of neurodegenerative disorders that includes Parkinson's disease (PD) and Alzheimer's disease (AD). Consideration is given here to evidence that several neurodegenerative diseases and syndromes share common elements, including profound LC cell loss, and may in fact be different manifestations of a common pathophysiological process. Findings in animal models of PD indicate that the modification of LC-noradrenergic activity alters electrophysiological, neurochemical and behavioral indices of neurotransmission in the nigrostriatal dopaminergic system, and influences the response of this system to experimental lesions. In models related to AD, noradrenergic mechanisms appear to play important roles in modulating the activity of the basalocortical cholinergic system and its response to injury, and to modify cognitive functions including memory and attention. Mechanisms by which noradrenaline may protect or promote recovery from neural damage are reviewed, including effects on neuroplasticity, neurotrophic factors, neurogenesis, inflammation, cellular energy metabolism and excitotoxicity, and oxidative stress. Based on evidence for facilitatory effects on transmitter release, motor function, memory, neuroprotection and recovery of function after brain injury, a rationale for the potential of noradrenergic-based approaches, specifically alpha2-adrenoceptor antagonists, in the treatment of central neurodegenerative diseases is presented.
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- 2004
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30. KC 12291: an atypical sodium channel blocker with myocardial antiischemic properties.
- Author
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John GW, Létienne R, Le Grand B, Pignier C, Vacher B, Patoiseau JF, Colpaert FC, and Coulombe A
- Subjects
- Animals, Cardiotonic Agents chemistry, Cardiotonic Agents pharmacokinetics, In Vitro Techniques, Ion Channel Gating, Sodium Channel Blockers chemistry, Sodium Channel Blockers pharmacokinetics, Thiadiazoles chemistry, Thiadiazoles pharmacokinetics, Cardiotonic Agents pharmacology, Myocardial Ischemia drug therapy, Sodium Channel Blockers pharmacology, Thiadiazoles pharmacology
- Abstract
KC 12291 was designed as a voltage-gated sodium channel (VGSC) blocker with cardioprotective properties. KC 12291 has moderate inhibitory effects on peak (or rapid) Na+ current, and markedly reduces sustained (or slowly or non-inactivating) Na+ current. This distinguishes KC 12291 from conventional VGSC blockers such as local anesthetics or antiarrhythmics, which have little or no cardioprotective properties. Since VGSCs represent the main pathway for ischemic Na+ loading by failing to inactivate fully, KC 12291 exerts pronounced antiischemic activity principally by reducing the amplitude of sustained Na+ current. In isolated atria and Langendorff-perfused hearts, KC 12291 inhibits diastolic contracture, renowned for its resistance to pharmacological inhibition, reduces ischemic Na+ loading and preserves cardiac energy status. KC 12291 exerts oral antiischemic activity in vivo in the absence of major hemodynamic effects. Cardiac VGSC blockers such as KC 12291, which block cardiac VGSCs in atypical fashion by effectively inhibiting the sustained component of Na+ current, represent, therefore, promising potential antiischemic and cardioprotective drugs.
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- 2004
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31. Protective effect of the alpha2-adrenoceptor antagonist, dexefaroxan, against spatial memory deficit induced by cortical devascularization in the adult rat.
- Author
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Chopin P, Debeir T, Raisman-Vozari R, Colpaert FC, and Marien MR
- Subjects
- Adrenergic alpha-2 Receptor Antagonists, Animals, Behavior, Animal drug effects, Brain Ischemia complications, Cerebral Cortex blood supply, Male, Memory Disorders etiology, Rats, Rats, Sprague-Dawley, Spatial Behavior drug effects, Adrenergic alpha-Antagonists pharmacology, Benzopyrans pharmacology, Brain Ischemia physiopathology, Cerebral Cortex physiopathology, Imidazoles pharmacology, Memory Disorders prevention & control, Vascular Surgical Procedures methods
- Abstract
The alpha2-adrenoceptor antagonist, dexefaroxan, has been shown in the rat to have neuroprotective and plastic effects against degenerative structural changes in elements of the basalocortical cholinergic system that result from cortical devascularization [Neuroscience 115 (2002) 41]. The present study, using the same experimental protocol, examined the functional consequences of cortical devascularization and dexefaroxan treatment in the Morris water maze memory test. Rats were first trained to find the hidden platform in the test, and then subjected to the devascularization procedure. Thirty-one days later, lesioned rats exhibited a significant deficit in recalling the platform location, compared with sham control animals. A 28-day subcutaneous infusion with dexefaroxan (0.63, 2.5, and 10 mg rat(-1) day(-1)), starting from the moment of the devascularization, protected against this spatial memory deficit.
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- 2004
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32. Ca2+ responses in Chinese hamster ovary-K1 cells demonstrate an atypical pattern of ligand-induced 5-HT1A receptor activation.
- Author
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Pauwels PJ and Colpaert FC
- Subjects
- Animals, CHO Cells, Cricetinae, Female, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Humans, Sulfur Radioisotopes, 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Calcium pharmacology, Receptor, Serotonin, 5-HT1A metabolism, Serotonin Receptor Agonists pharmacology
- Abstract
Little experimental evidence has been reported for diverse signaling via 5-hydroxytryptamine (5-HT)1A receptors despite the fact that agonists seem to be more efficacious at dorsal raphe somatodendritic 5-HT1A autoreceptors than at postsynaptic 5-HT1A receptors. The present study investigated Ca2+ responses in Chinese hamster ovary (CHO)-K1 cells expressing a human 5-HT1A receptor by 5-HT, prototypical 5-HT1A agonists, N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methyl-6-; methylaminopyridin-2-yl)-methylaminomethyl]-piperidine (F 14679), and especially N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methylpyridin-2-yl)-; methylaminomethyl]piperidine (F 13640) as representative ligands of a new chemical class (methylamino-pyridine) that combines both high efficacy and selectivity for 5-HT1A receptors. 5-HT (pEC50 = 6.70 +/- 0.02) induced a pertussis toxin-sensitive, transient high-magnitude Ca2+ response. High-magnitude Ca2+ responses (Emax, percentage versus 5-HT) were also found with F 13640 (107 +/- 4), 5-carboxamidotryptamine (100 +/- 3), and F 14679 (87 +/- 3). In contrast, the prototypical 5-HT1A receptor agonists buspirone, ipsapirone, and 8-(hydroxy-2-(di-n-propylamino)tetralin, and also flesinoxan and eptapirone, were virtually inactive (< or =5). This atypical pattern of 5-HT1A receptor activation contrasts with the broad spectrum of the ligands' partial agonist properties as observed by measuring guanosine 5'-O-(3-[35 S]thio)triphosphate ([35S]GTPgammaS) binding responses with membranes of either CHO-K1 or C6-glial cells stably expressing a human 5-HT1A receptor. Remarkably, differences between ligands that seem small in the [35S]GTPgammaS binding assay translate into huge differences in the magnitude of Ca2+ responses. Therefore, some of these 5-HT1A ligands (i.e., F 13640) may in a selective way induce responses that may be not at all be achieved with other ligands (i.e., buspirone). In conclusion, the pharmacology of 5-HT1A receptor ligands seems to be codetermined by the effector pathway.
- Published
- 2003
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33. The very-high-efficacy 5-HT1A receptor agonist, F 13640, preempts the development of allodynia-like behaviors in rats with spinal cord injury.
- Author
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Wu WP, Hao JX, Xu XJ, Wiesenfeld-Hallin Z, Koek W, and Colpaert FC
- Subjects
- Animals, Cold Temperature, Female, Motor Activity drug effects, Pain etiology, Pain Measurement drug effects, Pain Threshold drug effects, Photochemistry, Physical Stimulation, Rats, Rats, Sprague-Dawley, Spinal Cord Injuries complications, Time Factors, Vocalization, Animal drug effects, Behavior, Animal drug effects, Behavior, Animal physiology, Pain psychology, Piperidines pharmacology, Pyridines pharmacology, Receptor, Serotonin, 5-HT1A drug effects, Serotonin Receptor Agonists pharmacology, Spinal Cord Injuries psychology
- Abstract
Central neuropathic pain after spinal cord injury (SCI) presents a challenging clinical problem with limited treatment options. [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-([(5-methyl-pyridin-2-ylmethyl)-amino]-methyl)piperidin-1-yl]]-methadone (F 13640) is a recently discovered very-high-efficacy, selective 5-HT1A receptor agonist that produces a remarkably powerful, central analgesia through unprecedented neuroadaptive mechanisms. In a rat model of spinal cord injury pain, we previously found that chronic infusion of F 13640 alleviated pain-like behaviors. Here, we report that infusion of 0.63 mg/day of F 13640 for 8 weeks starting 24 h before the induction of injury significantly attenuates the development of chronic allodynia-like behavior in rats sustaining a photochemically-induced, ischaemic injury of the dorsal laminae of the L3-L5 segments of the spinal cord. Importantly, the preemptive effect of F 13640 persisted for 2 months after treatment was discontinued. The data warrant the study of the possible effects of the early administration of F 13640 in patients sustaining spinal cord injury.
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- 2003
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34. Continuous administration of the 5-hydroxytryptamine1A agonist (3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl) -amino]-methyl]piperidin-1-yl]-methadone (F 13640) attenuates allodynia-like behavior in a rat model of trigeminal neuropathic pain.
- Author
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Deseure K, Koek W, Adriaensen H, and Colpaert FC
- Subjects
- Analgesics, Opioid therapeutic use, Analysis of Variance, Animals, Behavior, Animal drug effects, Disease Models, Animal, Male, Pain etiology, Pain Measurement, Rats, Rats, Sprague-Dawley surgery, Pain drug therapy, Piperidines therapeutic use, Pyridines therapeutic use, Trigeminal Neuralgia physiopathology
- Abstract
(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methadone (F 13640) is a recently discovered high-efficacy 5-hydroxytryptamine (HT)1A receptor agonist that produces central analgesia through the neuroadaptive mechanisms of inverse tolerance and cooperation. In a rat model of trigeminal neuropathic pain, the chronic constriction injury of the infraorbital nerve causes allodynia-like behavior that develops within 2 weeks and remains stable thereafter. We report that early after surgery, during which time allodynia develops, the continuous 2-week infusion of 0.63 mg/day F 13640 inhibited the allodynia-like behavior, whereas 5 mg/day morphine showed no significant effect. When F 13640 infusion was initiated late after surgery, when allodynia was well established, it produced an antiallodynic effect that was apparent during the entire infusion period. In contrast, morphine infusion caused an initially marked antiallodynic effect to which tolerance developed within the 2-week infusion period. The GABA-B receptor agonist baclofen (1.06 mg/day) that has a recognized usefulness in the treatment of trigeminal neuralgia, demonstrated effectiveness in both conditions. The data are consistent with a theory of nociceptive signal transduction, as well as with previous data, in demonstrating the neuroadaptive mechanisms of inverse tolerance and cooperation. That is, in contrast with morphine, the antiallodynic effect induced by 5-HT1A receptor activation does not decay, but, if anything, grows with chronicity. Also, 5-HT1A receptor activation seemed to cooperate with nociceptive stimulation in, paradoxically, inducing an antiallodynic effect. The data presented here suggest that F 13640 may perhaps offer a lasting treatment of trigeminal neuralgia.
- Published
- 2003
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35. Mutation in a protein kinase C phosphorylation site of the 5-HT1A receptor preferentially attenuates Ca2+ responses to partial as opposed to higher-efficacy 5-HT1A agonists.
- Author
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Wurch T, Colpaert FC, and Pauwels PJ
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Animals, CHO Cells, Cricetinae, GTP-Binding Protein alpha Subunits, Gq-G11, Heterotrimeric GTP-Binding Proteins genetics, Humans, Ligands, Phosphorylation, Piperazines pharmacology, Pyridines pharmacology, Radioligand Assay, Receptors, Serotonin drug effects, Receptors, Serotonin, 5-HT1, Serotonin Antagonists pharmacology, Tetradecanoylphorbol Acetate pharmacology, Transfection, Calcium physiology, Mutation genetics, Mutation physiology, Protein Kinase C genetics, Receptors, Serotonin genetics, Serotonin Receptor Agonists pharmacology
- Abstract
The Thr(149)Ala mutation in a putative protein kinase C phosphorylation site of the 5-HT(1A) receptor's second intracellular loop has been shown to affect the closing of Ca(2+) channels and Ca(2+) mobilisation without interfering with the inhibitory cAMP pathway (Mol Pharmacol 52 (1997) 164). Here, the Ca(2+) responses for a series of 5-HT(1A) agonists were compared between the wild-type (wt) and mutant Thr(149)Ala 5-HT(1A) receptor as part of a fusion protein containing a G(alpha)(15) protein. Neither the mutation nor the fusion process modified the [(3)H]WAY 100635-based ligand binding profile of the fusion proteins as compared to the wt 5-HT(1A) receptor protein. Whereas at the wt 5-HT(1A) receptor, 5-HT induced a Ca(2+) response in CHO-K1 cells via endogenous G(i/o) proteins, the Ca(2+) response to 5-HT at the mutant Thr(149)Ala 5-HT(1A) receptor was fully dependent on either the co-expression or the fusion to a recombinant G(alpha)(15) protein. Buspirone, flesinoxan and 8-OH-DPAT produced a graded partial response (26 to 62%) at the wt 5-HT(1A):G(alpha)(15) fusion protein; F 13640, 5-CT and F 14679 behaved as higher-efficacy agonists with maximal Ca(2+) responses similar to 5-HT. The maximal Ca(2+) responses at the mutant Thr(149)Ala 5-HT(1A):G(alpha)(15) fusion protein were significantly attenuated for flesinoxan and 8-OH-DPAT (-45 and -36%, respectively); the response to the other 5-HT agonists was not significantly affected. A similar effect was observed upon treatment with phorbol 12-myristate 13-acetate at the Thr(149)Ala 5-HT(1A):G(alpha)(15) fusion protein. In conclusion, the amplitude of the Ca(2+) responses induced by partial, but not that to fuller 5-HT(1A) receptor agonists, is affected by the Thr(149)Ala mutation of the 5-HT(1A):G(alpha)(15) fusion protein.
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- 2003
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36. Donitriptan selectively decreases jugular venous oxygen saturation in the anesthetized pig: further insights into its mechanism of action relevant to headache relief.
- Author
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Letienne R, Verscheure Y, Perez M, Le Grand B, Colpaert FC, and John GW
- Subjects
- Anesthesia, Animals, Blood Gas Analysis, Carbon Dioxide blood, Carotid Arteries physiology, Electrocardiography drug effects, Hemodynamics drug effects, Hemoglobins metabolism, Male, Oxadiazoles pharmacology, Receptor, Serotonin, 5-HT1B, Receptor, Serotonin, 5-HT1D, Receptors, Serotonin drug effects, Serotonin Antagonists pharmacology, Swine, Tryptamines, Vascular Resistance drug effects, Vasoconstriction drug effects, Headache drug therapy, Jugular Veins physiology, Nitriles pharmacology, Nitriles therapeutic use, Oxygen blood, Piperazines pharmacology, Piperazines therapeutic use, Serotonin Receptor Agonists pharmacology, Serotonin Receptor Agonists therapeutic use
- Abstract
The effects of donitriptan on systemic arterial-jugular venous oxygen saturation difference were evaluated in pentobarbitone-anesthetized pigs. Oxygen and carbon dioxide partial pressures in systemic arterial and jugular venous blood as well as hemoglobin oxygen saturation were determined by conventional blood gas analysis. Vehicle (40% polyethyleneglycol in saline, n = 9) or donitriptan (0.01, 0.04, 0.16, 0.63, 2.5, 10, and 40 microg/kg, n = 7) were cumulatively infused over 15 min/dose. The involvement of 5-hydroxytryptamine(1B) (5-HT(1B)) receptors was assessed in the presence of the 5-HT(1B/1D) receptor antagonist, GR 127935. Donitriptan decreased markedly and dose dependently jugular venous oxygen saturation [ED(50) 0.5 (0.3-1.1) microg/kg], in parallel with increases in carotid vascular resistance [ED(50) 0.9 (0.7-1.1) microg/kg]. Since arterial oxygen saturation and partial pressure remained unchanged, donitriptan significantly increased arteriovenous oxygen saturation difference from 0.63 microg/kg (maximal variation: 57 +/- 18%, P < 0.05 compared with vehicle). Unexpectedly, donitriptan from 2.5 microg/kg induced marked and significant increases in carbon dioxide partial pressure (pVCO(2)) in venous blood (maximal increase 18.8 +/- 5.7%; P < 0.05 compared with vehicle). Pretreatment with GR 127935 (0.63 mg/kg, n = 5) abolished the fall in venous oxygen saturation and the increase in carotid vascular resistance and reduced the increases in pVCO(2) induced by donitriptan. The results demonstrate that donitriptan, via 5-HT(1B) receptor activation, decreases the oxygen saturation of venous blood draining the head, concomitantly with cranial vasoconstriction. Since donitriptan also increased pVCO(2), an effect upon cerebral oxygen consumption and metabolism is suggested in addition to cranial vasoconstriction, which may be relevant to its headache-relieving effects.
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- 2003
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37. Tolerance and inverse tolerance to the hyperalgesic and analgesic actions, respectively, of the novel analgesic, F 13640.
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Bruins Slot LA, Koek W, Tarayre JP, and Colpaert FC
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- Algorithms, Animals, Body Temperature drug effects, Dose-Response Relationship, Drug, Drug Tolerance, Hyperalgesia physiopathology, Male, Pain physiopathology, Pain prevention & control, Pain Threshold drug effects, Rats, Rats, Sprague-Dawley, Signal Transduction, Time Factors, Analgesics pharmacology, Hyperalgesia prevention & control, Piperidines pharmacology, Pyridines pharmacology
- Abstract
5-HT(1A) receptor activation by the very-high-efficacy, selective 5-HT(1A) receptor agonist F 13640 [(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-([(5-methyl-pyridin-2-ylmethyl)-amino]-methyl)piperidin-1-yl]-methanone] was recently discovered to constitute a novel central mechanism of broad-spectrum analgesia that, remarkably, grows rather than decays with chronicity. However, in rodents not exposed to nociception, F 13640 induces its analgesic effect only after having initially induced hyperalgesia. Numerical simulations implementing a signal transduction theory here show that the progressive increase in the intensity of nociceptive stimulation which F 13640 presumably mimics should eventually produce a large analgesic effect without initially causing marked pain. In vivo studies examined the effects of progressively increasing doses of F 13640 on the threshold of mechanically induced vocalization and, also, on the 5-HT syndrome in rats. The infusion of increasing (0.04-0.63 mg/rat/day) doses of F 13640 over a 5-week period induced a large analgesia preceded by a hyperalgesic effect that was small and comparable to that induced by initial exposure to a low, 0.04 mg/rat/day dose. Furthermore, increasing the dose of F 13640 induced tachyphylaxis to the 5-HT syndrome. Producing the mirror opposite of morphine's neuroadaptive actions, F 13640 causes an analgesia that becomes more powerful with chronic administration, and this at the expense of the initial hyperalgesia which it may also produce.
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- 2003
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38. Profound, non-opioid analgesia produced by the high-efficacy 5-HT(1A) agonist F 13640 in the formalin model of tonic nociceptive pain.
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Bardin L, Tarayre JP, Malfetes N, Koek W, and Colpaert FC
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- Analgesics, Opioid pharmacology, Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Hindlimb drug effects, Male, Morphine adverse effects, Morphine pharmacology, Naloxone pharmacology, Narcotic Antagonists pharmacology, Pain Measurement methods, Piperazines pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Serotonin drug effects, Receptors, Serotonin, 5-HT1, Serotonin Antagonists pharmacology, Analgesics, Non-Narcotic pharmacology, Pain Measurement drug effects, Pain Threshold drug effects, Piperidines pharmacology, Pyridines pharmacology, Serotonin Receptor Agonists pharmacology
- Abstract
Previously, we have reported that in rat models of chronic pain, in particular, the very-high-efficacy 5-HT(1A) agonist F 13640 induces unprecedented pain relief by novel neuroadaptative mechanisms that involve inverse tolerance and cooperation with nociceptive stimulation in producing analgesia. The present studies detailed the actions of F 13640 and other compounds in the formalin model of tonic nociceptive pain. Intraperitoneal injection of F 13640 (0.01-2.5 mg/kg; t -15 min) caused a dose-dependent and complete inhibition of the paw elevation and paw licking that occurred both early (0-5 min) and late (22.5-27.5 min) after the intraplantar injection of diluted formaldehyde (2.5%) in the rat. The extent to which F 13640 and other 5-HT(1A) receptor ligands inhibited these pain behaviors correlated (p < 0.05) with the extent to which they activated 5-HT(1A) receptors. Under similar conditions, some inhibitory effects were also observed with various agents that are known to produce analgesia by different peripheral and/or central mechanisms (e.g., opioids, NA/5-HT reuptake inhibitors, COX-2 inhibitors and other nonsteroidal anti-inflammatory drugs, gabapentin, and ABT-594). However, with the possible exception of morphine, the effects of all of these agents at nontoxic doses were lower than those of F 13640, in particular in inhibition of early paw elevation. The 5-HT(1A) antagonist WAY 100635, but not naloxone, antagonized the actions of F 13640. These results help to establish large-magnitude 5-HT(1A) receptor activation as a new molecular mechanism of profound, central analgesia and suggest that F 13640 may be particularly effective against pain arising from severe tonic nociceptive stimulation., (Copyright 2003 S. Karger AG, Basel)
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- 2003
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39. Discovering risperidone: the LSD model of psychopathology.
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Colpaert FC
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- History, 20th Century, Antipsychotic Agents history, Hallucinogens history, Lysergic Acid Diethylamide history, Psychopathology history, Risperidone history
- Abstract
In the 1970s and 1980s, Janssen Pharmaceutica Research, which had a broad interest in central nervous system disorders and nurtured intellectual freedom, developed original, and at times heretical, concepts. It took decades for the scientific community to endorse some of these concepts. Among them were such notions as an elementary particle of behaviour, the introduction of response quality in receptor theory, and the idea that tolerance does not develop to opioids. These concepts enabled the discovery of the antipsychotic risperidone, a unique full antagonist of the interoceptive effects of LSD.
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- 2003
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40. A persistent opioid-addiction state of memory.
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Bruins Slot LA and Colpaert FC
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- Animals, Dose-Response Relationship, Drug, Drug Tolerance, Learning drug effects, Male, Milk, Morphine administration & dosage, Narcotics administration & dosage, Rats, Rats, Sprague-Dawley, Memory drug effects, Morphine pharmacology, Morphine Dependence psychology, Narcotics pharmacology
- Abstract
We determined whether tolerance develops to a morphine-induced state of memory. Rats were injected with 5 mg/kg of morphine and trained to complete a FR-10 schedule of lever presses in daily sessions. The dose-response curve of morphine (1.25-40 mg/kg) in enabling retrieval was tested in one group immediately after criterion had been reached and, in another group, after an additional 40 training sessions. The additional training enhanced, rather than attenuated, the dependence of retrieval on morphine; this was because the further gain in response latency that developed during additional training also became state-dependent. Thus, because tolerance did not develop to the morphine state, an increasingly large body of engrams became encoded in that state, rendering retrieval increasingly dependent.
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- 2003
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41. Tacrine-scopolamine interactions on state-dependent retrieval.
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Bruins Slot LA, Chopin P, and Colpaert FC
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- Analysis of Variance, Animals, Conditioning, Operant physiology, Dose-Response Relationship, Drug, Drug Interactions, Male, Muscarinic Antagonists pharmacology, Psychomotor Performance drug effects, Rats, Rats, Sprague-Dawley, Conditioning, Operant drug effects, Memory drug effects, Scopolamine pharmacology, Tacrine pharmacology
- Abstract
Objectives: This study examined the effects of tacrine on scopolamine-induced state-dependence., Methods: Rats were trained to complete an FR10 schedule of lever presses for milk reward within 120 s after the onset of an operant session and were subsequently tested for the retrieval of the response in either the same or a different, pharmacologically defined, state., Results: In rats trained with 2.5 mg/kg scopolamine, the pre-test administration of 10 mg/kg tacrine prevented scopolamine from enabling the retrieval that otherwise occurred when animals were both trained and tested with scopolamine. However, retrieval of the response was also hampered in animals that were trained with tacrine-scopolamine co-administration and tested with saline, and vice versa, indicating that the co-administration of tacrine and scopolamine did not induce the saline-associated, presumably normal state. At >/=2.5 mg/kg doses, tacrine itself induced state-dependence with both tacrine-to-saline and saline-to-tacrine state changes., Conclusion: The findings indicate that tacrine is unable to normalize the particular mnesic state induced by scopolamine. The data may elucidate tacrine's limited therapeutic efficacy insofar as scopolamine's mnesic actions both model human pathology and are due to scopolamine producing state-dependence.
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- 2003
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42. Constitutive coupling of a chimeric dopamine D2/alpha 1B receptor to the phospholipase C pathway: inverse agonism to silent antagonism by neuroleptic drugs.
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Wurch T, Boutet-Robinet EA, Palmier C, Colpaert FC, and Pauwels PJ
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- Animals, Benzamides pharmacology, CHO Cells, Calcium metabolism, Cricetinae, Digitonin pharmacology, Dopamine metabolism, Female, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Inositol Phosphates metabolism, Kinetics, Ligands, Radioligand Assay, Receptors, Dopamine D2 agonists, Receptors, Dopamine D2 genetics, Recombinant Fusion Proteins metabolism, Transfection, Antipsychotic Agents pharmacology, Dopamine Agonists pharmacology, Dopamine Antagonists pharmacology, Receptors, Dopamine D2 metabolism, Type C Phospholipases metabolism
- Abstract
Neuroleptic drugs have been suggested to act as inverse agonists at the dopamine D2 receptor, but no link between therapeutic efficacy and ligand's intrinsic activity could be determined. Since the resolving capacity to monitor inverse agonism at dopamine D2 receptors is limited, we speculated that receptor constitutive activation could be enhanced by constructing chimeric D2/alpha 1B receptors. Marked inverse agonist responses with a series of dopamine antagonists were obtained by: 1) exchange of the D 2short receptor's 3ICL by that of the alpha 1B-adrenoceptor, 2) incorporation of an activating mutation (Ala 279 Glu) in the distal portion of its 3ICL, and 3) coexpression with a G alpha11 protein. This chimeric D2/alpha 1B receptor construct displayed a ligand binding profile comparable to that of the wild-type (wt) D 2short receptor and an effector activation profile close to that of the wt alpha 1B-adrenoceptor. Most of the dopamine antagonists attenuated by -54 to -59% basal inositol phosphates (IP) formation, thus clearly acting as inverse agonists. Ziprasidone behaved as a silent antagonist (+5% versus basal IP level) and antagonized both dopamine-mediated (pK B, 7.61) and tropapride-mediated (pK B, 8.52) IP responses. Clozapine, olanzapine, and raclopride displayed partial inverse agonist properties (-31, -67, and -71% versus tropapride, respectively), whereas bromerguride (+63%) and cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino tetralin) [(+)-UH 232] (+88%) demonstrated positive agonism. In conclusion, analyses with the chimeric D2/alpha 1B Ala 279 Glu 3ICL receptor construct suggest that neuroleptic drugs can be differentiated on the basis of their intrinsic activity, as they can either activate, inhibit, or be silent at this receptor construct.
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- 2003
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43. The 5-HT(1A) receptor agonist F 13640 attenuates mechanical allodynia in a rat model of trigeminal neuropathic pain.
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Deseure K, Koek W, Colpaert FC, and Adriaensen H
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- Aminopyridines pharmacology, Animals, Baclofen pharmacology, Behavior, Animal drug effects, Disease Models, Animal, Dose-Response Relationship, Drug, Male, Morphine pharmacology, Muscle Relaxants, Central pharmacology, Narcotics pharmacology, Pain physiopathology, Rats, Rats, Sprague-Dawley, Receptors, Serotonin, 5-HT1, Stress, Mechanical, Trigeminal Neuralgia physiopathology, Pain prevention & control, Piperidines pharmacology, Pyridines pharmacology, Receptors, Serotonin drug effects, Serotonin Receptor Agonists pharmacology, Trigeminal Neuralgia prevention & control
- Abstract
The effects of acute intraperitoneal injections of the 5-HT(1A) receptor agonists F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methadone] and F 13714 [3-chloro-4-fluorophenyl-(4-fluoro-4-[[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl-methanone] were studied in comparison with those of baclofen and morphine on responsiveness to von Frey hair stimulation after chronic constriction injury to the rat's infraorbital nerve (IoN-CCI). Following IoN-CCI, an ipsilateral hyperresponsiveness developed that remained stable in control rats throughout the period of drug testing. F 13640, F 13714, baclofen and morphine dose-dependently decreased the hyperresponsiveness; normalization of the response occurred at doses 0.63, 0.04, 5 and 10 mg/kg, respectively. Confirming earlier data, baclofen's effects further validate IoN-CCI as a model of trigeminal neuralgia. The effects of F 13640 and F 13714 are initial evidence that 5-HT(1A) receptor agonists produce profound analgesia in the IoN-CCI model. The present data extend recent evidence that high-efficacy 5-HT(1A) receptor activation constitutes a new mechanism of central analgesia the spectrum of which may also encompass trigeminal neuropathic pain.
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- 2002
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44. Large-amplitude 5-HT1A receptor activation: a new mechanism of profound, central analgesia.
- Author
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Colpaert FC, Tarayre JP, Koek W, Pauwels PJ, Bardin L, Xu XJ, Wiesenfeld-Hallin Z, Cosi C, Carilla-Durand E, Assié MB, and Vacher B
- Subjects
- Acetates pharmacology, Adrenergic Uptake Inhibitors pharmacology, Aminopyridines agonists, Analgesics pharmacology, Animals, CHO Cells, Cells, Cultured, Cricetinae, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Administration Routes veterinary, Drug Administration Schedule veterinary, Drug Synergism, Female, Fentanyl administration & dosage, Gabapentin, Guanosine 5'-O-(3-Thiotriphosphate), Hyperalgesia chemically induced, Imipramine pharmacology, Ketamine pharmacology, Male, Pain chemically induced, Pain drug therapy, Pain physiopathology, Pain Measurement drug effects, Pain Measurement methods, Pain Threshold physiology, Radioligand Assay, Rats, Rats, Sprague-Dawley, Receptors, Serotonin drug effects, Receptors, Serotonin, 5-HT1, Time Factors, Transfection, Amines, Aminopyridines pharmacology, Analgesia, Cyclohexanecarboxylic Acids, Morphine pharmacology, Piperidines pharmacology, Pyridines pharmacology, Receptors, Serotonin physiology, Serotonin Agents pharmacology, gamma-Aminobutyric Acid
- Abstract
We report the discovery of F 13640 and evidence suggesting this agent to produce powerful, broad-spectrum analgesia by novel molecular and neuroadaptative mechanisms. F 13640 stimulates G(alphaomicron) protein coupling to 5-HT(1A) receptors to an extent unprecedented by selective, non-native 5-HT(1A) ligands. Fifteen minutes after its injection in normal rats, F 13640 (0.01-2.5 mg/kg) decreases the vocalization threshold to paw pressure; 15 min upon injection in rats that are exposed to formalin-induced tonic nociception, F 13640 inhibits pain behavior. The initial hyperalgesia induced by 0.63 mg/kg F 13640 was followed, 8 hrs later, by paradoxical hypo-algesia; 5 mg/kg of morphine produces the opposite effects (i.e., hypo-algesia followed by hyper-algesia). Repeated F 13640 injections cause an increase in the basal vocalization threshold and a reduction of F 13640-produced hyperalgesia; in these conditions, morphine causes basal hyperalgesia and antinociceptive tolerance. Continuous two-week infusion of F 13640 (0.63 mg/day) exerts little effect on the threshold in normal rats, but markedly reduces analgesic self-administration in arthritic rats. F 13640 infusion also decreases allodynic responses to tactile and thermal stimulations in rats sustaining spinal cord or sciatic nerve injury. In these models of chronic nociceptive and neuropathic pain, the analgesia afforded by F 13640 consistently surpasses that of morphine (5 mg/day), imipramine (2.5 mg/day), ketamine (20 mg/day) and gabapentin (10 mg/day). Very-high-efficacy 5-HT(1A) receptor activation constitutes a novel mechanism of central analgesia that grows rather than decays with chronicity, that is amplified by nociceptive stimulation, and that may uniquely relieve persistent nociceptive and neuropathic pains.
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- 2002
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45. 5-HT1A receptor activation and anti-cataleptic effects: high-efficacy agonists maximally inhibit haloperidol-induced catalepsy.
- Author
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Prinssen EP, Colpaert FC, and Koek W
- Subjects
- Animals, Behavior, Animal drug effects, Catalepsy chemically induced, Dose-Response Relationship, Drug, Ligands, Male, Rats, Rats, Sprague-Dawley, Receptors, Serotonin, 5-HT1, Serotonin Antagonists pharmacology, Serotonin Receptor Agonists pharmacology, Antipsychotic Agents adverse effects, Catalepsy prevention & control, Haloperidol adverse effects, Receptors, Serotonin drug effects
- Abstract
Studies have shown that 5-HT1A receptor ligands modulate antipsychotic-induced catalepsy. Here, we further examined the role of intrinsic activity at 5-HT1A receptors in these effects. The anti-cataleptic effects of 5-HT(1A) receptor ligands with positive intrinsic activity [from high to low: 3-chloro-4-fluorophenyl-(4-fluoro-4-[[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl-methanone fumaric acid salt (F 13714), eptapirone, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 2-[4-[4-(7-methoxy-1-naphtyl) piperazino]butyl]-4-methyl-2H,4H-1,2,4-triazin-3,5-dione maleic acid salt (F 11461), buspirone, 2-[4-[4-(7-benzofuranyl)piperazino]butyl]-4-methyl-2H,4H-1,2,4-triazin-3,5-dione (F 12826), ipsapirone, and (s)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide hydrochloride (WAY 100135)] and negative intrinsic activity [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide dihydrochloride (WAY 100635)] were examined. Catalepsy was induced by the classical antipsychotic haloperidol (0.63 mg/kg) and measured in the cross-legged position test and in the bar test. All 5-HT1A receptor agonists, except WAY 100135, significantly attenuated the effects of haloperidol in the cross-legged position test. All agonists had similar effects in the bar test, except ipsapirone, which failed to attenuate haloperidol-induced catalepsy. In contrast to the effects observed with the agonists, the inverse agonist WAY 100635 appeared to enhance haloperidol-induced catalepsy in both tests, in agreement with earlier findings. The maximal effects of the 5-HT1A receptor ligands to attenuate catalepsy correlated positively with the rank order of their intrinsic activity at 5-HT1A receptors (either catalepsy test: r(S)=0.92, P<0.001). F 13714, which had the highest intrinsic activity, maximally inhibited haloperidol-induced catalepsy in the cross-legged position and bar tests (100% and 99% inhibition, respectively). Because the magnitude of the anti-cataleptic effects of 5-HT1A receptor ligands correlates positively with their intrinsic activity, it is likely that F 13714 has marked anti-cataleptic effects because of its high intrinsic activity at 5-HT1A receptors.
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- 2002
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46. Experimental conditions for the continuous subcutaneous infusion of four central analgesics in rats.
- Author
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Bruins Slot LA, Tarayre JP, Koek W, Ribet JP, and Colpaert FC
- Subjects
- Acetates administration & dosage, Acetates pharmacology, Analgesics chemistry, Analgesics therapeutic use, Anesthetics, Dissociative administration & dosage, Anesthetics, Dissociative pharmacology, Animals, Anticonvulsants administration & dosage, Anticonvulsants pharmacology, Antidepressive Agents, Tricyclic pharmacology, Chromatography, High Pressure Liquid, Chronic Disease, Convulsants pharmacology, Drug Stability, Gabapentin, Hypothermia chemically induced, Hypothermia prevention & control, Imipramine pharmacology, Ketamine administration & dosage, Ketamine pharmacology, Male, Morphine pharmacology, Pain drug therapy, Pain Measurement drug effects, Pentylenetetrazole antagonists & inhibitors, Pentylenetetrazole pharmacology, Rats, Rats, Sprague-Dawley, Solubility, Tetrabenazine, Amines, Analgesics administration & dosage, Cyclohexanecarboxylic Acids, Infusion Pumps, Implantable, gamma-Aminobutyric Acid
- Abstract
For the analysis of pharmacotherapeutic regimens for chronic pain in animals, it is important to establish delivery methods in which analgesics can be administered continuously and at a constant rate for a prolonged period of time. This allows for the assessment of how drug effects may vary over time in the presence of ongoing pain. The present study determined, for four analgesic compounds, the maximal doses that met all of the following criteria: (i) water-soluble, (ii) stable over 14 days at 38 degrees C, and (iii) devoid of undesirable side-effects in normal rats, as assessed by evolution of body weight and temperature after the subcutaneous implantation of an osmotic mini-pump that continuously infused the compounds over a 14-day period. The results showed the maximal doses to be 5 mg/rat/day for morphine hydrochloride, 2.5 mg/rat/day for imipramine hydrochloride, 20 mg/rat/day for ketamine hydrochloride, and 10 mg/rat/day for gabapentin. These doses were further found to be sufficient to express each compound's representative pharmacological activity. The conditions identified here appear appropriate for future studies of these four compounds in rat models of chronic pain and neuropathic allodynia.
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- 2002
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47. Evidence for protean agonism of RX 831003 at alpha 2A-adrenoceptors by co-expression with different G alpha protein subunits.
- Author
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Pauwels PJ, Rauly I, Wurch T, and Colpaert FC
- Subjects
- Adrenergic alpha-2 Receptor Antagonists, Adrenergic alpha-Antagonists metabolism, Adrenergic alpha-Antagonists pharmacology, Animals, Benzopyrans chemistry, Benzopyrans metabolism, CHO Cells, Cricetinae, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Guanosine 5'-O-(3-Thiotriphosphate) pharmacology, Humans, Imidazoles chemistry, Imidazoles metabolism, Receptors, Adrenergic, alpha-2 metabolism, Signal Transduction drug effects, Signal Transduction physiology, Adrenergic alpha-2 Receptor Agonists, Benzopyrans pharmacology, Heterotrimeric GTP-Binding Proteins biosynthesis, Imidazoles pharmacology, Receptors, Adrenergic, alpha-2 biosynthesis
- Abstract
Intrinsic properties of alpha(2) AR ligands were investigated by measuring two distinct signalling pathways via the alpha(2A) AR protein in CHO-K1 cells: (i) a Ca(2+) response mediated by a promiscuous G(alpha 15) protein; and (ii) a pertussis toxin-resistant [(35)S]GTP gamma S binding response mediated by a G(alpha o)Cys(351)Ile protein. The dexefaroxan analogue RX 831003 was virtually without intrinsic activity at the wt alpha(2A) AR via a G(alpha 15) protein, but induced a partial positive Ca(2+) response [pEC(50): 7.79 (0.17), E(max): 38+/-1% vs (-)-adrenaline] at the mutant Thr(373L)ys alpha(2A) AR. RX 831003 displayed a similar potency (pIC(50): 7.68 (0.21) for both the wt (E(max): -18+/-4%) and Thr(373)Lys alpha(2A) AR (E(max): -19+/-4%) inhibition of basal [(35)S]GTP gamma S binding via a G(alpha o)Cys(351)Ile protein. These data indicate that the alpha(2) AR ligand RX 831003 behaves as a protean agonist at the alpha(2A) AR and that its activity is highly dependent on the co-expressed G(alpha) protein subunit.
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- 2002
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48. Effects of acute and subchronic administration of dexefaroxan, an alpha(2)-adrenoceptor antagonist, on memory performance in young adult and aged rodents.
- Author
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Chopin P, Colpaert FC, and Marien M
- Subjects
- Adrenergic alpha-Agonists pharmacology, Animals, Anti-Anxiety Agents antagonists & inhibitors, Anti-Anxiety Agents pharmacology, Avoidance Learning drug effects, Basal Nucleus of Meynert physiology, Brimonidine Tartrate, Cholinesterase Inhibitors pharmacology, Cognition drug effects, Diazepam antagonists & inhibitors, Diazepam pharmacology, Excitatory Amino Acid Agonists toxicity, Ibotenic Acid toxicity, Male, Maze Learning drug effects, Mice, Muscarinic Antagonists pharmacology, Quinoxalines antagonists & inhibitors, Quinoxalines pharmacology, Rats, Rats, Sprague-Dawley, Scopolamine antagonists & inhibitors, Scopolamine pharmacology, Tacrine pharmacology, Adrenergic alpha-2 Receptor Antagonists, Adrenergic alpha-Antagonists pharmacology, Aging psychology, Benzopyrans pharmacology, Imidazoles pharmacology, Memory drug effects
- Abstract
The present study examined the influence of dexefaroxan, a potent and selective alpha(2)-adrenoceptor antagonist, on cognitive performance in rodents. In young adult rats, dexefaroxan reversed the deficits induced by UK 14304 [5-bromo-N-(4,5-dihydro-1-H-imidazol-2-yl)-6-quinoxalinamine], scopolamine, and diazepam in a passive avoidance task. In this test, dexefaroxan also attenuated the spontaneous forgetting induced by a 15-week training-testing interval. Moreover, dexefaroxan, given immediately after training, increased the memory performance of rats trained with a weak electric footshock in the passive avoidance test, facilitated spatial memory processes in the Morris water maze task in rats, and increased the performance of mice in an object recognition test. Thus, dexefaroxan appears to have a promnesic effect in these tests by facilitating the processes of memory retention, rather than acquisition or other noncognitive influences. The facilitatory effects of dexefaroxan in young adult rats persisted even after a 21- to 25-day constant subcutaneous infusion by using osmotic minipumps, indicating that tolerance to the promnesic effect of the drug did not occur during this prolonged treatment interval. Furthermore, in the passive avoidance and Morris water maze tests, dexefaroxan ameliorated the age-related memory deficits of 24-month-old rats to a level that was comparable to that of young adult animals, and reversed the memory deficits induced by excitotoxin lesions of the nucleus basalis magnocellularis region. Together, these findings support a potential utility of dexefaroxan in the treatment of cognitive deficits occurring in Alzheimer's disease.
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- 2002
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49. Sign-reversal during persistent activation in mu-opioid signal transduction.
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Bruins Slot LA, Pauwels PJ, and Colpaert FC
- Subjects
- Analysis of Variance, Animals, CHO Cells, Calcium metabolism, Cricetinae, Fentanyl pharmacology, Male, Models, Biological, Morphine pharmacology, Rats, Rats, Sprague-Dawley, Regression Analysis, Cells metabolism, Computer Simulation, Narcotics pharmacology, Receptors, Opioid, mu metabolism, Signal Transduction physiology
- Abstract
A concept of signal transduction in biological systems specifies that any instantaneous input is appreciated by its departure from the moving average of past activity. The concept provides an adequate account of the occurrence of both the one-directional (e.g. analgesic) effects induced by opioid receptor activation, and of the contra-directional (e.g. hyperalgesic) effects that can be observed when activation is discontinued. Following this transduction concept, the numerical simulations reported here revealed, remarkably, that under some parametric conditions, the input's effect may reverse even as input is maintained at a constant magnitude. In in vitro conditions that are proximal to the signal transduction that occurs when an opioid agonist binds to the G-protein coupled opioid receptor, the effects of opioid receptor activation were monitored by measuring time-dependent Ca(2+) responses in CHO-K1 cells transfected with a mu-opioid receptor and G(alpha 15) protein. The results indicate morphine to produce an initial increase in intracellular Ca(2+) concentration followed by a decrease below basal level. The occurrence of a sign-reversal was confirmed in native conditions of receptor-to-G protein coupling; the continuous in vivo infusion over a 2-week period of 0.31 mg rat(-1)day(-1) of fentanyl initially caused an increase of the mechanical threshold to induce a pain response (i.e. analgesia) that was followed by a decrease (i.e. hyperalgesia). The findings indicate that with opioid signaling systems, transduction mechanisms operate that may cause the sign of the effect to reverse not only when activation is discontinued but also whilst it is maintained at a constant magnitude., (Copyright 2002 Elsevier Science Ltd. All rights reserved.)
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- 2002
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50. PPARalpha and PPARdelta activators inhibit cytokine-induced nuclear translocation of NF-kappaB and expression of VCAM-1 in EAhy926 endothelial cells.
- Author
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Rival Y, Benéteau N, Taillandier T, Pezet M, Dupont-Passelaigue E, Patoiseau JF, Junquéro D, Colpaert FC, and Delhon A
- Subjects
- Active Transport, Cell Nucleus, Binding Sites, Cell Nucleus drug effects, Cell Nucleus metabolism, Cells, Cultured, Chemokine CCL2 metabolism, Cytokines metabolism, Down-Regulation drug effects, Endothelium, Vascular metabolism, Gene Expression drug effects, Humans, Intercellular Adhesion Molecule-1 metabolism, Monocytes drug effects, Monocytes metabolism, Phenoxyacetates, Signal Transduction drug effects, Signal Transduction physiology, Acetates pharmacology, Endothelium, Vascular drug effects, NF-kappa B metabolism, Peroxisome Proliferators pharmacology, Phenols pharmacology, Pyrimidines pharmacology, Receptors, Cytoplasmic and Nuclear metabolism, Transcription Factors metabolism, Vascular Cell Adhesion Molecule-1 biosynthesis
- Abstract
Endothelium injury is a primary event in atherogenesis, which is followed by monocyte infiltration, macrophage differentiation, and smooth muscle cell migration. Peroxisome proliferator-activated receptors (PPARs) are transcription factors now recognized as important mediators in the inflammatory response. The aim of this study was to develop a human endothelial model to evaluate anti-inflammatory properties of PPAR activators. PPAR proteins (alpha, delta and gamma) are expressed in EAhy926 endothelial cells (ECs). Pirinixic acid (Wy-14643), fenofibrate, fenofibric acid, the Merck ligand PPARdelta activator L-165041, 15-deoxy-Delta(12,14)-prostaglandin J2, but not rosiglitazone (BRL-49653) inhibited the induced expression of vascular cell adhesion molecule-1 (VCAM-1), as measured by enzyme linked immunosorbent assay (ELISA), and monocyte binding to activated-EAhy926 cells. The PPARdelta activator L-165041 had the greatest potency to reduce cytokine-induced monocyte chemotactic protein-1 (MCP-1) secretion. All PPAR activators tested which impaired VCAM-1 expression reduced significantly nuclear p65 amount. These results show that EAhy926 endothelial cells are an adequate tool to substantiate and characterize inflammatory impacts of PPAR activators.
- Published
- 2002
- Full Text
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