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1.
FASEB J ; 29(10): 4285-98, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26136480

RESUMO

Transient receptor potential vanilloid 1 (TRPV1) is involved in sensory nerve nociceptive signaling. Recently, it has been discovered that TRPV1 receptors also regulate basal body temperature in multiple species from mice to humans. In the present study, we investigated whether TRPV1 modulates basal sympathetic nervous system (SNS) activity. C57BL6/J wild-type (WT) mice and TRPV1 knockout (KO) mice were implanted with radiotelemetry probes for measurement of core body temperature. AMG9810 (50 mg/kg) or vehicle (2% DMSO/5% Tween 80/10 ml/kg saline) was injected intraperitoneally. Adrenoceptor antagonists or vehicle (5 ml/kg saline) was injected subcutaneously. In WT mice, the TRPV1 antagonist, AMG9810, caused significant hyperthermia, associated with increased noradrenaline concentrations in brown adipose tissue. The hyperthermia was significantly attenuated by the ß-adrenoceptor antagonist propranolol, the mixed α-/ß-adrenoceptor antagonist labetalol, and the α1-adrenoceptor antagonist prazosin. TRPV1 KO mice have a normal basal body temperature, indicative of developmental compensation. d-Amphetamine (potent sympathomimetic) caused hyperthermia in WT mice, which was reduced in TRPV1 KO mice, suggesting a decreased sympathetic drive in KOs. This study provides new evidence that TRPV1 controls thermoregulation upstream of the SNS, providing a potential therapeutic target for sympathetic hyperactivity thermoregulatory disorders.


Assuntos
Regulação da Temperatura Corporal/fisiologia , Temperatura Corporal/fisiologia , Sistema Nervoso Simpático/fisiologia , Canais de Cátion TRPV/fisiologia , Acrilamidas/administração & dosagem , Acrilamidas/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/farmacologia , Animais , Temperatura Corporal/genética , Regulação da Temperatura Corporal/genética , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Febre/genética , Febre/fisiopatologia , Humanos , Injeções Intraperitoneais , Injeções Subcutâneas , Labetalol/administração & dosagem , Labetalol/farmacologia , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prazosina/administração & dosagem , Prazosina/farmacologia , Propranolol/administração & dosagem , Propranolol/farmacologia , Receptores Adrenérgicos alfa 1/fisiologia , Receptores Adrenérgicos beta/fisiologia , Sistema Nervoso Simpático/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/genética , Telemetria/métodos
2.
J Immunol ; 188(11): 5741-51, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22547700

RESUMO

The transient receptor potential vanilloid 1 (TRPV1) is primarily localized to sensory nerve fibers and is associated with the stimulation of pain and inflammation. TRPV1 knockout (TRPV1KO) mice show enhanced LPS-induced sepsis compared with wild type (WT). This implies that TRPV1 may have a key modulatory role in increasing the beneficial and reducing the harmful components in sepsis. We investigated immune and inflammatory mechanisms in a cecal ligation and puncture (CLP) model of sepsis over 24 h. CLP TRPV1KO mice exhibited significant hypothermia, hypotension, and organ dysfunction compared with CLP WT mice. Analysis of the inflammatory responses at the site of initial infection (peritoneal cavity) revealed that CLP TRPV1KO mice exhibited: 1) decreased mononuclear cell integrity associated with apoptosis, 2) decreased macrophage tachykinin NK(1)-dependent phagocytosis, 3) substantially decreased levels of nitrite (indicative of NO) and reactive oxygen species, 4) increased cytokine levels, and 5) decreased bacteria clearance when compared with CLP WT mice. Therefore, TRPV1 deletion is associated with impaired macrophage-associated defense mechanisms. Thus, TRPV1 acts to protect against the damaging impact of sepsis and may influence the transition from local to a systemic inflammatory state.


Assuntos
Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Canais de Cátion TRPV/deficiência , Canais de Cátion TRPV/genética , Regulação para Cima/imunologia , Animais , Feminino , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/antagonistas & inibidores , Peritônio/imunologia , Peritônio/patologia , Peritônio/cirurgia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Síndrome de Resposta Inflamatória Sistêmica/genética , Canais de Cátion TRPV/biossíntese , Regulação para Cima/genética
3.
Arthritis Rheum ; 63(3): 819-29, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21360511

RESUMO

OBJECTIVE: To investigate the involvement of transient receptor potential ankyrin 1 (TRPA1) in inflammatory hyperalgesia mediated by tumor necrosis factor α(TNFα) and joint inflammation. METHODS: Mechanical hyperalgesia was assessed in CD1 mice, mice lacking functional TRP vanilloid 1 (TRPV1-/-) or TRPA1 (TRPA1-/-), or respective wildtype (WT) mice. An automated von Frey system was used, following unilateral intraplantar injection of TNFα or intraarticular injection of Freund's complete adjuvant (CFA). Knee swelling and histologic changes were determined in mice treated with intraarticular injections of CFA. RESULTS: TNFα induced cyclooxygenase-independent bilateral mechanical hyperalgesia in CD1 mice. The selective TRPV1 receptor antagonist SB-366791 had no effect on mechanical hyperalgesia when it was coinjected with TNFα, but intrathecally administered SB- 366791 attenuated bilateral hyperalgesia, indicating the central but not peripheral involvement of TRPV1 receptors. A decrease in pain sensitivity was also observed in TRPV1-/- mice. Intraplantar coadministration of the TRPA1 receptor antagonist AP-18 with TNFα inhibited bilateral hyperalgesia. Intrathecal treatment with AP-18 also reduced TNFα-induced hyperalgesia. CFA-induced mechanical hyperalgesia in CD1 mice was attenuated by AP-18 (administered by intraarticular injection 22 hours after the administration of CFA). Furthermore, intraarticular CFA­induced ipsilateral mechanical hyperalgesia was maintained for 3 weeks in TRPA1 WT mice. In contrast, TRPA1-/- mice exhibited mechanical hyperalgesia for only 24 hours after receiving CFA. CONCLUSION: Evidence suggests that endogenous activation of peripheral TRPA1 receptors plays a critical role in the development of TNFα-induced mechanical hyperalgesia and in sustaining the mechanical hyperalgesia observed after intraaarticular injection of CFA. These results suggest that blockade of TRPA1 receptors may be beneficial in reducing the chronic pain associated with arthritis.


Assuntos
Artrite Experimental/imunologia , Hiperalgesia/imunologia , Canais de Cátion TRPV/imunologia , Canais de Potencial de Receptor Transitório/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adjuvantes Imunológicos/farmacologia , Anilidas/farmacologia , Animais , Artralgia/induzido quimicamente , Artralgia/imunologia , Artrite Experimental/induzido quimicamente , Cinamatos/farmacologia , Modelos Animais de Doenças , Feminino , Adjuvante de Freund/farmacologia , Hiperalgesia/induzido quimicamente , Injeções Intra-Articulares , Injeções Espinhais , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Canal de Cátion TRPA1 , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/genética , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/genética , Fator de Necrose Tumoral alfa/farmacologia
4.
mSphere ; 2(1)2017.
Artigo em Inglês | MEDLINE | ID: mdl-28194448

RESUMO

The intestinal microbiome plays an essential role in regulating many aspects of host physiology, and its disruption through antibiotic exposure has been implicated in the development of a range of serious pathologies. The complex metabolic relationships that exist between members of the intestinal microbiota and the potential redundancy in functional pathways mean that an integrative analysis of changes in both structure and function are needed to understand the impact of antibiotic exposure. We used a combination of next-generation sequencing and nuclear magnetic resonance (NMR) metabolomics to characterize the effects of two clinically important antibiotic treatments, ciprofloxacin and vancomycin-imipenem, on the intestinal microbiomes of female C57BL/6 mice. This assessment was performed longitudinally and encompassed both antibiotic challenge and subsequent microbiome reestablishment. Both antibiotic treatments significantly altered the microbiota and metabolite compositions of fecal pellets during challenge and recovery. Spearman's correlation analysis of microbiota and NMR data revealed that, while some metabolites could be correlated with individual operational taxonomic units (OTUs), frequently multiple OTUs were associated with a significant change in a given metabolite. Furthermore, one metabolite, arginine, can be associated with increases/decreases in different sets of OTUs under differing conditions. Taken together, these findings indicate that reliance on shifts in one data set alone will generate an incomplete picture of the functional effect of antibiotic intervention. A full mechanistic understanding will require knowledge of the baseline microbiota composition, combined with both a comparison and an integration of microbiota, metabolomics, and phenotypic data. IMPORTANCE Despite the fundamental importance of antibiotic therapies to human health, their functional impact on the intestinal microbiome and its subsequent ability to recover are poorly understood. Much research in this area has focused on changes in microbiota composition, despite the interdependency and overlapping functions of many members of the microbial community. These relationships make prediction of the functional impact of microbiota-level changes difficult, while analyses based on the metabolome alone provide relatively little insight into the taxon-level changes that underpin changes in metabolite levels. Here, we used combined microbiota and metabolome profiling to characterize changes associated with clinically important antibiotic combinations with distinct effects on the gut. Correlation analysis of changes in the metabolome and microbiota indicate that a combined approach will be essential for a mechanistic understanding of the functional impact of distinct antibiotic classes.

5.
Arthritis Res Ther ; 18: 7, 2016 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-26754745

RESUMO

BACKGROUND: The effect of cold temperature on arthritis symptoms is unclear. The aim of this study was to investigate how environmental cold affects pain and blood flow in mono-arthritic mice, and examine a role for transient receptor potential ankyrin 1 (TRPA1), a ligand-gated cation channel that can act as a cold sensor. METHODS: Mono-arthritis was induced by unilateral intra-articular injection of complete Freund's adjuvant (CFA) in CD1 mice, and in mice either lacking TRPA1 (TRPA1 KO) or respective wildtypes (WT). Two weeks later, nociception and joint blood flow were measured following exposure to 10 °C (1 h) or room temperature (RT). Primary mechanical hyperalgesia in the knee was measured by pressure application apparatus; secondary mechanical hyperalgesia by automated von Frey system; thermal hyperalgesia by Hargreaves technique, and weight bearing by the incapacitance test. Joint blood flow was recorded by full-field laser perfusion imager (FLPI) and using clearance of (99m)Technetium. Blood flow was assessed after pretreatment with antagonists of either TRPA1 (HC-030031), substance P neurokinin 1 (NK1) receptors (SR140333) or calcitonin gene-related peptide (CGRP) (CGRP8-37). TRPA1, TAC-1 and CGRP mRNA levels were examined in dorsal root ganglia, synovial membrane and patellar cartilage samples. RESULTS: Cold exposure caused bilateral primary mechanical hyperalgesia 2 weeks after CFA injection, in a TRPA1-dependent manner. In animals maintained at RT, clearance techniques and FLPI showed that CFA-treated joints exhibited lower blood flow than saline-treated joints. In cold-exposed animals, this reduction in blood flow disappears, and increased blood flow in the CFA-treated joint is observed using FLPI. Cold-induced increased blood flow in CFA-treated joints was blocked by HC-030031 and not observed in TRPA1 KOs. Cold exposure increased TRPA1 mRNA levels in patellar cartilage, whilst reducing it in synovial membranes from CFA-treated joints. CONCLUSIONS: We provide evidence that environmental cold exposure enhances pain and increases blood flow in a mono-arthritis model. These changes are dependent on TRPA1. Thus, TRPA1 may act locally within the joint to influence blood flow via sensory nerves, in addition to its established nociceptive actions.


Assuntos
Artrite Experimental/metabolismo , Velocidade do Fluxo Sanguíneo/fisiologia , Temperatura Baixa/efeitos adversos , Adjuvante de Freund/toxicidade , Articulações/metabolismo , Canais de Potencial de Receptor Transitório/biossíntese , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Adjuvante de Freund/administração & dosagem , Membro Posterior/efeitos dos fármacos , Membro Posterior/metabolismo , Membro Posterior/patologia , Injeções Intra-Articulares , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Canal de Cátion TRPA1 , Canais de Potencial de Receptor Transitório/deficiência
6.
Pain ; 142(3): 264-274, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19231080

RESUMO

TNFalpha plays a pivotal role in rheumatoid arthritis (RA) but little is known of the mechanisms that link the inflammatory and nociceptive effects of TNFalpha. We have established a murine model of TNFalpha-induced TRPV1-dependent bilateral thermal hyperalgesia that then allowed us to identify distinct peripheral mechanisms involved in mediating TNFalpha-induced ipsilateral and contralateral hyperalgesia. Thermal hyperalgesia and inflammation were assessed in both hindpaws following unilateral intraplantar (i.pl.) TNFalpha. The hyperalgesic mechanisms were analysed through pharmacogenetic approaches involving TRPV1(-/-) mice and TRPV1 antagonists. To study the mediators downstream of TNFalpha, cyclooxygenase (COX) and PKC inhibitors were utilised and cytokine and prostaglandin levels assessed. The role of neutrophils was determined through use of the selectin inhibitor, fucoidan. We show that TNFalpha (10pmol) causes thermal hyperalgesia (1-4h) in the ipsilateral inflamed and contralateral uninjured hindpaws, which is TRPV1-dependent. GF109203X, a PKC inhibitor, suppressed the hyperalgesia indicating that PKC is involved in TRPV1 sensitisation. Ipsilateral COX-2-derived prostaglandins were also crucial to the development of the bilateral hyperalgesia. The prevention of neutrophil accumulation with fucoidan attenuated hyperalgesia at 4 but not at 1h, indicating a role in the maintenance but not in the induction of bilateral hyperalgesia. However, TNFalpha-induced IL-1beta generation in both paws and the presence of local IL-1beta in the contralateral paw were essential for the development of bilateral hyperalgesia. These results identify a series of peripheral events through which TNFalpha triggers and maintains bilateral inflammatory pain. This potentially allows a better understanding of mechanisms involved in TNFalpha-dependent pain pathways in symmetrical diseases such as arthritis.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Temperatura Alta , Hiperalgesia/fisiopatologia , Interleucina-1beta/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais , Canais de Cátion TRPV/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL
7.
Eur J Pain ; 13(8): 812-9, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18976941

RESUMO

Temporomandibular disorders represent one of the major challenges in dentistry therapeutics. This study was undertaken to evaluate the time course of carrageenan-induced inflammation in the rat temporomandibular joint (TMJ) and to investigate the role of tachykinin NK(1) receptors. Inflammation was induced by a single intra-articular (i.art.) injection of carrageenan into the left TMJ (control group received sterile saline). Inflammatory parameters such as plasma extravasation, leukocyte influx and mechanical allodynia (measured as the head-withdrawal force threshold) and TNFalpha and IL-1beta concentrations were measured in the TMJ lavages at selected time-points. The carrageenan-induced responses were also evaluated after treatment with the NK(1) receptor antagonist SR140333. The i.art. injection of carrageenan into the TMJ caused a time-dependent plasma extravasation associated with mechanical allodynia, and a marked neutrophil accumulation between 4 and 24h. Treatment with SR140333 substantially inhibited the increase in plasma extravasation and leukocyte influx at 4 and 24h, as well as the production of TNFalpha and IL-1beta into the joint cavity, but failed to affect changes in head-withdrawal threshold. The results obtained from the present TMJ-arthritis model provide, for the first time, information regarding the time course of this experimental inflammatory process. In addition, our data show that peripheral NK(1) receptors mediate the production of both TNFalpha and IL-1beta in the TMJ as well as some of the inflammatory signs, such as plasma extravasation and leukocyte influx, but not the nociceptive component.


Assuntos
Inflamação/patologia , Receptores da Neurocinina-1/fisiologia , Transtornos da Articulação Temporomandibular/patologia , Animais , Carragenina , Interpretação Estatística de Dados , Extravasamento de Materiais Terapêuticos e Diagnósticos , Inflamação/induzido quimicamente , Interleucina-1beta/metabolismo , Contagem de Leucócitos , Masculino , Antagonistas dos Receptores de Neurocinina-1 , Dor/etiologia , Dor/fisiopatologia , Peroxidase/metabolismo , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Quinuclidinas/farmacologia , Quinuclidinas/uso terapêutico , Compostos Radiofarmacêuticos , Ratos , Ratos Wistar , Soroalbumina Radioiodada , Substância P/metabolismo , Transtornos da Articulação Temporomandibular/induzido quimicamente , Fator de Necrose Tumoral alfa/metabolismo
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