79 results on '"De Felipe, C."'
Search Results
2. Remote heart failure management using a multiparameter implantable cardioverter-defibrillator alert: the multicentric RE-HEART registry
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De Juan Baguda, J, primary, Gavira Gomez, J.J, additional, Pachon Iglesias, M, additional, Pena Conde, L, additional, Rubin Lopez, J.M, additional, Cozar Leon, R, additional, Arcocha Torres, M.F, additional, Goirigolzarri Artaza, J.M, additional, De Diego Rus, C, additional, Medina Gil, J.M, additional, Martinez Mateo, V, additional, Martinez Martinez, J.G, additional, Alonso Salinas, G.L, additional, Briz De Felipe, C, additional, and Salguero Bodes, R, additional
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- 2020
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3. O6 THE INVOLVEMENT OF NK-1 RECEPTOR IN THE BEHAVIOURAL EFFECTS OF ETHANOL
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Pastor, R., Font, L., Hunt, S.P., De Felipe, C., and Miquel, M.
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- 2005
4. FLRT3 is expressed in sensory neurons after peripheral nerve injury and regulates neurite outgrowth
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Robinson, M., Parsons Perez, M. C., Tébar, L., Palmer, J., Patel, A., Marks, D., Sheasby, A., De Felipe, C., Coffin, R., Livesey, F. J., and Hunt, S. P.
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- 2004
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5. Comparison of the phenotype of NK1R−/− mice with pharmacological blockade of the substance P (NK 1 ) receptor in assays for antidepressant and anxiolytic drugs
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Rupniak, N.M.J., Carlson, E.J., Webb, J.K., Harrison, T., Porsolt, R.D., Roux, S., de Felipe, C., Hunt, S.P., Oates, B., and Wheeldon, A.
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- 2001
6. Role of central and peripheral tachykinin NK1 receptors in capsaicin-induced pain and hyperalgesia in mice
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Laird, J.M.A., Roza, C., De Felipe, C., Hunt, S.P., and Cervero, F.
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- 2001
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7. Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation
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Lambrecht, B.n., Germonpre, P.r., Everaert, E.g., Carro-Muino, I., De Veerman, Marijke, De Felipe, C., Hunt, S.p., Thielemans, Kris, Joos, Gunther, Pauwels, R.a., Physiology, Basic (bio-) Medical Sciences, Laboratory of Molecullar and Cellular Therapy, and Immunomodulation in Chronic Inflammatory Diseases
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- 1999
8. Pharmacological blockade or genetic deletion of substance P (NK1) receptors attenuates neonatal vocalisation in guinea-pigs and mice
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Rupniak, N.M.J, primary, Carlson, E.C, additional, Harrison, T, additional, Oates, B, additional, Seward, E, additional, Owen, S, additional, de Felipe, C, additional, Hunt, S, additional, and Wheeldon, A, additional
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- 2000
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9. Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene
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Laird, J.M.A., primary, Olivar, T., additional, Roza, C., additional, De Felipe, C., additional, Hunt, S.P., additional, and Cervero, F., additional
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- 2000
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10. Comparison of cardiorespiratory reflexes in NK1 receptor knockout, heterozygous and wild-type mice in vivo
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Butcher, J.W, primary, De Felipe, C, additional, Smith, A.J.H, additional, Hunt, S.P, additional, and Paton, J.F.R, additional
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- 1998
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11. The differential control of c-jun expression in regenerating sensory neurons and their associated glial cells
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De Felipe, C, primary and Hunt, SP, additional
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- 1994
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12. Theiler's Murine Encephalomyelitis Virus-binding Activity on Neural and Non-neural Cell Lines and Tissues
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Rubio, N., primary, de Felipe, C., additional, and Torres, C., additional
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- 1990
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13. Organ donation in Spain.
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Lucas, MF, Miranda, B, de Felipe, C, Naya, M, González-Posada, JM, and Matesanz, R
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- 1999
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14. Neurochemical findings in neuroacanthocytosis.
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de Yebenes, J. G., Brin, M. F., Mena, M. A., De Felipe, C., del Rio, R. M., Bazan, E., Martinez, A., Fahn, S., Del Rio, J., Vazquez, A., and de Seijas, E. Varela
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- 1988
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15. Update on organ donation and retrieval in Spain.
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Miranda, B, Gonzalez Alvarez, I, Cuende, N, Naya, M T, and De Felipe, C
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- 1999
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16. Deletion of tachykinin NK1 receptor gene in mice does not alter respiratory network maturation but alters respiratory responses to hypoxia
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Hilaire G, Burnet H, Ptak K, Sieweke M, bruno blanchi, De Felipe C, Hunt S, and Monteau R
17. The use of NK-1 receptor null mice to assess the significance of substance P in the carotid body function
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Alberto José Rico Martín, Prieto-Lloret J, Df, Donnelly, De Felipe C, Gonzalez C, and Rigual R
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Mice, Knockout ,Carotid Body ,Mice ,Carotid Sinus ,Animals ,Female ,In Vitro Techniques ,Receptors, Neurokinin-1 ,Substance P ,Hypoxia ,Immunohistochemistry ,Chemoreceptor Cells
18. Implicación del neuropéptido sustancia P en el desarrollo y expresión de la sensibilización motora inducida por anfetamina y morfina.
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Del Rio, E., El Banoua, F., and De Felipe, C.
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- 2007
19. Comparison of cardiorespiratory reflexes in NK 1 receptor knockout, heterozygous and wild-type mice in vivo
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Butcher, J.W, De Felipe, C, Smith, A.J.H, Hunt, S.P, and Paton, J.F.R
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- 1998
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20. Adrenocortical and behavioural response to chronic restraint stress in neurokinin-1 receptor knockout mice.
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Delgado-Morales R, del Río E, Gómez-Román A, Bisagno V, Nadal R, de Felipe C, and Armario A
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- Adaptation, Ocular, Animals, Chi-Square Distribution, Male, Maze Learning drug effects, Mice, Mice, Inbred C57BL, Mice, Knockout, Radioimmunoassay methods, Restraint, Physical methods, Time Factors, Behavior, Animal physiology, Corticosterone blood, Receptors, Neurokinin-1 deficiency, Stress, Psychological blood, Stress, Psychological metabolism, Stress, Psychological physiopathology
- Abstract
Brain substance P and its receptor (neurokinin-1, NK1) have a widespread brain distribution and are involved in an important number of behavioural and physiological responses to emotional stimuli. However, the role of NK1 receptors in the consequences of exposure to chronic stress has not been explored. The present study focused on the role of these receptors in the hypothalamic-pituitary-adrenal (HPA) response to daily repeated restraint stress (evaluated by plasma corticosterone levels), as well as on the effect of this procedure on anxiety-like behaviour, spatial learning and memory in the Morris water maze (MWM), a hippocampus-dependent task. Adult null mutant NK1-/- mice, with a C57BL/6J background, and the corresponding wild-type mice showed similar resting corticosterone levels and, also, did not differ in corticosterone response to a first restraint. Nevertheless, adaptation to the repeated stressor was faster in NK1-/- mice. Chronic restraint modestly increased anxiety-like behaviour in the light-dark test, irrespective of genotype. Throughout the days of the MWM trials, NK1-/- mice showed a similar learning rate to that of wild-type mice, but had lower levels of thigmotaxis and showed a better retention in the probe trial. Chronic restraint stress did not affect these variables in either genotype. These results indicate that deletion of the NK1 receptor does not alter behavioural susceptibility to chronic repeated stress in mice, but accelerates adaptation of the HPA axis. In addition, deletion may result in lower levels of thigmotaxis and improved short-term spatial memory, perhaps reflecting a better learning strategy in the MWM., (Copyright © 2011 Elsevier Inc. All rights reserved.)
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- 2012
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21. Vanilloid receptor TRPV1, sensory C-fibers, and vascular autoregulation: a novel mechanism involved in myogenic constriction.
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Scotland RS, Chauhan S, Davis C, De Felipe C, Hunt S, Kabir J, Kotsonis P, Oh U, and Ahluwalia A
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- 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid pharmacology, Animals, CHO Cells, Capsaicin pharmacology, Capsaicin toxicity, Cation Transport Proteins antagonists & inhibitors, Cricetinae, Endothelium, Vascular physiology, Gadolinium pharmacology, Ganglia, Sympathetic drug effects, Guanethidine pharmacology, Hydroxyeicosatetraenoic Acids pharmacology, Ion Channels drug effects, Male, Mesenteric Arteries drug effects, Mesenteric Arteries innervation, Mice, Mice, Knockout, Nerve Fibers, Unmyelinated drug effects, Nociceptors drug effects, Nociceptors physiology, Peptides, Cyclic pharmacology, Piperidines pharmacology, Pressure, Quinuclidines pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Neurokinin-1 deficiency, Receptors, Neurokinin-1 genetics, Ruthenium Red pharmacology, Sodium Channel Blockers pharmacology, Splanchnic Circulation drug effects, Stress, Mechanical, Sympathectomy, Chemical, TRPV Cation Channels, Tetrodotoxin pharmacology, Vascular Resistance drug effects, Vasoconstriction drug effects, Capsaicin analogs & derivatives, Ion Channels physiology, Mesenteric Arteries physiology, Models, Cardiovascular, Models, Neurological, Nerve Fibers, Unmyelinated physiology, Splanchnic Circulation physiology, Vascular Resistance physiology, Vasoconstriction physiology
- Abstract
Myogenic constriction describes the innate ability of resistance arteries to constrict in response to elevations in intraluminal pressure and is a fundamental determinant of peripheral resistance and, hence, organ perfusion and systemic blood pressure. However, the receptor/cell-type that senses changes in pressure on the blood vessel wall and the pathway that couples this to constriction of vascular smooth muscle remain unclear. In this study, we show that elevation of intraluminal transmural pressure of mesenteric small arteries in vitro results in a myogenic response that is profoundly suppressed following ablation of sensory C-fiber activity (using in vitro capsaicin desensitization resulted in 72.8+/-10.3% inhibition, n=8; P<0.05). Activation of C-fiber nerve endings by pressure was attributable to stimulation of neuronal vanilloid receptor, TRPV1, because blockers of this channel, capsazepine (71.9+/-11.1% inhibition, n=9; P<0.001) and ruthenium red (46.1+/-11.7% inhibition, n=4; P<0.05), suppressed the myogenic constriction. In addition, this C-fiber dependency is likely related to neuropeptide substance P release and activity because blockade of tachykinin NK1 receptors (66.3+/-13.7% inhibition, n=6; P<0.001), and not NK2 receptors (n=4, NS), almost abolished the myogenic response. Previous studies support a role for 20-hydroxyeicosatetraenoic acid (20-HETE) in myogenic constriction responses; herein, we show that 20-HETE-induced constriction of mesenteric resistance arteries is blocked by capsazepine. Together, these results suggest that elevation of intraluminal pressure is associated with generation of 20-HETE that, in turn, activates TRPV1 on C-fiber nerve endings resulting in depolarization of nerves and consequent vasoactive neuropeptide release. These findings identify a novel mechanism contributing to Bayliss' myogenic constriction and highlights an alternative pathway that may be targeted in the therapeutics of vascular disease, such as hypertension, where enhanced myogenic constriction plays a role in the pathogenesis.
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- 2004
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22. Bone cancer pain: the effects of the bisphosphonate alendronate on pain, skeletal remodeling, tumor growth and tumor necrosis.
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Sevcik MA, Luger NM, Mach DB, Sabino MA, Peters CM, Ghilardi JR, Schwei MJ, Röhrich H, De Felipe C, Kuskowski MA, and Mantyh PW
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- Activating Transcription Factor 3, Animals, Behavior, Animal, Biomarkers, Tumor, Bone Neoplasms complications, Bone Neoplasms pathology, Male, Mice, Mice, Inbred C3H, Necrosis, Osteoclasts drug effects, Osteoclasts pathology, Osteolysis etiology, Osteolysis pathology, Pain etiology, Pain pathology, Sarcoma complications, Sarcoma pathology, Transcription Factors metabolism, Alendronate pharmacology, Bone Neoplasms drug therapy, Osteolysis drug therapy, Pain drug therapy, Sarcoma drug therapy
- Abstract
Patients with metastatic breast, lung or prostate cancer frequently have significant bone cancer pain. In the present report we address, in a single in vivo mouse model, the effects the bisphosphonate alendronate has on bone cancer pain, bone remodeling and tumor growth and necrosis. Following injection and confinement of green fluorescent protein-transfected murine osteolytic tumor cells into the marrow space of the femur of male C3H/HeJ mice, alendronate was administered chronically from the time the tumor was established until the bone cancer pain became severe. Alendronate therapy reduced ongoing and movement-evoked bone cancer pain, bone destruction and the destruction of sensory nerve fibers that innervate the bone. Whereas, alendronate treatment did not change viable tumor burden, both tumor growth and tumor necrosis increased. These data emphasize that it is essential to utilize a model where pain, skeletal remodeling and tumor growth can be simultaneously assessed, as each of these can significantly impact patient quality of life and survival.
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- 2004
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23. Serotonin transporter in substance P (neurokinin 1) receptor knock-out mice.
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David DJ, Froger N, Guiard B, Przybylski C, Jego G, Boni C, Hunt SP, De Felipe C, Hamon M, Jacquot C, Gardier AM, and Lanfumey L
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- Animals, Autoradiography, Citalopram pharmacology, Extracellular Fluid metabolism, Frontal Lobe drug effects, Frontal Lobe metabolism, Hippocampus drug effects, Hippocampus metabolism, Membrane Glycoproteins genetics, Membrane Transport Proteins genetics, Mice, Mice, Knockout, Microdialysis, Nerve Tissue Proteins genetics, RNA, Messenger analysis, RNA, Messenger metabolism, Raphe Nuclei drug effects, Reverse Transcriptase Polymerase Chain Reaction, Serotonin analysis, Serotonin Plasma Membrane Transport Proteins, Selective Serotonin Reuptake Inhibitors pharmacology, Membrane Glycoproteins metabolism, Membrane Transport Proteins metabolism, Nerve Tissue Proteins metabolism, Raphe Nuclei metabolism, Receptors, Neurokinin-1 genetics, Serotonin metabolism
- Abstract
We recently demonstrated that mice lacking the gene for substance P (neurokinin 1) receptors (NK1-/-) show improved cortical dialysate serotonin (5-HT) responses to paroxetine [J. Neurosci. 21 (2001) 8188]. To test for changes that may involve the 5-HT transporter (5-HTT) in these mutant mice, in vivo/in vitro studies were performed. Autoradiographic quantification of 5-HTT was performed: [3H]citalopram binding did not reveal any modification of 5-HT binding sites in the dorsal raphe nucleus (DRN) of wild-type NK1+/+ control and mutant NK1-/- mice. These results were further confirmed by 5-HTT mRNA quantification using competitive reverse transcription and polymerase chain reaction (RT-PCR) assay, which showed similar messenger levels in the DRN of both mice genotypes. The functional status of 5-HTT in vivo was tested by using the zero net flux method of quantitative microdialysis in two serotonergic nerve terminal regions, the frontal cortex and ventral hippocampus, of wild-type NK1+/+ and NK1-/- mice. Neither basal extracellular 5-HT levels nor the 5-HT extraction fraction of the probe (Ed an index of 5-HT uptake in vivo) differed between wild-type and mutant mice in the two brain regions studied. These results suggest that no compensatory response to the constitutive deletion of the tachykinin NK1 receptor involving changes in the activity of the selective 5-HT transporter occurred in the DRN, frontal cortex and ventral hippocampus in mice.
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- 2004
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24. Blockade of substance P (neurokinin 1) receptors enhances extracellular serotonin when combined with a selective serotonin reuptake inhibitor: an in vivo microdialysis study in mice.
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Guiard BP, Przybylski C, Guilloux JP, Seif I, Froger N, De Felipe C, Hunt SP, Lanfumey L, and Gardier AM
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- Animals, Drug Administration Routes, Extracellular Fluid chemistry, Extracellular Fluid metabolism, Frontal Lobe drug effects, Injections, Intraperitoneal, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microdialysis, Paroxetine pharmacology, Perfusion, Raphe Nuclei drug effects, Receptors, Neurokinin-1 metabolism, Serotonin analysis, Frontal Lobe metabolism, Neurokinin-1 Receptor Antagonists, Piperidines pharmacology, Raphe Nuclei metabolism, Serotonin metabolism, Selective Serotonin Reuptake Inhibitors pharmacology, Tetrazoles pharmacology
- Abstract
Abstract Substance P antagonists of the neurokinin-1 receptor type (NK1) are gaining growing interest as new antidepressant therapies. It has been postulated that these drugs exert this putative therapeutic effect without direct interactions with serotonin (5-HT) neurones. Our recent microdialysis experiment performed in NK1 receptor knockout mice suggested evidence of changes in 5-HT neuronal function (Froger et al. 2001). The aim of the present study was to evaluate the effects of coadministration of the selective 5-HT reuptake inhibitor (SSRI) paroxetine with a NK1 receptor antagonist (GR205171 or L733060), given either intraperitoneally (i.p.) or locally into the dorsal raphe nucleus, on extracellular levels of 5-HT ([5-HT]ext) in the frontal cortex and the dorsal raphe nucleus using in vivo microdialysis in awake, freely moving mice. The systemic or intraraphe administration of a NK1 receptor antagonist did not change basal cortical [5-HT]ext in mice. A single systemic dose of paroxetine (4 mg/kg; i.p.) resulted in a statistically significant increase in [5-HT]ext with a larger extent in the dorsal raphe nucleus (+ 138% over basal AUC values), than in the frontal cortex (+ 52% over basal AUC values). Co-administration of paroxetine (4 mg/kg; i.p.) with the NK1 receptor antagonists, GR205171 (30 mg/kg; i.p.) or L733060 (40 mg/kg; i.p.), potentiated the effects of paroxetine on cortical [5-HT]ext in wild-type mice, whereas GR205171 (30 mg/kg; i.p.) had no effect on paroxetine-induced increase in cortical [5-HT]ext in NK1 receptor knock-out mice. When GR205171 (300 micro mol/L) was perfused by 'reverse microdialysis' into the dorsal raphe nucleus, it potentiated the effects of paroxetine on cortical [5-HT]ext, and inhibited paroxetine-induced increase in [5-HT]ext in the dorsal raphe nucleus. Finally, in mice whose 5-HT transporters were first blocked by a local perfusion of 1 micro mol/L of citalopram into the frontal cortex, a single dose of paroxetine (4 mg/kg i.p.) decreased cortical 5-HT release, and GR205171 (30 mg/kg i.p.) reversed this effect. The present findings suggest that NK1 receptor antagonists, when combined with a SSRI, augment 5-HT release by modulating substance P/5-HT interactions in the dorsal raphe nucleus.
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- 2004
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25. Mechanisms of action of the antidepressants fluoxetine and the substance P antagonist L-000760735 are associated with altered neurofilaments and synaptic remodeling.
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Guest PC, Knowles MR, Molon-Noblot S, Salim K, Smith D, Murray F, Laroque P, Hunt SP, De Felipe C, Rupniak NM, and McAllister G
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- Animals, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Cerebral Cortex ultrastructure, Guinea Pigs, Heat-Shock Proteins biosynthesis, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurofilament Proteins biosynthesis, Receptors, Neurokinin-1 biosynthesis, Receptors, Neurokinin-1 deficiency, Synapses metabolism, Synapses ultrastructure, Antidepressive Agents pharmacology, Fluoxetine pharmacology, Neurofilament Proteins ultrastructure, Neurokinin-1 Receptor Antagonists, Synapses drug effects
- Abstract
Antidepressants are widely prescribed in the treatment of depression, although the mechanism of how they exert their therapeutic effects is poorly understood. To shed further light on their mode of action, we have attempted to identify a common proteomic signature in guinea pig brains after chronic treatment with two different antidepressants. Both fluoxetine and the substance P receptor (NK(1)R) antagonist (SPA) L-000760735 altered cortical expression of multiple heat shock protein 60 forms along with neurofilaments and related proteins that are critical determinants of synaptic structure and function. Analysis of NK(1)R-/- mice showed similar alterations of neurofilaments confirming the specificity of the effects observed with chronic NK(1)R antagonist treatment. To determine if these changes were associated with structural modification of synapses, we carried out electron microscopic analysis of cerebral cortices from fluoxetine-treated guinea pigs. This showed an increase in the percentage of synapses with split postsynaptic densities (PSDs), a phenomenon that is characteristic of activity-dependent synaptic rearrangement. These findings suggest that cortical alterations of the neurofilament pathway and increased synaptic remodeling are associated with the mechanism of these two antidepressant drug treatments and may contribute to their psychotherapeutic actions.
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- 2004
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26. Generation of embryonic stem cells and transgenic mice expressing green fluorescence protein in midbrain dopaminergic neurons.
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Zhao S, Maxwell S, Jimenez-Beristain A, Vives J, Kuehner E, Zhao J, O'Brien C, de Felipe C, Semina E, and Li M
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- Animals, Cells, Cultured, Dopamine genetics, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental physiology, Green Fluorescent Proteins, Homeodomain Proteins biosynthesis, Homeodomain Proteins genetics, Luminescent Proteins genetics, Male, Mesencephalon cytology, Mesencephalon embryology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons cytology, Pregnancy, Stem Cells cytology, Transcription Factors biosynthesis, Transcription Factors genetics, Dopamine biosynthesis, Luminescent Proteins biosynthesis, Mesencephalon metabolism, Neurons metabolism, Stem Cells metabolism
- Abstract
We have generated embryonic stem (ES) cells and transgenic mice with green fluorescent protein (GFP) inserted into the Pitx3 locus via homologous recombination. In the central nervous system, Pitx3-directed GFP was visualized in dopaminergic (DA) neurons in the substantia nigra and ventral tegmental area. Live primary DA neurons can be isolated by fluorescence-activated cell sorting from these transgenic mouse embryos. In culture, Pitx3-GFP is coexpressed in a proportion of ES-derived DA neurons. Furthermore, ES cell-derived Pitx3-GFP expressing DA neurons responded to neurotrophic factors and were sensitive to DA-specific neurotoxin N-4-methyl-1, 2, 3, 6-tetrahydropyridine. We anticipate that the Pitx3-GFP ES cells could be used as a powerful model system for functional identification of molecules governing mDA neuron differentiation and for preclinical research including pharmaceutical drug screening and transplantation. The Pitx3 knock-in mice, on the other hand, could be used for purifying primary neurons for molecular studies associated with the midbrain-specific DA phenotype at a level not previously feasible. These mice would also provide a useful tool to study DA fate determination from embryo- or adult-derived neural stem cells.
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- 2004
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27. Inhibition of inflammation and hyperalgesia in NK-1 receptor knock-out mice.
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Kidd BL, Inglis JJ, Vetsika K, Hood VC, De Felipe C, Bester H, Hunt SP, and Cruwys SC
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- Animals, Arthritis, Experimental chemically induced, Arthritis, Experimental prevention & control, Female, Hyperalgesia prevention & control, Inflammation prevention & control, Male, Mice, Mice, Knockout, Arthritis, Experimental genetics, Hyperalgesia genetics, Inflammation genetics, Receptors, Neurokinin-1 deficiency, Receptors, Neurokinin-1 genetics
- Abstract
We sought to characterise the contribution of the neuropeptide substance P to the outcome of two models of footpad inflammation of differing severity. In an intense inflammatory model produced by intra-plantar Mycobacterium tuberculosus (10 mg/ml) substantial reductions in footpad swelling, histological outcome and mechanical hyperalgesia were observed from early time points in mice lacking the neurokin-1 receptor for substance P compared with wild-type controls. Conversely, in a less intense model (M. tuberculosus 1 mg/ml) no differences were observed other than for a reduction in mechanical hyperalgesia at later time points (day 9 onwards). The results point to a previously unrecognised influence of substance P on peripheral tissue injury and the maintenance of hyperalgesia during more severe or more chronic phases of inflammatory disease.
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- 2003
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28. Increased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout mice.
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Morcuende S, Gadd CA, Peters M, Moss A, Harris EA, Sheasby A, Fisher AS, De Felipe C, Mantyh PW, Rupniak NM, Giese KP, and Hunt SP
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- Animals, Animals, Newborn, Antidepressive Agents administration & dosage, Behavior, Animal drug effects, Blotting, Western, Bromodeoxyuridine pharmacokinetics, Cell Count, Cell Division drug effects, Cell Survival drug effects, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Conditioning, Psychological, Fear drug effects, Genotype, Hippocampus, Immobilization, Immunohistochemistry, Male, Maze Learning drug effects, Mice, Mice, Inbred C57BL, Phosphorus Isotopes metabolism, Radiation-Sensitizing Agents pharmacokinetics, Reaction Time drug effects, Receptors, Neurokinin-1 deficiency, Receptors, Neurokinin-1 genetics, Thymidine metabolism, Time Factors, Tritium metabolism, Brain-Derived Neurotrophic Factor metabolism, Cell Division physiology, Mice, Knockout metabolism, Receptors, Neurokinin-1 metabolism
- Abstract
It has previously been shown that chronic treatment with antidepressant drugs increases neurogenesis and levels of brain-derived neurotrophic factor in the hippocampus. These changes have been correlated with changes in learning and long-term potentiation and may contribute to the therapeutic efficacy of antidepressant drug treatment. Recently, antagonists at the neurokinin-1 receptor, the preferred receptor for the neuropeptide substance P, have been shown to have antidepressant activity. Mice with disruption of the neurokinin-1 receptor gene are remarkably similar both behaviourally and neurochemically to mice maintained chronically on antidepressant drugs. We demonstrate here that there is a significant elevation of neurogenesis but not cell survival in the hippocampus of neurokinin-1 receptor knockout mice. Neurogenesis can be increased in wild-type but not neurokinin-1 receptor knockout mice by chronic treatment with antidepressant drugs which preferentially target noradrenergic and serotonergic pathways. Hippocampal levels of brain-derived neurotrophic factor are also two-fold higher in neurokinin-1 receptor knockout mice, whereas cortical levels are similar. Finally, we examined hippocampus-dependent learning and memory but found no clear enhancement in neurokinin-1 receptor knockout mice. These data argue against a simple correlation between increased levels of neurogenesis or brain-derived neurotrophic factor and mnemonic processes in the absence of increased cell survival. They support the hypothesis that increased neurogenesis, perhaps accompanied by higher levels of brain-derived neurotrophic factor, may contribute to the efficacy of antidepressant drug therapy.
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- 2003
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29. Neurokinin-1 receptor-expressing neurons in the amygdala modulate morphine reward and anxiety behaviors in the mouse.
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Gadd CA, Murtra P, De Felipe C, and Hunt SP
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- Amygdala cytology, Amygdala drug effects, Animals, Behavior, Animal drug effects, Behavior, Animal physiology, Cocaine pharmacology, Conditioning, Psychological, Crosses, Genetic, Drug Administration Routes, Illicit Drugs pharmacology, Immunotoxins pharmacology, Male, Maze Learning drug effects, Mice, Mice, Inbred Strains, Mice, Knockout, Motor Activity drug effects, Narcotics pharmacology, Neurons cytology, Neurons drug effects, Nucleus Accumbens cytology, Nucleus Accumbens drug effects, Nucleus Accumbens metabolism, Receptors, Neurokinin-1 deficiency, Receptors, Neurokinin-1 genetics, Ribosome Inactivating Proteins, Type 1, Saporins, Spatial Behavior drug effects, Substance P analogs & derivatives, Substance P pharmacology, Amygdala metabolism, Anxiety genetics, Morphine pharmacology, Neurons metabolism, Receptors, Neurokinin-1 metabolism, Reward
- Abstract
Mice lacking the neurokinin-1 (NK1) receptor, the preferred receptor for the neuropeptide substance P (SP), do not show many of the behaviors associated with morphine reward. To identify the areas of the brain that might contribute to this effect, we assessed the behavioral effects of ablation of neurons expressing the NK1 receptor in specific regions of the mouse brain using the neurotoxin substance P-saporin. In a preliminary investigation, bilateral ablation of these neurons from the amygdala, but not the nucleus accumbens and dorsomedial caudate putamen, brought about reductions in morphine reward behavior. Subsequently, the effect of ablation of these neurons in the amygdala on anxiety behavior was assessed using the elevated plus maze (EPM), before conditioned place preference (CPP), and locomotor responses to morphine were measured. Loss of NK1 receptor-expressing neurons in the amygdala caused an increase in anxiety-like behavior on the EPM. It also brought about a reduction in morphine CPP scores and the stimulant effect of acute morphine administration relative to saline controls, without affecting CPP to cocaine. NK1 receptor-expressing neurons in the mouse amygdala therefore modulate morphine reward behaviors. These observations mirror those observed in NK1 receptor knock-out (NK1-/-) mice and suggest that the amygdala is an important area for the effects of SP and the NK1 receptor in the motivational properties of opiates, as well as the control of behaviors related to anxiety.
- Published
- 2003
30. Multiplex proteomic analysis by two-dimensional differential in-gel electrophoresis.
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Knowles MR, Cervino S, Skynner HA, Hunt SP, de Felipe C, Salim K, Meneses-Lorente G, McAllister G, and Guest PC
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- Animals, Cerebral Cortex metabolism, Gene Expression Regulation, Hydrogen-Ion Concentration, Image Processing, Computer-Assisted, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Isoforms, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Electrophoresis, Gel, Two-Dimensional methods, Proteome chemistry
- Abstract
This paper describes the use of fluorescence two-dimensional differential in-gel electrophoresis in a multiplex analysis of two distinct proteomes. As a model system, cerebral cortex tissues were analyzed from neurokinin1 receptor knockout (NK(1)R-/-) and wild type (NK(1)R+/+) mice in an attempt to identify molecular pathways involved in the function of this protein. Paired NK(1)R-/- and NK(1)R+/+ samples were labeled with fluorescent Cy3 and Cy5 dyes and electrophoresed on the same two-dimensional gels. Scanning the gels at wavelengths specific for each dye revealed the two different proteomes which were overlaid and the differences in abundance of specific protein spots were determined by the Amersham Biosciences DeCyder Differential In-gel Analysis software. A Cy2-labeled sample pool was co-electrophoresed with all Cy3- and Cy5-labeled sample pairs as an internal standard providing a link for inter-gel comparisons and for more robust statistical analysis of the data. Eight spots were found to be upregulated and two downregulated in the NK(1)R-/- mice compared to NK(1)R+/+ controls. Matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF) mass fingerprinting was used to identify the proteins. The results illustrate the power of this multiplex proteomics technology and illustrate how proteomics can be used to understand gene function.
- Published
- 2003
- Full Text
- View/download PDF
31. Clinical and neuroinflammatory responses to meningoencephalitis in substance P receptor knockout mice.
- Author
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Kennedy PG, Rodgers J, Bradley B, Hunt SP, Gettinby G, Leeman SE, de Felipe C, and Murray M
- Subjects
- Animals, Diminazene, Disease Models, Animal, Hippocampus pathology, Meningoencephalitis pathology, Meningoencephalitis physiopathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Neurokinin-1 genetics, Receptors, Neurokinin-2 antagonists & inhibitors, Receptors, Neurokinin-2 physiology, Receptors, Neurokinin-3 antagonists & inhibitors, Receptors, Neurokinin-3 physiology, Trypanosomiasis, African pathology, Trypanosomiasis, African physiopathology, Meningoencephalitis parasitology, Receptors, Neurokinin-1 physiology, Trypanosomiasis, African complications
- Abstract
Human African trypanosomiasis, also known as sleeping sickness, affects the CNS at the late stage of the disease. Untreated the disease is invariably fatal, and melarsoprol, the only available and effective treatment for CNS disease, is associated in up to 10% of cases with a severe post-treatment reactive encephalopathy (PTRE), which can itself cause death. We used a reproducible mouse model of the PTRE to investigate the pathogenesis and treatment of this condition. Mice infected with Trypanosoma brucei brucei and treated subcuratively with diminazene aceturate develop a severe meningoencephalitis that closely resembles PTRE. We previously reported that substance P plays an important role in PTRE. We investigated the effect of disrupting the gene encoding for the NK1 receptor in mice on the clinical and neuroinflammatory response in this model. After induction of PTRE, NK1-/- mice showed a significant reduction in clinical impairment compared with NK1+/+ mice, but the severity of the neuroinflammatory response was significantly greater in NK1-/- mice. To explore the mechanisms of this dissociated phenotype, we treated infected NK1-/- mice with antagonists to NK2 and NK3 receptors, either singly or in combination. While none of these antagonist treatments altered the clinical score, combined treatment with the NK2 and NK3 antagonists significantly reduced the neuroinflammatory grading score in the NK1-/- mice. Thus, the clinical and neuroinflammatory responses to parasite invasion can be mediated by different pathways, and, importantly, the neuroinflammatory response is altered by alternative tachykinin receptor usage. These findings could be exploited to develop novel anti-inflammatory therapies in Human African trypanosomiasis by modulating the NK1 receptor as well as the parasite.
- Published
- 2003
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- View/download PDF
32. Deletion of tachykinin NK1 receptor gene in mice does not alter respiratory network maturation but alters respiratory responses to hypoxia.
- Author
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Hilaire G, Burnet H, Ptak K, Sieweke M, Blanchi B, De Felipe C, Hunt S, and Monteau R
- Subjects
- Animals, Animals, Newborn, Brain Stem physiopathology, In Vitro Techniques, Mice, Mice, Knockout, Receptors, Neurokinin-1 genetics, Receptors, Neurokinin-1 physiology, Respiratory System growth & development, Spinal Cord physiopathology, Hypoxia physiopathology, Receptors, Neurokinin-1 deficiency, Respiratory Mechanics
- Published
- 2003
- Full Text
- View/download PDF
33. The use of NK-1 receptor null mice to assess the significance of substance P in the carotid body function.
- Author
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Rico AJ, Prieto-Lloret J, Donnelly DF, De Felipe C, Gonzalez C, and Rigual R
- Subjects
- Animals, Carotid Sinus innervation, Chemoreceptor Cells metabolism, Female, Hypoxia metabolism, Immunohistochemistry, In Vitro Techniques, Mice, Mice, Knockout, Receptors, Neurokinin-1 genetics, Receptors, Neurokinin-1 metabolism, Carotid Body metabolism, Receptors, Neurokinin-1 deficiency, Substance P metabolism
- Published
- 2003
- Full Text
- View/download PDF
34. Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2.
- Author
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Sabino MA, Ghilardi JR, Jongen JL, Keyser CP, Luger NM, Mach DB, Peters CM, Rogers SD, Schwei MJ, de Felipe C, and Mantyh PW
- Subjects
- Animals, Bone Neoplasms enzymology, Bone Neoplasms pathology, Cell Division drug effects, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Disease Models, Animal, Hyperostosis drug therapy, Hyperostosis enzymology, Hyperostosis pathology, Male, Mice, Mice, Inbred C3H, Neurons, Afferent drug effects, Neurons, Afferent physiology, Osteoclasts cytology, Osteoclasts drug effects, Osteoclasts pathology, Osteosarcoma enzymology, Osteosarcoma pathology, Pain enzymology, Pain etiology, Prostaglandin-Endoperoxide Synthases, Spinal Cord drug effects, Spinal Cord physiopathology, Bone Neoplasms complications, Bone Neoplasms drug therapy, Cyclooxygenase Inhibitors pharmacology, Isoenzymes antagonists & inhibitors, Osteosarcoma complications, Osteosarcoma drug therapy, Pain drug therapy
- Abstract
More than half of all chronic cancer pain arises from metastases to bone, and bone cancer pain is one of the most difficult of all persistent pain states to fully control. Several tumor types including sarcomas and breast, prostate, and lung carcinomas grow in or preferentially metastasize to the skeleton where they proliferate, and induce significant bone remodeling, bone destruction, and cancer pain. Many of these tumors express the isoenzyme cycloxygenase-2 (COX-2), which is involved in the synthesis of prostaglandins. To begin to define the role COX-2 plays in driving bone cancer pain, we used an in vivo model where murine osteolytic 2472 sarcoma cells were injected and confined to the intramedullary space of the femur in male C3HHeJ mice. After tumor implantation, mice develop ongoing and movement-evoked bone cancer pain-related behaviors, extensive tumor-induced bone resorption, infiltration of the marrow space by tumor cells, and stereotypic neurochemical alterations in the spinal cord reflective of a persistent pain state. Thus, after injection of tumor cells, bone destruction is first evident at day 6, and pain-related behaviors are maximal at day 14. A selective COX-2 inhibitor was administered either acutely [NS398; 100 mg/kg, i.p.] on day 14 or chronically in chow [MF. tricyclic; 0.015%, p.o.] from day 6 to day 14 after tumor implantation. Acute administration of a selective COX-2 inhibitor attenuated both ongoing and movement-evoked bone cancer pain, whereas chronic inhibition of COX-2 significantly reduced ongoing and movement-evoked pain behaviors, and reduced tumor burden, osteoclastogenesis, and bone destruction by >50%. The present results suggest that chronic administration of a COX-2 inhibitor blocks prostaglandin synthesis at multiple sites, and may have significant clinical utility in the management of bone cancer and bone cancer pain.
- Published
- 2002
35. Chemoreceptor activity is normal in mice lacking the NK1 receptor.
- Author
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Rigual R, Rico AJ, Prieto-Lloret J, de Felipe C, González C, and Donnelly DF
- Subjects
- Animals, Carotid Body cytology, Catecholamines metabolism, Dopamine metabolism, Female, Hypoxia metabolism, Hypoxia physiopathology, Mice, Mice, Knockout, Neurons, Afferent cytology, Norepinephrine metabolism, Receptors, Neurokinin-1 genetics, Sensory Receptor Cells cytology, Signal Transduction physiology, Superior Cervical Ganglion cytology, Superior Cervical Ganglion metabolism, Synaptic Transmission physiology, Visceral Afferents cytology, Carotid Body metabolism, Neurons, Afferent metabolism, Receptors, Neurokinin-1 deficiency, Sensory Receptor Cells metabolism, Substance P metabolism, Visceral Afferents metabolism
- Abstract
Substance P has been proposed to be an important neurotransmitter in the carotid body with the neurokinin 1 (NK1) receptor, mediating excitation between the glomus cells and afferent nerve endings. In order to better understand the role of substance P, this study examined chemoreceptor afferent activity, in vitro, and tissue catecholamine levels and release in adult, wild-type mice and mice lacking the gene for the NK1 receptor (NK1-KO). Groups did not differ significantly in body weight, carotid body dopamine content or carotid body norepinephrine content. In wild-type mice, single unit activity increased from 0.59 +/- 0.14 Hz to 19.78 +/- 2.27 Hz during superfusion with strong hypoxia (PO2 approximately 25 Torr). Chemoreceptor activity in NK1-KO mice, increased from 0.71 +/- 0.23 to 21.50 +/- 3.62 Hz, and neither baseline or peak frequencies were significantly different from the wild-type group. Less severe hypoxia (PO2 approximately 45 torr), evoked peak activities of 12.50 +/- 1.88 and 10.64 +/- 3.72 Hz in wild-type and NK1-KO mice, which were also not significantly different. In response to severe hypoxia, free-tissue catecholamine increased to 4.92 +/- 0.85 microm in wild-type mice and 4.26 +/- 0.63 microm in NK1-KO mice, which were also not significantly different. It may therefore be concluded that loss of NK1 receptors has little effect on chemoreceptor function in the mouse, and thus they play, at best, a minor role in the hypoxic chemoreception process.
- Published
- 2002
- Full Text
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36. Lack of self-administration and behavioural sensitisation to morphine, but not cocaine, in mice lacking NK1 receptors.
- Author
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Ripley TL, Gadd CA, De Felipe C, Hunt SP, and Stephens DN
- Subjects
- Animals, Conditioning, Operant drug effects, Conditioning, Operant physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Motor Activity physiology, Receptors, Neurokinin-1 genetics, Self Administration methods, Self Administration psychology, Cocaine administration & dosage, Cocaine pharmacology, Morphine administration & dosage, Motor Activity drug effects, Receptors, Neurokinin-1 deficiency
- Abstract
Mice lacking the NK1 receptor, the preferred receptor for substance P, demonstrate normal analgesic responses to morphine on the hot plate assay, but have been predicted, on the basis of conditioned place preference studies, to be insensitive to the rewarding properties of opiates. In this study, self-administration and the development and maintenance of locomotor sensitisation of both morphine and cocaine were investigated in mice that lacked the NK1 gene (NK1 knockout mice, NK1(-/-)). Both wildtype and NK1(-/-) mice learned an operant lever-press response to obtain food. When intravenous infusions of morphine (0.2 mg/kg/infusion) were substituted for the food reward, the wildtype mice initially reduced rates of lever pressing, but then increased them on the rewarded lever to obtain approx. 10 infusions per 90 min session; in contrast, NK1(-/-) mice continued to operate both the rewarded, and non-rewarded levers at low rates. Additionally, NK1(-/-) mice failed, following repeated administration, to sensitise to the locomotor stimulant effects of morphine (15 mg/kg, i.p.). These deficits were specific to opiates, since NK1(-/-) mice responding for food or cocaine self-administration (0.65 mg/kg/infusion) did not differ from wildtypes, and they showed normal behavioural sensitisation to repeated cocaine administration (10 mg/kg, i.p.). These results demonstrate that NK1 receptors are critical for the reinforcing properties of morphine, and for adaptive responses elicited by repeated opiate administration. It is postulated that substance P and the NK1 receptor may be necessary for the development of opiate, but not cocaine addiction.
- Published
- 2002
- Full Text
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37. The murine neurokinin NK1 receptor gene contributes to the adult hypoxic facilitation of ventilation.
- Author
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Ptak K, Burnet H, Blanchi B, Sieweke M, De Felipe C, Hunt SP, Monteau R, and Hilaire G
- Subjects
- Action Potentials drug effects, Action Potentials genetics, Animals, Animals, Newborn, Cell Differentiation drug effects, Female, Gene Expression Regulation, Developmental drug effects, Gene Expression Regulation, Developmental physiology, Hypoxia, Brain genetics, Hypoxia, Brain metabolism, Immunohistochemistry, Male, Medulla Oblongata cytology, Medulla Oblongata metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Net cytology, Nerve Net metabolism, Phrenic Nerve physiology, Receptors, Neurokinin-1 genetics, Respiratory Center cytology, Respiratory Center metabolism, Substance P pharmacology, Synaptic Transmission drug effects, Synaptic Transmission genetics, Cell Differentiation genetics, Medulla Oblongata growth & development, Nerve Net growth & development, Receptors, Neurokinin-1 deficiency, Respiratory Center growth & development, Respiratory Physiological Phenomena drug effects, Substance P metabolism
- Abstract
Substance P and neurokinin-1 receptors (NK1) modulate the respiratory activity and are expressed early during development. We tested the hypothesis that NK1 receptors are involved in prenatal development of the respiratory network by comparing the resting respiratory activity and the respiratory response to hypoxia of control mice and mutant mice lacking the NK1 receptor (NK1-/-). In vitro and in vivo experiments were conducted on neonatal, young and adult mice from wild-type and NK1-/- strains. In the wild strain, immunohistological, pharmacological and electrophysiological studies showed that NK1 receptors were expressed within medullary respiratory areas prior to birth and that their activation at birth modulated central respiratory activity and the membrane properties of phrenic motoneurons. Both the membrane properties of phrenic motoneurons and the respiratory activity generated in vitro by brainstem-spinal cord preparation from NK1-/- neonate mice were similar to that from the wild strain. In addition, in vivo ventilation recordings by plethysmography did not reveal interstrain differences in resting breathing parameters. The facilitation of ventilation by short-lasting hypoxia was similar in wild and NK1-/- neonates but was significantly weaker in adult NK1-/- mice. Results demonstrate that NK1 receptors do appear to be necessary for a normal respiratory response to short-lasting hypoxia in the adult. However, NK1 receptors are not obligatory for the prenatal development of the respiratory network, for the production of the rhythm, or for the regulation of breathing by short-lasting hypoxia in neonates.
- Published
- 2002
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38. Pain perception in mice lacking the beta3 subunit of voltage-activated calcium channels.
- Author
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Murakami M, Fleischmann B, De Felipe C, Freichel M, Trost C, Ludwig A, Wissenbach U, Schwegler H, Hofmann F, Hescheler J, Flockerzi V, and Cavalié A
- Subjects
- Amino Acid Sequence, Animals, Calcium Channels chemistry, Calcium Channels genetics, Evoked Potentials, Male, Mice, Neurons physiology, Patch-Clamp Techniques, Spinal Cord physiopathology, Calcium Channels physiology, Ion Channel Gating, Pain physiopathology, Sensory Thresholds
- Abstract
The importance of voltage-activated calcium channels in pain processing has been suggested by the spinal antinociceptive action of blockers of N- and P/Q-type calcium channels as well as by gene targeting of the alpha1B subunit (N-type). The accessory beta3 subunits of calcium channels are preferentially associated with the alpha1B subunit in neurones. Here we show that deletion of the beta3 subunit by gene targeting affects strongly the pain processing of mutant mice. We pinpoint this defect in the pain-related behavior and ascending pain pathways of the spinal cord in vivo and at the level of calcium channel currents and proteins in single dorsal root ganglion neurones in vitro. The pain induced by chemical inflammation is preferentially damped by deletion of beta3 subunits, whereas responses to acute thermal and mechanical harmful stimuli are reduced moderately or not at all, respectively. The defect results in a weak wind-up of spinal cord activity during intense afferent nerve stimulation. The molecular mechanism responsible for the phenotype was traced to low expression of N-type calcium channels (alpha1B) and functional alterations of calcium channel currents in neurones projecting to the spinal cord.
- Published
- 2002
- Full Text
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39. Changes in molecular isoform distribution of acetylcholinesterase in rat cortex and cerebrospinal fluid after intracerebroventricular administration of amyloid beta-peptide.
- Author
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Sáez-Valero J, de Ceballos ML, Small DH, and de Felipe C
- Subjects
- Acetylcholinesterase metabolism, Amyloid beta-Peptides administration & dosage, Animals, Injections, Intraventricular, Male, Peptide Fragments administration & dosage, Rats, Rats, Wistar, Acetylcholinesterase cerebrospinal fluid, Acetylcholinesterase drug effects, Amyloid beta-Peptides pharmacology, Cerebral Cortex drug effects, Cerebral Cortex enzymology, Peptide Fragments pharmacology
- Abstract
Previous studies have shown that an abnormal salt-soluble form of G(1) acetylcholinesterase (AChE) is increased in the Alzheimer's disease (AD) brain. The aim of the present study was to examine changes in AChE activity in an in vivo model of beta-amyloid peptide (A beta) administration. Rats received intracerebroventricular injections of A beta(25-35) (20 microg/day for seven days). Levels of AChE were measured in cerebral cortex and cerebrospinal fluid (CSF) after two months. A beta(25-35) administration did not alter total AChE activity in the cerebral cortex or CSF. However, analysis of salt-extractable AChE isoforms revealed an increase in the proportion of G(1) in both cortex and CSF, similar to that previously observed in AD patients. The results support the view that changes in AChE isoform pattern in the AD brain are a direct consequence of A beta accumulation.
- Published
- 2002
- Full Text
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40. Attenuation of thermal nociception and hyperalgesia by VR1 blockers.
- Author
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García-Martinez C, Humet M, Planells-Cases R, Gomis A, Caprini M, Viana F, De La Pena E, Sanchez-Baeza F, Carbonell T, De Felipe C, Pérez-Paya E, Belmonte C, Messeguer A, and Ferrer-Montiel A
- Subjects
- Animals, Calcium metabolism, Capsaicin pharmacology, Dose-Response Relationship, Drug, Electrophysiology, Glycine pharmacology, Inflammation drug therapy, Knee physiology, Male, Mice, Mice, Inbred ICR, Mustard Plant, Neurons metabolism, Pain Threshold, Peptoids, Plant Extracts pharmacology, Plant Oils, Rats, Rats, Wistar, Recombinant Proteins metabolism, Stress, Mechanical, Time Factors, Xenopus, Hot Temperature, Hyperalgesia, Pain drug therapy, Receptors, Drug antagonists & inhibitors
- Abstract
Vanilloid receptor subunit 1 (VR1) appears to play a critical role in the transduction of noxious chemical and thermal stimuli by sensory nerve endings in peripheral tissues. Thus, VR1 antagonists are useful compounds to unravel the contribution of this receptor to pain perception, as well as to induce analgesia. We have used a combinatorial approach to identify new, nonpeptidic channel blockers of VR1. Screening of a library of trimers of N-alkylglycines resulted in the identification of two molecules referred to as DD161515 [N-[2-(2-(N-methylpyrrolidinyl)ethyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide] and DD191515 [[N-[3-(N,N-diethylamino)propyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide] that selectively block VR1 channel activity with micromolar efficacy, rivaling that characteristic of vanilloid-related inhibitors. These compounds appear to be noncompetitive VR1 antagonists that recognize a receptor site distinct from that of capsaicin. Intraperitoneal administration of both trialkylglycines into mice significantly attenuated thermal nociception as measured in the hot plate test. It is noteworthy that these compounds eliminated pain and neurogenic inflammation evoked by intradermal injection of capsaicin into the animal hindpaw, as well as the thermal hyperalgesia induced by tissue irritation with nitrogen mustard. In contrast, responses to mechanical stimuli were not modified by either compound. Modulation of sensory nerve fibers excitability appears to underlie the peptoid analgesic activity. Collectively, these results indicate that blockade of VR1 activity attenuates chemical and thermal nociception and hyperalgesia, supporting the tenet that this ionotropic receptor contributes to chemical and thermal sensitivity and pain perception in vivo. These trialkylglycine-based, noncompetitive VR1 antagonists may likely be developed into analgesics to treat inflammatory pain.
- Published
- 2002
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41. Comparison of the phenotype of NK1R-/- mice with pharmacological blockade of the substance P (NK1 ) receptor in assays for antidepressant and anxiolytic drugs.
- Author
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Rupniak NM, Carlson EJ, Webb JK, Harrison T, Porsolt RD, Roux S, de Felipe C, Hunt SP, Oates B, and Wheeldon A
- Subjects
- Animals, Arousal drug effects, Brain drug effects, Cricetinae, Dose-Response Relationship, Drug, Gerbillinae, Guinea Pigs, Helplessness, Learned, Male, Mice, Morpholines pharmacology, Motivation, Neurokinin-1 Receptor Antagonists, Piperidines pharmacology, Rats, Rats, Sprague-Dawley, Species Specificity, Tetrazoles pharmacology, Anti-Anxiety Agents pharmacology, Antidepressive Agents pharmacology, Anxiety genetics, Arousal genetics, Depression genetics, Mutation genetics, Phenotype, Receptors, Neurokinin-1 genetics
- Abstract
The phenotype of NK1R-/- mice was compared with that of acute pharmacological blockade of the tachykinin NK1 receptor on sensorimotor function and in assays relevant to depressive illness and anxiety. The dose range for L-760735 and GR205171 that was associated with functional blockade of central NK1 receptors in the target species was established by antagonism of the behavioural effects of intracerebroventricular NK1 agonist challenge in gerbils, mice and rats. The caudal grooming and scratching response to GR73632 was absent in NK1R-/- mice, confirming that the receptor had been genetically ablated. There was no evidence of sedation or motor impairment in NK1R-/- mice or following administration of L-760735 to gerbils, even at doses in excess of those required for central NK1 receptor occupancy. In the resident-intruder and forced swim test, the behaviour of NK1R-/- mice, or animals treated acutely with L-760735 or GR205171, resembled that seen with the clinically used antidepressant drug fluoxetine. However, the effects of GR205171 were not clearly enantioselective in mice. In contrast, although NK1R-/- mice also exhibited an increase in the duration of struggle behaviour in the tail suspension test, this was not observed following pharmacological blockade with L-760735 in gerbils or GR205171 in mice, suggesting that this may reflect a developmental alteration in the knockout mouse. There was no effect of NK1 receptor blockade with L-760735 in guinea-pigs or GR205171 in rats, or deletion of the NK1 receptor in mice, on behaviour in the elevated plus-maze test for anxiolytic activity. These findings extend previous observations on the phenotype of the NK1R-/- mouse and establish a broadly similar profile following acute pharmacological blockade of the receptor. These studies also serve to underscore the limitations of currently available antagonists that are suitable for use in rat and mouse behavioural assays.
- Published
- 2001
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42. 5-hydroxytryptamine (5-HT)1A autoreceptor adaptive changes in substance P (neurokinin 1) receptor knock-out mice mimic antidepressant-induced desensitization.
- Author
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Froger N, Gardier AM, Moratalla R, Alberti I, Lena I, Boni C, De Felipe C, Rupniak NM, Hunt SP, Jacquot C, Hamon M, and Lanfumey L
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Animals, Drug Resistance physiology, Electrophysiology, Immunohistochemistry, In Vitro Techniques, Male, Mice, Mice, Knockout, Neurons drug effects, Neurons metabolism, Paroxetine pharmacology, Piperazines pharmacokinetics, Pyridines pharmacokinetics, Pyrimidines pharmacology, RNA, Messenger metabolism, Raphe Nuclei cytology, Raphe Nuclei drug effects, Raphe Nuclei metabolism, Receptors, Neurokinin-1 genetics, Receptors, Serotonin genetics, Receptors, Serotonin, 5-HT1, Serotonin Antagonists pharmacokinetics, Serotonin Receptor Agonists pharmacology, Selective Serotonin Reuptake Inhibitors pharmacology, Substance P metabolism, Antidepressive Agents pharmacology, Autoreceptors metabolism, Receptors, Neurokinin-1 deficiency, Receptors, Serotonin metabolism
- Abstract
Antagonists at substance P receptors of the neurokinin 1 (NK1) type have been shown to represent a novel class of antidepressant drugs, with comparable clinical efficacy to the selective serotonin (5-HT) reuptake inhibitors (SSRIs). Because 5-HT(1A) receptors may be critically involved in the mechanisms of action of SSRIs, we examined whether these receptors could also be affected in a model of whole-life blockade of NK1 receptors, i.e. knock-out mice lacking the latter receptors (NK1-/-). 5-HT(1A) receptor labeling by the selective antagonist radioligand [(3)H]N-[2-[4-(2-methoxyphenyl)1-piperazinyl]-ethyl]-N-(2-pyridinyl)-cyclohexanecarboxamide (WAY 100635) and 5-HT(1A)-dependent [(35)S]GTP-gamma-S binding at the level of the dorsal raphe nucleus (DRN) in brain sections, as well as the concentration of 5-HT(1A) mRNA in the anterior raphe area were significantly reduced (-19 to -46%) in NK1-/- compared with NK1+/+ mice. Furthermore, a approximately 10-fold decrease in the potency of the 5-HT(1A) receptor agonist ipsapirone to inhibit the discharge of serotoninergic neurons in the dorsal raphe nucleus within brainstem slices, and reduced hypothermic response to 8-OH-DPAT, were noted in NK1-/- versus NK1+/+ mice. On the other hand, cortical 5-HT overflow caused by systemic injection of the SSRI paroxetine was four- to sixfold higher in freely moving NK1-/- mutants than in wild-type NK1+/+ mice. Accordingly, the constitutive lack of NK1 receptors appears to be associated with a downregulation/functional desensitization of 5-HT(1A) autoreceptors resembling that induced by chronic treatment with SSRI antidepressants. Double immunocytochemical labeling experiments suggest that such a heteroregulation of 5-HT(1A) autoreceptors in NK1-/- mutants does not reflect the existence of direct NK1-5-HT(1A) receptor interactions in normal mice.
- Published
- 2001
43. The NK1 receptor is essential for the full expression of noxious inhibitory controls in the mouse.
- Author
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Bester H, De Felipe C, and Hunt SP
- Subjects
- Animals, Brain cytology, Brain metabolism, Brain Stem cytology, Brain Stem metabolism, Cell Count, Conditioning, Psychological, Crosses, Genetic, Forelimb, Hindlimb, Hot Temperature, Immunohistochemistry, Lumbosacral Region, Mice, Mice, Inbred Strains, Mice, Knockout, Neck, Neurokinin-1 Receptor Antagonists, Pain physiopathology, Pain Measurement, Proto-Oncogene Proteins c-fos metabolism, Receptors, Neurokinin-1 deficiency, Receptors, Neurokinin-1 genetics, Spinal Cord cytology, Spinal Cord metabolism, Stress, Physiological metabolism, Stress, Physiological physiopathology, Substance P metabolism, Neural Inhibition, Pain metabolism, Receptors, Neurokinin-1 metabolism
- Abstract
Behavioral analysis of the NK1 receptor gene knock-out (NK1-/-) mouse indicated that substance P was closely involved in orchestrating the physiological and behavioral response of the animal to major environmental stressors. In particular, endogenous pain control mechanisms, such as stress-induced analgesia were substantially impaired in mutant mice, suggesting a reduction in descending inhibitory controls to the spinal cord from the brainstem. To directly test the integrity of descending controls in NK1-/- mice, we have analyzed c-Fos expression in laminae I-II of the lumbar and cervical cord and in the rostral ventromedial medulla in an experimental paradigm known to require recruitment of descending inhibitory controls. Anesthetized mice were stimulated with water at 50 degrees C either on their forepaw, hindpaw, or on both the hindpaw plus forepaw concurrently. Wild-type mice, naive or treated with an NK1 antagonist (RP67580) or its inactive isomer (RP68651), were compared with NK1-/- mice. C-Fos expression at the lumbar laminae I-II level was significantly reduced, whereas it was significantly greater in the raphe magnus and pallidus nuclei in the double stimulation situation in wild-type compared with NK1-/- mice. Blocking the NK1 receptor pharmacologically reproduced, in an enantiomere-selective manner, the data from NK1-/- mice, with no evidence for recruitment of descending inhibition at the lumbar cord level after forepaw stimulation. The present study demonstrates that the NK1 receptor is essential for the full development of noxiously evoked descending inhibition.
- Published
- 2001
44. Rewarding effects of opiates are absent in mice lacking the receptor for substance P.
- Author
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Murtra P, Sheasby AM, Hunt SP, and De Felipe C
- Subjects
- Animals, Cocaine pharmacology, Conditioning, Classical, Corpus Striatum drug effects, Corpus Striatum metabolism, Cyclic AMP metabolism, Female, Locomotion drug effects, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Morphine metabolism, Morphine Dependence metabolism, Narcotics metabolism, Proto-Oncogene Proteins c-fos biosynthesis, Receptors, Dopamine D1 metabolism, Receptors, Dopamine D2 metabolism, Receptors, Neurokinin-1 deficiency, Receptors, Neurokinin-1 genetics, Receptors, Opioid, mu metabolism, Reward, Morphine pharmacology, Narcotics pharmacology, Receptors, Neurokinin-1 metabolism
- Abstract
Modulation of substance P activity offers a radical new approach to the management of depression, anxiety and stress. The substance P receptor is highly expressed in areas of the brain that are implicated in these behaviours, but also in other areas such as the nucleus accumbens which mediate the motivational properties of both natural rewards such as food and of drugs of abuse such as opiates. Here we show a loss of the rewarding properties of morphine in mice with a genetic disruption of the substance P receptor. The loss was specific to morphine, as both groups of mice responded when cocaine or food were used as rewards. The physical response to opiate withdrawal was also reduced in substance P receptor knockout mice. We conclude that substance P has an important and specific role in mediating the motivational aspects of opiates and may represent a new pharmacological route for the control of drug abuse.
- Published
- 2000
- Full Text
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45. Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation.
- Author
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Lambrecht BN, Germonpré PR, Everaert EG, Carro-Muino I, De Veerman M, de Felipe C, Hunt SP, Thielemans K, Joos GF, and Pauwels RA
- Subjects
- Animals, Antigen Presentation, Cell Division immunology, Dendritic Cells cytology, Ligands, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Signal Transduction immunology, T-Lymphocytes cytology, Cell Communication immunology, Dendritic Cells immunology, Receptors, Antigen, T-Cell immunology, Substance P immunology, T-Lymphocytes immunology
- Abstract
Substance P (SP) is an immunoregulatory tachykinin which augments antigen- and mitogen-induced lymphocyte proliferation via signaling through the neurokinin-1 receptor (NK1-R). Non-neuronal cells of the immune system such as monocytes, T lymphocytes and eosinophils can be a source of SP. We have investigated if antigen-presenting dendritic cells (DC) produce SP. DC were grown from bone marrow precursors using a cocktail of GM-CSF, IL-4 and Flt-3 ligand. Reverse transcriptase-PCR amplification using primers for the mouse preprotachykinin-A gene and direct DNA sequencing of amplified products from purified DC demonstrated the presence of the gamma-transcript of the gene, coding for SP and neurokinin A. At the protein level, mouse DC expressed SP as determined by an enzyme immunoassay and confirmed by immunostaining. The functional role of endogenous SP release was determined. During the interaction with syngeneic or allogeneic DC, the addition of a specific NK1-R antagonist partly reduced proliferation in responding T lymphocytes. This was confirmed by using responders derived from NK1-R-deficient mice. In the absence of DC, proliferation of T cells induced by direct TCR ligation and soluble CD28 was partly dependent on signaling through NK1-R, revealing an autocrine effect of SP production by T cells. In conclusion, these results demonstrate that endogenously produced SP contributes to T cell proliferation induced by DC or TCR / CD28 stimulation.
- Published
- 1999
- Full Text
- View/download PDF
46. Disruption of the substance P receptor (neurokinin-1) gene does not prevent upregulation of preprotachykinin-A mRNA in the spinal cord of mice following peripheral inflammation.
- Author
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Palmer JA, De Felipe C, O'Brien JA, and Hunt SP
- Subjects
- Animals, Dynorphins genetics, Freund's Adjuvant, Gene Expression immunology, Hyperalgesia genetics, Hyperalgesia immunology, Mice, Mice, Knockout, Neuritis chemically induced, Peripheral Nerves immunology, Posterior Horn Cells chemistry, RNA, Messenger metabolism, Receptors, Neurokinin-1 analysis, Substance P genetics, Neuritis immunology, Posterior Horn Cells immunology, Protein Precursors genetics, Receptors, Neurokinin-1 genetics, Tachykinins genetics
- Abstract
The neuropeptide substance P is thought to play an important role in nociception, although the function of the peptide remains controversial. Following peripheral inflammation there is a pronounced upregulation of substance P expression both in sensory neurons and in postsynaptic neurons within the spinal cord. We have examined the levels of expression of mRNA encoding substance P and dynorphin following the development of inflammatory hyperalgesia in mice in which the substance P receptor gene, also known as the neurokinin-1 receptor gene, has been disrupted by homologous recombination. We show that inflammatory hyperalgesia following injection of complete Freund's adjuvant develops normally in animals that lack the neurokinin-1 receptor and that expression of mRNAs encoding substance P and the neuropeptide dynorphin are upregulated regardless of the genotype of the mouse. This suggests that substance P activity is not required for the development and maintenance of inflammatory hyperalgesia and that the upregulation of substance P expression is mediated by neurotransmitters other than substance P.
- Published
- 1999
- Full Text
- View/download PDF
47. c-Jun expression after axotomy of corneal trigeminal ganglion neurons is dependent on the site of injury.
- Author
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De Felipe C and Belmonte C
- Subjects
- Animals, Axotomy, Cornea cytology, Epithelial Cells physiology, Fluorescent Antibody Technique, Gene Expression physiology, Male, Mice, Mice, Inbred Strains, Nerve Regeneration physiology, Neurons, Afferent chemistry, Nociceptors physiology, Pain physiopathology, Presynaptic Terminals chemistry, Presynaptic Terminals physiology, Trigeminal Ganglion chemistry, Cornea innervation, Corneal Injuries, Neurons, Afferent physiology, Proto-Oncogene Proteins c-jun genetics, Trigeminal Ganglion cytology
- Abstract
The proto-oncogene c-Jun has been implicated in the control of neuronal responses to injury and in axonal growth during regenerative processes. We have investigated the expression of c-Jun during normal terminal remodelling in trigeminal ganglion neurons innervating the cornea and after acute injury of epithelial nerve terminals or parent axons. Remodelling and rearrangement, or damage limited to corneal epithelium endings, was not a trigger for activation of c-Jun expression. However, injury of parent axons in the stroma or in the orbital ciliary nerves induced c-Jun expression in 50% of the population of corneal neurons, which included all of the large myelinated and 20% of the small neuropeptide-containing corneal neurons. This suggests that c-Jun expression in trigeminal ganglion neurons is not associated with normal remodelling or regeneration of peripheral nerve terminals, and that it takes place only when parent axons are injured. A substantial number of damaged neurons do not express c-Jun, indicating that in primary sensory neurons, injury and regeneration may not always be coupled to the expression of this proto-oncogene.
- Published
- 1999
- Full Text
- View/download PDF
48. Organ donation in Spain.
- Author
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Miranda B, Fernández Lucas M, de Felipe C, Naya M, González-Posada JM, and Matesanz R
- Subjects
- Attitude of Health Personnel, Humans, Patient Selection, Spain, Tissue and Organ Procurement economics, Tissue and Organ Procurement statistics & numerical data, Waiting Lists, Organ Transplantation economics, Organ Transplantation legislation & jurisprudence, Organ Transplantation statistics & numerical data, Tissue Donors statistics & numerical data, Tissue and Organ Procurement organization & administration
- Published
- 1999
- Full Text
- View/download PDF
49. Impaired IL-1beta-induced neutrophil accumulation in tachykinin NK1 receptor knockout mice.
- Author
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Ahluwalia A, De Felipe C, O'Brien J, Hunt SP, and Perretti M
- Subjects
- Animals, Cell Movement drug effects, Female, Inflammation Mediators metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutrophils cytology, Substance P pharmacology, Interleukin-1 metabolism, Neutrophils metabolism, Receptors, Neurokinin-1 genetics
- Abstract
Tachykinin NK1 receptors play an important role in the development of neurogenic inflammatory responses. We have used the murine air-pouch model to investigate whether the neurogenic component of the cellular inflammatory response to interleukin-1beta (IL-1beta, 10 ng into the air-pouch) is altered in NK1 receptor knockout mice compared to wild type controls. Air-pouches were washed following a 4 h IL-1beta treatment, the wash collected and neutrophil number estimated using a Neubauer haemocytometer. The response to IL-1beta was significantly attenuated in NK1 receptor +/- (40% reduction) and -/- mice (62% reduction) compared to wild type controls (+/+), whilst the response to cytokine-induced neutrophil chemoattractant (CINC, 0.3 microg) was unaffected. The response to substance P (7.5 nmol) was attenuated by approximately 50% in both NK1 receptor +/- and -/- mice compared to wild type controls. In conclusion NK1 receptors play a significant role in the cellular response to IL-1beta in a model of inflammation.
- Published
- 1998
- Full Text
- View/download PDF
50. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P.
- Author
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De Felipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, and Hunt SP
- Subjects
- Analgesics, Opioid pharmacology, Animals, Electric Stimulation, Electromyography, Female, Formaldehyde pharmacology, Gene Targeting, Hyperalgesia etiology, Male, Mice, Mice, Inbred C57BL, Morphine pharmacology, Mutagenesis, Neuritis chemically induced, Neuritis physiopathology, Pain Threshold, Physical Stimulation, Receptors, Neurokinin-1 deficiency, Receptors, Neurokinin-1 genetics, Stress, Physiological physiopathology, Aggression, Analgesia, Pain, Receptors, Neurokinin-1 physiology, Substance P physiology
- Abstract
The peptide neurotransmitter substance P modulates sensitivity to pain by activating the neurokinin-1 (NK-1) receptor, which is expressed by discrete populations of neurons throughout the central nervous system. Substance P is synthesized by small-diameter sensory 'pain' fibres, and release of the peptide into the dorsal horn of the spinal cord following intense peripheral stimulation promotes central hyperexcitability and increased sensitivity to pain. However, despite the availability of specific NK-1 antagonists, the function of substance P in the perception of pain remains unclear. Here we investigate the effect of disrupting the gene encoding the NK-1 receptor in mice. We found that the mutant mice were healthy and fertile, but the characteristic amplification ('wind up') and intensity coding of nociceptive reflexes was absent. Although substance P did not mediate the signalling of acute pain or hyperalgesia, it was essential for the full development of stress-induced analgesia and for an aggressive response to territorial challenge, demonstrating that the peptide plays an unexpected role in the adaptive response to stress.
- Published
- 1998
- Full Text
- View/download PDF
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