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1.
Bioorg Med Chem Lett ; 20(15): 4683-8, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20566291

RESUMO

Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.


Assuntos
Analgésicos/química , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio/química , Neuralgia/tratamento farmacológico , Pirazóis/química , Piridazinas/química , Piridinas/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Analgésicos/síntese química , Analgésicos/uso terapêutico , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio/metabolismo , Canais de Cálcio Tipo L , Ligantes , Pirazóis/síntese química , Piridazinas/síntese química , Piridazinas/uso terapêutico , Piridinas/síntese química , Ratos , Relação Estrutura-Atividade
2.
J Med Chem ; 52(19): 5785-8, 2009 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-19743867

RESUMO

We report the synthesis and SAR of a series of novel azaindole CB(2) agonists. 6-Azaindole 18 showed activity in an acute pain model but was inactive in a chronic model. 18 is a Pgp substrate with low brain penetration. The template was redesigned, and the resulting 5-azaindole 36 was a potent CB(2) agonist with high CNS penetration. This compound was efficacious in the acute model and the chronic joint pain model.


Assuntos
Aminopiridinas/uso terapêutico , Encéfalo/metabolismo , Morfolinas/uso terapêutico , Dor/tratamento farmacológico , Receptor CB2 de Canabinoide/agonistas , Aminopiridinas/farmacocinética , Animais , Compostos Aza , Células CHO , Linhagem Celular , Doença Crônica , Cricetinae , Cricetulus , Descoberta de Drogas , Humanos , Indóis , Morfolinas/farmacocinética , Ratos , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 19(15): 4504-8, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19520573

RESUMO

A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.


Assuntos
Aminas/síntese química , Inibidores de Ciclo-Oxigenase 2/síntese química , Éteres/síntese química , Pirimidinas/síntese química , Sulfonas/síntese química , Aminas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Farmacêutica/métodos , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Desenho de Fármacos , Éteres/farmacologia , Humanos , Inflamação , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Doenças Neurodegenerativas/tratamento farmacológico , Pirimidinas/farmacologia , Ratos , Sulfonas/farmacologia
4.
Bioorg Med Chem Lett ; 19(1): 259-63, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19010671

RESUMO

We describe herein the medicinal chemistry approach which led to the discovery of a novel pyridine-3-carboxamide series of CB(2) receptor agonists. The SAR of this new template was evaluated and culminated in the identification of analogue 14a which demonstrated efficacy in an in vivo model of inflammatory pain.


Assuntos
Analgésicos/síntese química , Piridinas/síntese química , Piridinas/uso terapêutico , Receptor CB2 de Canabinoide/agonistas , Amidas/síntese química , Amidas/farmacologia , Amidas/uso terapêutico , Analgesia/métodos , Animais , Modelos Animais de Doenças , Descoberta de Drogas/métodos , Inflamação , Dor/tratamento farmacológico , Piridinas/farmacologia , Relação Estrutura-Atividade
5.
Neurosci Lett ; 441(1): 110-4, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18597934

RESUMO

We have investigated a possible role for the ATP receptor subunit P2X(3), in the development of neuropathic pain following injury to a peripheral branch of the trigeminal nerve. In nine anaesthetised adult ferrets the left lingual nerve was sectioned and recovery permitted for 3 days, 3 weeks or 3 months (3 ferrets per group). A retrograde tracer, fluorogold, was applied to the nerve to allow identification of cell bodies in the trigeminal ganglion with axons in the injured nerve. Indirect immunofluorescence for P2X(3) and image analysis was used to quantify the percentage area of staining at the site of injury. Additionally, the proportion of fluorogold-positive cells that expressed P2X(3) was determined and compared with expression in non-fluorogold containing cells in another part of the ganglion. Comparisons were made with results from control animals that only received the tracer injection. After lingual nerve injury there was no significant change in P2X(3) expression at the site of nerve injury or within cell bodies linked to either injured (lingual) or uninjured (ophthalmic) axons, at any of the time periods investigated. Overall, this study suggests that P2X(3) expression at these sites is not involved in the development of neuropathic pain following lingual nerve injury.


Assuntos
Traumatismos do Nervo Lingual , Nervo Lingual/metabolismo , Receptores Purinérgicos P2/metabolismo , Animais , Feminino , Furões , Lateralidade Funcional , Receptores Purinérgicos P2X3 , Recuperação de Função Fisiológica/fisiologia , Estilbamidinas , Fatores de Tempo
6.
Neurosci Lett ; 443(1): 41-5, 2008 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-18634850

RESUMO

Abnormal neural activity generated at a site of nerve injury is thought to contribute to the development of dysaesthesia. Vanilloid receptor 1 (TRPV1), a transducer of noxious stimuli, may be involved in the initiation of this abnormal activity and could provide a useful therapeutic target. We investigated the effect of a specific TRPV1 antagonist (SB-750364) on injury-induced discharge in the lingual nerve. In 12 anaesthetised adult ferrets the left lingual nerve was sectioned and animals were allowed to recover for 3-7 days. In terminal experiments under general anaesthesia, the nerve was re-exposed and electrophysiological recordings made from spontaneously active axons in fine filaments dissected from the nerve central to both the injury site and the junction with the chorda tympani. SB-750364 was infused via the cephalic vein in order to achieve three increasing but stable systemic blood levels of the compound (0.3, 1.0 and 3.0 microM). Twenty-eight spontaneously active units were studied, with discharge frequencies ranging from 0.02 to 4.9 Hz. There was a significant reduction in spontaneous activity in 17 units (61%) at 1.0 microM or less of SB-750364 (p<0.01; Friedman test with Dunn's multiple comparisons). A further 4 units (14%) showed a significant reduction in activity at 3.0 microM (p<0.01). In the remaining 7 units (25%) the discharge was unaffected (p>0.05). These data show that the TRPV1 antagonist SB-750364 can reduce the level of spontaneous activity initiated in some axons following lingual nerve injury.


Assuntos
Traumatismos dos Nervos Cranianos , Nervo Lingual/efeitos dos fármacos , Canais de Cátion TRPV/antagonistas & inibidores , Potenciais de Ação/efeitos dos fármacos , Animais , Traumatismos dos Nervos Cranianos/tratamento farmacológico , Traumatismos dos Nervos Cranianos/patologia , Traumatismos dos Nervos Cranianos/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Furões , Nervo Lingual/fisiopatologia , Traumatismos do Nervo Lingual , Masculino , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/fisiologia , Estimulação Física , Canais de Cátion TRPV/metabolismo
7.
J Pain ; 9(7): 580-7, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18420461

RESUMO

UNLABELLED: The role of specific nicotinic receptor (nAChR) subtypes in antinociception has not been fully elucidated because of the lack, until recently, of selective tool compounds. (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiopene-2-carboxamide) (compound B) is reported to be an agonist selective for the alpha(7)nAChR and in the present study was found to be efficacious in inflammatory pain models in 2 species. Compound B reversed complete Freund adjuvant-induced reductions in paw withdrawal thresholds in rat and mouse in a dose-related manner, producing maximum reversals of 65% +/- 4% at 10 mg/kg and 87% +/- 15% at 20 mg/kg. When rats and mice were predosed with the centrally penetrant, broad-spectrum nicotinic receptor antagonist mecamylamine, the efficacy of the agonist was significantly inhibited, producing reversals of only 11% +/- 5% at 10 mg/kg and 5% +/- 13% at 20 mg/kg, confirming activity via nicotinic receptors. Rats were also predosed systemically with the selective low-brain penetrant alpha(7)-antagonist methyllycaconitine, which had no effect on agonist activity (90% +/- 18% at 10 mg/kg), suggesting a central involvement. This hypothesis was further established with methyllycaconitine completely inhibited the agonist effect when dosed intrathecally (1% +/- 7%). PERSPECTIVE: These studies provide good rationale for the utility of selective, central nervous system penetrant agonists at the alpha(7)-nicotinic receptor for the treatment of inflammatory pain.


Assuntos
Benzofuranos/farmacologia , Hiperalgesia/tratamento farmacológico , Quinuclidinas/farmacologia , Receptores Nicotínicos/fisiologia , Aconitina/administração & dosagem , Aconitina/análogos & derivados , Aconitina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzofuranos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Adjuvante de Freund , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/fisiopatologia , Injeções Intraperitoneais , Masculino , Mecamilamina/administração & dosagem , Mecamilamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Dor/fisiopatologia , Medição da Dor/métodos , Quinuclidinas/administração & dosagem , Ratos , Suporte de Carga/fisiologia , Receptor Nicotínico de Acetilcolina alfa7
8.
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
9.
J Med Chem ; 50(11): 2597-600, 2007 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-17477516

RESUMO

Selective CB2 receptor agonists are promising potential therapeutic agents for the treatment of inflammatory and neuropathic pain. A focused screen identified a pyrimidine ester as a partial agonist at the CB2 receptor with micromolar potency. Subsequent lead optimization identified 35, GW842166X, as the optimal compound in the series. 35 has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain and was selected as a clinical candidate for this indication.


Assuntos
Analgésicos/síntese química , Dor/tratamento farmacológico , Piranos/síntese química , Pirimidinas/síntese química , Receptor CB2 de Canabinoide/agonistas , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Meia-Vida , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Dor/metabolismo , Piranos/farmacocinética , Piranos/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade
10.
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
11.
Eur J Pain ; 11(2): 192-201, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16542859

RESUMO

We have investigated a possible role for vanilloid receptor 1 (TRPV1), a transducer of noxious stimuli, in the development of neuropathic pain following injury to a peripheral branch of the trigeminal nerve. In nine adult ferrets the left lingual nerve was sectioned and recovery permitted for 3 days, 3 weeks or 3 months (3 ferrets per group). A retrograde tracer, fluorogold, was injected into the damaged nerve to identify associated cell bodies in the trigeminal ganglion. Three further ferrets, receiving only tracer injection, served as uninjured controls. Indirect immunofluorescence for TRPV1 and image analysis was used to quantify the percentage area of staining (PAS) of TRPV1 in the left and right lingual nerves. Additionally, the proportion of fluorogold positive and fluorogold negative cells expressing TRPV1 in the ganglion was determined. TRPV1 expression increased significantly at the injury site of damaged nerves 3 days after injury and this was matched by a reduction in the proportion of fluorogold positive cells expressing TRPV1 in the ganglion. At 3 weeks TRPV1 expression at the injury site was still high, while in the ganglion was significantly greater than in the controls. In the 3-month recovery group TRPV1 expression in both nerve fibres and ganglion cells, was not significantly different from controls and there were no changes in expression in the fluorogold negative cells in the ganglion at any time point studied. These data suggest that after injury there is an increase in the axonal transport of TRPV1 from the cell bodies to the damaged axons and this is followed by an increase in synthesis in the ganglion. These changes in expression may be involved in development of sensory disturbances or dysaesthesia after injury.


Assuntos
Traumatismos do Nervo Lingual , Nervo Lingual/metabolismo , Neuralgia/metabolismo , Canais de Cátion TRPV/metabolismo , Gânglio Trigeminal/metabolismo , Animais , Feminino , Furões , Técnica Indireta de Fluorescência para Anticorpo , Corantes Fluorescentes , Estilbamidinas
12.
Brain Res ; 1127(1): 59-65, 2007 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-17109831

RESUMO

The lingual nerve, a peripheral branch of the trigeminal nerve, can be damaged during the surgical removal of lower third molar teeth. This damage can lead to the development of dysaesthesia, with some patients complaining of burning pain. We investigated the hypothesis that vanilloid receptor 1 (TRPV1), a transducer of noxious heat stimuli, was involved in the development of this burning pain. Neuroma specimens were obtained from patients undergoing microsurgical repair of a damaged lingual nerve. Repair was undertaken where there was little evidence of spontaneous recovery, 7-41 months after the initial injury. Preoperatively the incidence of dysaesthesia was determined by reported symptoms and using visual analogue scales (VAS) for pain, tingling and discomfort. Nine neuromas were studied from patients with burning dysaesthesia and six from patients with a sensory deficit but no dysaesthesia. Indirect immunofluorescence for protein gene product (PGP) 9.5 and TRPV1 was used to quantify the percentage area of PGP 9.5 positive neuronal tissue that also expressed TRPV1. The results showed no significant difference between the mean percentage area of TRPV1 expression in neuromas from patients with or without burning dysaesthesia. Furthermore, there was no correlation between TRPV1 expression and the VAS scores for pain, tingling or discomfort. However, if data from all patients was pooled, there was a negative correlation between the level of TRPV1 expression and the time after initial injury. These data do not rule out involvement of TRPV1 in the aetiology of burning dysaesthesia following lingual nerve injury but suggest that TRPV1 at the injury site does not play a primary role.


Assuntos
Traumatismos do Nervo Lingual , Nervo Lingual/metabolismo , Neuralgia/metabolismo , Neuroma/metabolismo , Canais de Cátion TRPV/metabolismo , Doenças do Nervo Trigêmeo/metabolismo , Adulto , Doença Crônica , Feminino , Humanos , Nervo Lingual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Dente Serotino/anatomia & histologia , Neuralgia/etiologia , Neuralgia/fisiopatologia , Neuroma/etiologia , Neuroma/fisiopatologia , Nociceptores/metabolismo , Procedimentos Cirúrgicos Bucais/efeitos adversos , Dor Intratável/etiologia , Dor Intratável/metabolismo , Dor Intratável/fisiopatologia , Parestesia/etiologia , Parestesia/metabolismo , Parestesia/fisiopatologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/fisiopatologia , Doenças do Nervo Trigêmeo/etiologia , Doenças do Nervo Trigêmeo/fisiopatologia
13.
Exp Neurol ; 202(1): 207-16, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16908020

RESUMO

We have investigated the expression of TTX-sensitive (TTXs) and TTX-resistant (TTXr) sodium channel subtypes following injury to the inferior alveolar nerve (IAN), in order to determine their potential role in the development of trigeminal neuropathic pain. In seven anaesthetised ferrets, fluorogold (2%) was injected into the left IAN to identify cell bodies with axons in this nerve. In four animals, the nerve was sectioned distal to the injection site and the remaining three served as controls. After 3 days, the animals were perfused with 4% paraformaldehyde. The left and right IANs and trigeminal ganglia were processed using indirect immunofluorescence with specific primary antibodies to TTXs subtypes Na(v)1.3 and Na(v)1.7 and TTXr subtypes Na(v)1.8 and Na(v)1.9. Image analysis was used to quantify the percentage area of staining (PAS) in the nerves. In the ganglia, counts were made of positively labelled cells in the fluorogold population. PAS for Na(v)1.8 and Na(v)1.9 was significantly greater in injured nerves than in either contralateral or control nerves. After injury, significantly fewer cells in the ganglia expressed Na(v)1.3 (controls 36.9%; injured 13.1%), Na(v)1.7 (controls 17.0%; injured 8.1%) and Na(v)1.9 (controls 60.3%; injured 29.0%) (p<0.05, unpaired t test). These changes are different from those previously reported in the dorsal root ganglion following damage to peripheral nerves of spinal origin. As they occur at a time of known high abnormal neural discharge, it seems likely that changes in sodium channel expression may play a role in nerve injury-induced trigeminal pain.


Assuntos
Regulação da Expressão Gênica/fisiologia , Canais de Sódio/metabolismo , Doenças do Nervo Trigêmeo/fisiopatologia , Animais , Furões , Imuno-Histoquímica/métodos , Nervo Mandibular/metabolismo , Nervo Mandibular/patologia , Canais de Sódio/classificação , Gânglio Trigeminal/metabolismo , Doenças do Nervo Trigêmeo/patologia
14.
Pain ; 120(1-2): 170-181, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16360270

RESUMO

Nitric oxide (NO), synthesised by different isoforms of nitric oxide synthase (NOS), has been linked with the development and maintenance of nociception. We studied the role of the inducible isoform, iNOS, in two different rat pain models with an inflammatory component. iNOS was immunohistochemically detected locally in the paw 6h after Freund's Complete Adjuvant (FCA) injection, showing a plateau at 24-72 h and falling slowly in the following weeks. This correlated with the late phase of the hypersensitivity to pain revealed in the behavioural tests. A highly selective iNOS inhibitor GW274150 (1-30 mg/kg orally, 24h after FCA) suppressed the accumulation of nitrite in the inflamed paw indicating substantial iNOS inhibition. At the same time it partially reversed FCA-induced hypersensitivity to pain and edema in a dose-dependent manner. After Chronic Constriction Injury (CCI) surgery to the sciatic nerve, iNOS presence was only detected locally in the region of the nerve (inflammatory cells). GW274150 (3-30 mg/kg orally, 21 days after surgery) also reversed significantly the CCI-associated hypersensitivity to pain. No iNOS was detectable in dorsal root ganglia, spinal cord or brain in either model. This study demonstrates a role for peripherally-expressed iNOS in pain conditions with an inflammatory component and the potential value of iNOS inhibitors in such conditions.


Assuntos
Hiperalgesia/diagnóstico , Hiperalgesia/enzimologia , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Sulfetos/administração & dosagem , Analgésicos/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Adjuvante de Freund , Hiperalgesia/induzido quimicamente , Inflamação/induzido quimicamente , Inflamação/diagnóstico , Masculino , Óxido Nítrico Sintase/administração & dosagem , Ratos , Resultado do Tratamento
15.
Pain ; 118(3): 327-335, 2005 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-16289798

RESUMO

The aim of the present study was to investigate the effects of cannabinoid agonists on established inflammatory hyperalgesia. We have compared the effects of pre-administration versus post-administration of a potent non-selective cannabinoid agonist HU210 and a selective CB2 receptor agonist JWH-133 on hindpaw weight bearing and paw oedema in the carrageenan model of inflammatory hyperalgesia. For comparative purposes we also determined the effects of the mu-opioid receptor agonist morphine and the COX2 inhibitor rofecoxib in this model. At 3 h following intraplantar injection of carrageenan (2%, 100 microl) there was a significant (P < 0.001) reduction in weight bearing on the ipsilateral hindpaw, compared to vehicle treated rats and a concomitant increase in ipsilateral hindpaw volume (P < 0.001), compared to vehicle treated rats. Systemic administration of HU210 (10 microg/kg) and JWH-133 (10 mg/kg) at 3 h following injection of carrageenan, significantly attenuated decreases in ipsilateral hindpaw weight bearing (P < 0.05 for both) and paw volume (P < 0.001 for both). Pre-administration of HU210 and JWH-133 had similar effects on weight bearing in this model. Pre-administered HU210 also significantly decreased carrageenan-induced changes in paw volume (P < 0.001), this was not the case for JWH-133. Effects of post-administered HU210 and JWH-133 on ipsilateral hindpaw weight bearing and paw volume were comparable to the effect of systemic post-administration of morphine and rofecoxib (3 mg/kg for both). In summary, both HU210 and JWH-133 attenuated established inflammatory hypersensitivity and swelling, suggesting that cannabinoid-based drugs have clinical potential for the treatment of established inflammatory pain responses.


Assuntos
Canabinoides/administração & dosagem , Dronabinol/análogos & derivados , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Inflamação/tratamento farmacológico , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Analgésicos/administração & dosagem , Animais , Carragenina , Dronabinol/administração & dosagem , Combinação de Medicamentos , Hiperalgesia/etiologia , Hiperalgesia/prevenção & controle , Inflamação/induzido quimicamente , Inflamação/complicações , Inflamação/fisiopatologia , Masculino , Ratos , Resultado do Tratamento , Suporte de Carga
16.
Brain Res ; 1027(1-2): 11-7, 2004 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-15494152

RESUMO

Damage to the inferior alveolar nerve (IAN) may result in permanent painful dysaesthesia, and there is compelling evidence to suggest that ectopic activity from the injury site plays a crucial role in the initiation of this disorder. The aim of this study was to determine whether neuronal nitric oxide synthase (nNOS), a regulator of neuronal excitability, could be involved in the development of the abnormal activity. In seven ferrets, the left IAN was exposed and a retrograde tracer, fluorogold, was applied to the nerve for the identification of cell bodies in the trigeminal ganglion with axons in the IAN. In four animals, the nerve was sectioned distal to the injection site, and three served as controls. After 3 days, the animals were perfused with fixative, and the left and right IANs and trigeminal ganglia were processed using indirect immunofluorescence for nNOS. Image analysis was used to quantify the percentage area of staining (PAS) at the injury site. In the ganglia, counts were made of positively labelled cells in the fluorogold population. At the injury site, PAS was significantly greater in injured nerves than in either contralateral or control nerves, and contralateral PAS was elevated compared to control. In the ganglia, the proportion of nNOS-labelled cells was significantly reduced following injury. These results indicate a possible translocation of the nNOS protein from the cell body to the site of nerve injury, where it accumulates. Thus, nNOS could play a role in the development of ectopic activity at a site of trigeminal nerve injury.


Assuntos
Traumatismos dos Nervos Cranianos/enzimologia , Regulação Enzimológica da Expressão Gênica , Nervo Mandibular/enzimologia , Óxido Nítrico Sintase/metabolismo , Animais , Contagem de Células/métodos , Traumatismos dos Nervos Cranianos/patologia , Diagnóstico por Imagem/métodos , Furões , Corantes Fluorescentes/metabolismo , Lateralidade Funcional/fisiologia , Imuno-Histoquímica/métodos , Nervo Mandibular/patologia , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo I , Estilbamidinas/metabolismo , Traumatismos do Nervo Trigêmeo
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