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1.
Neurosci Lett ; 505(2): 146-9, 2011 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-22005578

RESUMO

The development of ectopic neural discharge at a site of peripheral nerve injury is thought to contribute to the initiation of sensory disturbances and pain. We have previously shown that this discharge can be initiated or increased by the neuropeptide calcitonin gene-related peptide (CGRP). We have now studied a potential therapeutic approach to reducing the discharge by evaluating the effect of a systemically administered monoclonal antibody to CGRP on injury-induced activity in the lingual nerve. In 16 anaesthetised adult ferrets the left lingual nerve was sectioned. One day after the injury, the animals received a subcutaneous injection of either a monoclonal antibody to CGRP or a vehicle control. Three days after the injury, under a second anaesthetic, single-unit electrophysiological recordings were made from central to the injury site (469 and 391 units were analysed in antibody and vehicle groups, respectively), and the proportion of units that were spontaneously active was determined. In the vehicle-treated animals 6.4±2.7 [SEM]% of the units were spontaneously active, with conduction velocities of 8.8-40.8m/s and discharge frequencies of 0.03-2.7Hz. In the monoclonal antibody-treated animals 5.7±2.0% of the units were spontaneously active, with conduction velocities of 13.9-38.8m/s and discharge frequencies of 0.07-1.8Hz. There was no significant difference between these two groups (for spontaneous activity and conduction velocity: p>0.05, Student's t-test; for discharge frequency: p>0.05, Mann-Whitney test), suggesting that the spontaneous activity initiated by a nerve injury cannot be modulated by administration of a monoclonal antibody to CGRP.


Assuntos
Analgesia/métodos , Anticorpos Monoclonais/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/imunologia , Traumatismos do Nervo Lingual/metabolismo , Traumatismos do Nervo Lingual/terapia , Neuralgia/metabolismo , Neuralgia/terapia , Animais , Axotomia/métodos , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Modelos Animais de Doenças , Feminino , Furões , Injeções Subcutâneas/métodos , Traumatismos do Nervo Lingual/imunologia , Neuralgia/imunologia
2.
Brain Res ; 1368: 19-27, 2011 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-20977893

RESUMO

Activity-induced neuronal plasticity is partly facilitated by the expression of the immediate-early gene c-fos and the resulting transcription factor Fos. Expression of Fos is associated with nociceptive afferent activation, but a detailed stimulation-transcription pathway for Fos expression has not yet been determined in the trigeminal system. This study utilized a novel in vitro model to determine whether Fos expression can be induced in trigeminal subnucleus caudalis by NMDA or neurokinin-1 receptor activation, and whether inhibition of intracellular kinases has any effect on Fos expression induced by activation of these receptors. Brainstems of male Wistar rats were excised and maintained in artificial cerebrospinal fluid at 37°C. NMDA or the specific neurokinin-1 receptor agonist [Sar(9),Met(O(2))(11)]-SP was applied. These agonists were subsequently tested in the presence of the protein kinase A inhibitor Rp-cAMP or protein kinase C inhibitor chelerythrine chloride. In all experiments the sodium channel blocker tetrodotoxin was used to prevent indirect neuronal activation. Brainstems were processed immunocytochemically for Fos expression, and positive cells were counted in the trigeminal subnucleus caudalis. NMDA and [Sar(9),Met(O(2))(11)]-SP significantly increased Fos expression, but these increases could be prevented by chelerythrine chloride. Rp-cAMP had no effect on Fos induced by NMDA but caused a significant reduction in Fos induced by [Sar(9),Met(O(2))(11)]-SP. These data demonstrate that in trigeminal subnucleus caudalis activation of either NK1 or NMDA receptors alone induces Fos expression; protein kinases A and C are involved in NK1R-induced Fos while protein kinase A is not required for NMDA receptor-induced Fos.


Assuntos
N-Metilaspartato/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores da Neurocinina-1/agonistas , Núcleos do Trigêmeo/metabolismo , Animais , Benzofenantridinas/farmacologia , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Genes Precoces , Genes fos , Técnicas In Vitro , Masculino , Modelos Animais , Plasticidade Neuronal , Proteína Quinase C/antagonistas & inibidores , Ratos , Ratos Wistar , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Tionucleotídeos/farmacologia , Núcleos do Trigêmeo/efeitos dos fármacos
3.
Eur J Pain ; 12(3): 385-94, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17897851

RESUMO

We have developed a model to study central changes following inflammation of the tooth pulp in the ferret and have examined Fos expression in the trigeminal nucleus following stimulation of non-inflamed and inflamed tooth pulps. The aim of this study was to establish the ability of this model to predict analgesic efficacy in clinical studies of inflammatory pain. We addressed this by assessing the effects of the neurokinin-1 receptor antagonist GR205171A and ibuprofen on Fos expression following stimulation of the inflamed pulp and comparing this with known analgesic efficacy. Adult ferrets were prepared under anaesthesia to allow tooth pulp stimulation, recording from the digastric muscle and intravenous injections at a subsequent experiment. In some animals pulpal inflammation was induced, by introducing human caries into a deep buccal cavity. After 5 days, animals were reanaesthetised, treated with vehicle, GR205171A or ibuprofen and the teeth were stimulated at ten times the threshold of the jaw-opening reflex. Stimulation of all tooth pulps induced ipsilateral Fos in trigeminal subnuclei caudalis and oralis. GR205171A had no significant effect on Fos expression in the trigeminal nucleus of animals with either non-inflamed or inflamed tooth pulps. Ibuprofen reduced Fos expression in the trigeminal nucleus and this effect was most marked in animals with pulpal inflammation. These results differ from those previously described using a range of other animal models, but agree with known clinical efficacy of neurokinin-1 receptor antagonists and ibuprofen. Therefore this model is likely to be of use in accurately predicting the analgesic efficacy of novel compounds.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Polpa Dentária/inervação , Regulação da Expressão Gênica/efeitos dos fármacos , Genes fos/efeitos dos fármacos , Ibuprofeno/farmacologia , Proteínas do Tecido Nervoso/biossíntese , Antagonistas dos Receptores de Neurocinina-1 , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas c-fos/biossíntese , Pulpite/fisiopatologia , Substância P/análogos & derivados , Núcleos do Trigêmeo/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Dente Canino , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Estimulação Elétrica , Furões , Ibuprofeno/uso terapêutico , Proteínas do Tecido Nervoso/genética , Fragmentos de Peptídeos/uso terapêutico , Pulpite/tratamento farmacológico , Pulpite/genética , Receptores da Neurocinina-1/fisiologia , Substância P/farmacologia , Substância P/uso terapêutico , Neuralgia do Trigêmeo/tratamento farmacológico , Neuralgia do Trigêmeo/etiologia , Neuralgia do Trigêmeo/fisiopatologia , Núcleos do Trigêmeo/fisiopatologia
4.
Eur J Oral Sci ; 115(1): 40-7, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17305715

RESUMO

We have previously carried out detailed characterization and identification of Fos expression within the trigeminal nucleus after tooth pulp stimulation in ferrets. The aim of this study was to determine the effect of pulpal inflammation on the excitability of central trigeminal neurons following tooth pulp stimulation. Adult ferrets were prepared under anesthesia to allow tooth pulp stimulation, recording from the digastric muscle, and intravenous injections at a subsequent experiment. In some animals, pulpal inflammation was induced by introducing human caries into a deep buccal cavity. After 5 d, animals were re-anaethetized, and the teeth were stimulated at 10 times the threshold of the jaw-opening reflex. Stimulation of all tooth pulps induced ipsilateral Fos in the trigeminal subnuclei caudalis and oralis. All non-stimulated animals showed negligible Fos labeling, with no differences recorded between inflamed and non-inflamed groups. Following tooth pulp stimulation, Fos expression was greater in animals with inflamed teeth than in animals with non-inflamed teeth, with the greatest effect seen in the subnucleus caudalis. These results suggest that inflammation increases the number of trigeminal brainstem neurons activated by tooth pulp stimulation; this may be mediated by peripheral or central mechanisms.


Assuntos
Proteínas Proto-Oncogênicas c-fos/biossíntese , Pulpite/fisiopatologia , Núcleo Espinal do Trigêmeo/metabolismo , Animais , Cárie Dentária/complicações , Polpa Dentária/inervação , Estimulação Elétrica , Furões , Expressão Gênica , Pulpite/etiologia
5.
Exp Brain Res ; 160(3): 360-7, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15448960

RESUMO

Dorsal horn neurons that express the neurokinin 1 receptor (NK-1R) play an important role in nociceptive processing. The targetting of NK-1R neurons by serotoninergic (5-hydroxytryptamine, 5-HT) axons would provide a straightforward means to exert an inhibitory analgesic effect at spinal level. This study used single cell electrophysiology to analyse and correlate the responses of rat deep DH neurons in vitro to both 5-HT and the NK-1R agonist [Sar9,Met(O2)11]-substance P (SP). Subsequently a combination of immunocytochemistry and confocal imaging was applied to biocytin-filled laminae III-VI neurons to reveal putative 5-HT innervation in this neuronal sample. A population of neurons was identified in which 5-HT (50 microM) significantly attenuated the dorsal root-evoked excitatory postsynaptic potential and [Sar9,Met(O2)11]-SP (2 microM) induced a direct tetrodotoxin-resistant depolarisation. Immunolabelling revealed that all of these neurons were inhibited by 5-HT, including those that were excited by [Sar9,Met(O2)11]-SP, were overlaid by a plexus of 5-HT immunoreactive fibres and in some instances, closely apposed putative contacts with somata and proximal dendrites identified although their incidence was low. Inhibition by 5-HT of deep DH neurons directly responsive to SP may account at least in part for monoamine-induced modulation of nociceptive processing in the spinal cord.


Assuntos
Inibição Neural/fisiologia , Células do Corno Posterior/fisiologia , Serotonina/fisiologia , Substância P/fisiologia , Animais , Eletrofisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Inibição Neural/efeitos dos fármacos , Células do Corno Posterior/efeitos dos fármacos , Ratos , Ratos Wistar , Serotonina/farmacologia , Substância P/farmacologia
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