RESUMO
AIMS: This programme investigated topical regorafenib, a multikinase inhibitor, in patients with neovascular age-related macular degeneration (nAMD). METHODS: Topical regorafenib was investigated in an open-label, phase IIa/b study in which patients with choroidal neovascularization (CNV) secondary to nAMD received regorafenib (25 µl, 30 mg ml-1 ) three times a day for 12 weeks. The primary endpoint of the phase II/a/b study was mean change in best-corrected visual acuity (BCVA) from baseline to weeks 4 and 12. RESULTS: In nAMD patients (N = 51), mean changes in BCVA were +1.2 [90% confidence interval (CI) -0.61, 2.97] and -2.4 (90% CI -4.18, -0.54) letters at weeks 4 and 12, respectively. Ocular treatment-emergent adverse events (TEAEs) (study eye) were reported in 21 patients by week 12. There was one serious ocular TEAE (visual acuity reduced) that was not drug related. Twenty patients required rescue (intravitreal ranibizumab). CONCLUSIONS: The programme was terminated after phase IIa ended because efficacy was lower than with current nAMD treatments. According to elaborate post hoc analyses, the most likely reason was insufficient exposure in the target compartment (back of the eye).
Assuntos
Inibidores da Angiogênese/administração & dosagem , Degeneração Macular/tratamento farmacológico , Soluções Oftálmicas/administração & dosagem , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Acuidade Visual/efeitos dos fármacos , Administração Oftálmica , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Feminino , Humanos , Masculino , Soluções Oftálmicas/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Piridinas/efeitos adversos , Resultado do TratamentoRESUMO
AIM: Regorafenib is a multikinase inhibitor under investigation for use in neovascular age-related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy volunteers to provide information on safety, tolerability and systemic exposure. METHODS: This was a single-centre, randomized, double-masked, parallel-group, dose-escalation, placebo-controlled study. Subjects received regorafenib eye drops (30 mg ml-1 , 25 µl) as a 0.75 mg single dose (Cohort 1), 0.75 mg twice daily (bid) or thrice daily (tid) over 14 days (Cohorts 2 and 3, respectively), 1.5 mg tid unilaterally for 3 days, then bilaterally for up to 14 days (Cohort 4), or placebo. Plasma samples were taken to estimate systemic exposure. Safety and functional assessments were performed throughout the study. RESULTS: Thirty-six subjects received regorafenib and 12 received placebo. Regorafenib was safe and well tolerated over the dose range. No pathological changes occurred in the anterior, vitreous or posterior eye compartments. Mild eyelid redness, oedema and conjunctival hyperaemia were observed across all regorafenib cohorts; these were comparable with the effects seen with placebo. Predominant symptoms were blurred vision in the active and placebo groups. Systemic safety evaluations showed no clinically relevant findings. Absolute systemic exposure after multiple administrations of regorafenib eye drops at a dose of 0.75 mg was 600-700-fold lower than after multiple oral administration of 160 mg day-1 , the dose approved in cancer indications. CONCLUSION: These results indicate a favourable safety and tolerability profile of regorafenib eye drops up to 30 mg ml-1 tid for use in clinical studies.
Assuntos
Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Administração Oftálmica , Administração Oral , Adolescente , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas/efeitos adversos , Soluções Oftálmicas/farmacocinética , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/sangue , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/administração & dosagem , Piridinas/sangue , Adulto JovemRESUMO
OBJECTIVE: In spite of successful treatment of immune-mediated arthritis, many patients still experience pain. We undertook this study to investigate whether antigen-induced arthritis (AIA) in rats triggers neuronal changes in sensory neurons that outlast the inflammatory process. METHODS: We induced unilateral AIA in the knee joint and assessed in sensory neurons the expression of CREB, a transcription factor that regulates genes involved in neuronal plasticity. We tested whether neutralization of the effects of tumor necrosis factor (TNF) by etanercept or infliximab or neutralization of the effects of interleukin-1ß (IL-1ß) by anakinra influences the up-regulation of phospho-CREB, and we studied the up-regulation of phospho-CREB by IL-1ß and TNF in cultured dorsal root ganglion (DRG) neurons. RESULTS: Unilateral AIA caused bilateral up-regulation of phospho-CREB in lumbar DRG neurons. While inflammation and pain subsided within 21 days, the up-regulation of phospho-CREB still persisted on day 42. At this time point mechanical hyperalgesia at the knee reappeared in the absence of swelling. TNF neutralization during AIA significantly reduced pain-related behavior but did not prevent phospho-CREB up-regulation. In contrast, anakinra, which only reduced thermal hyperalgesia, prevented phospho-CREB up-regulation, suggesting a role of IL-1ß in this process. In cultured DRG neurons the application of IL-1ß significantly enhanced phospho-CREB. CONCLUSION: Immune-mediated arthritis causes neuroplastic changes in sensory neurons that outlast the inflammatory phase. Such changes may facilitate the persistence or recurrence of pain after remission of arthritis. IL-1ß is an important trigger in this process, although its neutralization barely reduced mechanical hyperalgesia during inflammation.
Assuntos
Artrite Experimental/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Hiperalgesia/genética , Células Receptoras Sensoriais/metabolismo , Animais , Antirreumáticos/farmacologia , Artrite Experimental/metabolismo , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Etanercepte/farmacologia , Feminino , Gânglios Espinais/citologia , Regulação da Expressão Gênica , Hiperalgesia/metabolismo , Infliximab/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/farmacologia , Plasticidade Neuronal , Dor/genética , Dor/metabolismo , Ratos , Ratos Endogâmicos Lew , Células Receptoras Sensoriais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
In addition to the proinflammatory cytokines tumor necrosis factor-α, interleukin-6 and interleukin-1ß, the cytokine interleukin-17 (IL-17) is considered an important mediator of autoimmune diseases such as rheumatoid arthritis. Because tumor necrosis factor-α and interleukin-1ß have the potential to influence the expression of transduction molecules such as transient receptor potential vanilloid 1 (TRPV1) in dorsal root ganglion (DRG) neurons and thus to contribute to pain we explored in the present study whether IL-17A activates DRG neurons and influences the expression of TRPV1. The IL-17A receptor was visualized in most neurons in dorsal root ganglion (DRG) sections as well as in cultured DRG neurons. Upon long-term exposure to IL-17A, isolated and cultured rat DRG neurons showed a significant upregulation of extracellular-regulated kinase (ERK) and nuclear factor κB (NFκB). Long-term exposure of neurons to IL-17A did not upregulate the expression of TRPV1. However, we found a pronounced upregulation of transient receptor potential vanilloid 4 (TRPV4) which is considered a candidate transduction molecule for mechanical hyperalgesia. Upon the injection of zymosan into the paw, IL-17A-deficient mice showed less mechanical hyperalgesia than wild type mice but thermal hyperalgesia was not attenuated in IL-17A-deficient mice. These data show, therefore, a particular role of IL-17 in mechanical hyperalgesia, and they suggest that this effect is linked to an activation and upregulation of TRPV4.
Assuntos
Hiperalgesia/metabolismo , Interleucina-17/metabolismo , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Canais de Cátion TRPV/metabolismo , Animais , Gânglios Espinais/metabolismo , Masculino , Camundongos , Camundongos Knockout , Ratos , Ratos Wistar , Regulação para CimaRESUMO
Synaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as stiffness, spasms and anxiety occur in paraneoplastic stiff person syndrome with autoantibodies against the intracellular synaptic protein amphiphysin. Here we show that intrathecal application of purified anti-amphiphysin immunoglobulin G antibodies induces stiff person syndrome-like symptoms in rats, including stiffness and muscle spasms. Using in vivo recordings of Hoffmann reflexes and dorsal root potentials, we identified reduced presynaptic GABAergic inhibition as an underlying mechanism. Anti-amphiphysin immunoglobulin G was internalized into neurons by an epitope-specific mechanism and colocalized in vivo with presynaptic vesicular proteins, as shown by stimulation emission depletion microscopy. Neurons from amphiphysin deficient mice that did not internalize the immunoglobulin provided additional evidence of the specificity in antibody uptake. GABAergic synapses appeared more vulnerable than glutamatergic synapses to defective endocytosis induced by anti-amphiphysin immunoglobulin G, as shown by increased clustering of the endocytic protein AP180 and by defective loading of FM 1-43, a styryl dye used to label cell membranes. Incubation of cultured neurons with anti-amphiphysin immunoglobulin G reduced basal and stimulated release of γ-aminobutyric acid substantially more than that of glutamate. By whole-cell patch-clamp analysis of GABAergic inhibitory transmission in hippocampus granule cells we showed a faster, activity-dependent decrease of the amplitude of evoked inhibitory postsynaptic currents in brain slices treated with antibodies against amphiphysin. We suggest that these findings may explain the pathophysiology of the core signs of stiff person syndrome at the molecular level and show that autoantibodies can alter the function of inhibitory synapses in vivo upon binding to an intraneuronal key protein by disturbing vesicular endocytosis.
Assuntos
Autoanticorpos/uso terapêutico , Proteínas do Tecido Nervoso/imunologia , Inibição Neural/imunologia , Rigidez Muscular Espasmódica/imunologia , Rigidez Muscular Espasmódica/terapia , Ácido gama-Aminobutírico/metabolismo , Idoso , Animais , Autoanticorpos/administração & dosagem , Autoanticorpos/fisiologia , Células Cultivadas , Endocitose/imunologia , Feminino , Humanos , Imunização Passiva/métodos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/fisiologia , Imunoglobulina G/uso terapêutico , Potenciais Pós-Sinápticos Inibidores/fisiologia , Injeções Espinhais , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Ratos , Ratos Endogâmicos Lew , Rigidez Muscular Espasmódica/patologia , Ácido gama-Aminobutírico/deficiênciaRESUMO
INTRODUCTION: Interleukin-6 (IL-6) is a key player in systemic arthritis, involved in inflammation and joint destruction. IL-6 signalling has also been revealed in nerve cells. Recently, IL-6 and in particular IL-6 together with its soluble IL-6 receptor (sIL-6R) were shown to induce a long-lasting robust sensitization of joint nociceptors for mechanical stimuli which was difficult to reverse, suggesting that IL-6 signalling plays a significant role in the generation and maintenance of arthritic pain. Here we tested in a preclinical model of arthritis, antigen-induced arthritis (AIA) in the rat, whether systemic or local neutralization of IL-6/sIL-6R complexes with soluble glycoprotein 130 (sgp130) alters arthritic pain and how sgp130 influences the inflammatory process in AIA. METHODS: Rats with AIA were either treated with sgp130 or saline intra-peritoneally or intra-articularly (each group n = 9). Then, pain-related and locomotor behaviour, as well as joint swelling, were measured during an observation period of 21 days, followed by histopathological end-point analysis for inflammatory and destructive changes. RESULTS: A single intra-articular application of sgp130 at the time of AIA induction barely reduced the development of AIA, but significantly attenuated pain-related behaviour, that is, primary mechanical hyperalgesia in the acute phase of AIA. By contrast, repeated systemic application of sgp130 after onset of AIA only slightly attenuated pain at a late stage of AIA. None of the treatments reduced secondary hyperalgesia. Furthermore, in the present study joint destruction at 21 days was significantly attenuated after intra-articular sgp130 treatment, but not after systemic sgp130. CONCLUSIONS: In addition to its role in chronic inflammation, IL-6 in the joint plays a significant role in the generation and maintenance of arthritic joint pain at acute and chronic stages of AIA. The particular effectiveness of intra-articular injection of sgp130 indicates, first, that IL-6/sIL-6R in the inflamed joint, rather than circulating IL-6/sIL-6R, is responsible for the generation of hyperalgesia, and, second, that early neutralization of IL-6/sIL-6R is particularly successful in producing antinociception. Furthermore, neutralization of IL-6/sIL-6R (and possibly other cytokines which use the transmembrane signal-transducing subunit gp130) directly at the site of joint inflammation seems to be effective in the prevention of joint destruction.
Assuntos
Artrite Experimental/tratamento farmacológico , Glicoproteínas/farmacologia , Dor/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Comportamento Animal/efeitos dos fármacos , Feminino , Glicoproteínas/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Injeções Intra-Articulares , Injeções Intraperitoneais , Interleucina-6/metabolismo , Atividade Motora/efeitos dos fármacos , Dor/metabolismo , Dor/patologia , Ratos , Ratos Endogâmicos Lew , Transdução de Sinais/imunologia , SolubilidadeRESUMO
BACKGROUND: Age has been identified as an independent risk factor for cardiovascular diseases. In addition, autonomic imbalance toward sympathetic preponderance has been shown to facilitate the occurrence of heart disease. Here, we aimed to assess autonomic modulation of cardiovascular parameters during normal ageing applying well-established linear and novel nonlinear parameters. METHODS: Linear and nonlinear measures of heart rate variability and complexity as well as measures of QT interval variability and baroreflex sensitivity were obtained from a total of 131 healthy, medication-free participants from a continuous age range between 20 and 90 years, who were allocated to three different age groups. RESULTS: Heart rate variability and complexity significantly decreased with age, while regularity of heart rate time series increased. In addition, QT interval variability linearly increased with age, while baroreflex sensitivity showed a pronounced decrease. Overall, concerning effects of ageing, linear and nonlinear parameters showed equal differentiation between groups. CONCLUSION: These data indicate a shift of autonomic balance toward sympathetic predominance in higher age groups, limiting the reactiveness of the cardiovascular system to adjust to different demands and increasing the risk for developing tachyarrhythmias.
Assuntos
Barorreflexo , Eletrocardiografia/métodos , Frequência Cardíaca , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas , Análise de Variância , Pressão Sanguínea , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Fumar , Adulto JovemRESUMO
BACKGROUND: Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. RESULTS: Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G)-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1beta), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1beta. The increase of the anti-inflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-1beta, and IL-10 following CFA, overall corroborating the inhibitor data. CONCLUSION: These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression.
Assuntos
Citocinas/metabolismo , Hiperalgesia/enzimologia , Hiperalgesia/imunologia , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/biossíntese , Animais , Citocinas/efeitos dos fármacos , Citocinas/genética , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Adjuvante de Freund/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hiperalgesia/fisiopatologia , Mediadores da Inflamação/farmacologia , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Isoenzimas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Nociceptores/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Gait abnormalities have been suggested to provide an objective measure for joint pain in animal models. Here, we aimed to assess whether parameters of gait analysis correlate with measures of pain-related behavior in experimental monoarthritis. For this purpose, antigen-induced arthritis was induced in the left knee joints of 68 female Lewis rats, of which 30 were treated with tumor necrosis factor-alpha(TNF)-neutralizing compounds. During the course of arthritis, paw print analysis parameters and measures for mechanical and thermal hyperalgesia were obtained. Knee joints harvested on either day 3 or day 21 were scored histologically for signs of inflammation and cartilage and bone destructions. Data were compared to those obtained from 33 immunized control rats and correlated for days 3 and 21. Arthritic rats showed distinct asymmetric gait abnormalities. In the acute stage of antigen-induced arthritis, but not in the chronic phase, there was a significant correlation between the gait parameter 'left-right distance' and measures of primary and secondary hyperalgesia. Both in the acute and chronic phases, however, the gait parameter 'angle between paws' indicating outward rotation of paws mainly correlated with joint destruction as assessed using histology. Etanercept treatment exhibited pronounced anti-nociceptive and pro-locomotional effects, but the described correlations remained. In conclusion, some parameters of gait analysis may represent a good measure for arthritis pain, mainly in acute inflammation, while others are increasingly influenced by mechanical joint deformation as indicated by cartilage and bone destructions. Thus, gait abnormalities may not unequivocally be suitable for objective pain assessment in all stages of experimental arthritis.
Assuntos
Artrite Experimental/complicações , Coxeadura Animal/etiologia , Limiar da Dor/fisiologia , Dor/complicações , Análise de Variância , Animais , Artrite Experimental/etiologia , Testes Imunológicos de Citotoxicidade/efeitos adversos , Modelos Animais de Doenças , Feminino , Hiperalgesia/etiologia , Artropatias/complicações , Artropatias/etiologia , Dor/etiologia , Medição da Dor/métodos , Ratos , Ratos Endogâmicos Lew , Estatística como Assunto , Fatores de TempoRESUMO
After peripheral nerve damage macrophages infiltrate the dorsal root ganglia (DRG) in which cell bodies of lesioned neurons are located. However, infiltration of macrophages into the DRGs was also reported in complete Freund's adjuvant (CFA)-induced inflammation raising the question whether CFA inflammation induces nerve cell damage or whether peripheral inflammation may also trigger macrophage infiltration into DRGs. Related questions are, first, which signals trigger macrophage infiltration into DRGs and, second, is macrophage infiltration correlated with pain-related behavior. Using the rat model of unilateral antigen-induced arthritis (AIA) in the knee we found a massive infiltration of ED1(+) macrophages into the ipsi- and contralateral lumbar DRGs but not into thoracic DRGs. At no time point of AIA DRG neurons showed expression of activating transcription factor-3 (ATF3) indicating that macrophage infiltration is not explainable by nerve cell lesions in this model. During AIA, lumbar but not thoracic DRGs exhibited a bilateral de novo expression of vascular cell adhesion molecule-1 (VCAM-1) which is known to be involved in macrophage infiltration. Tumor necrosis factor-alpha (TNF-alpha) neutralization with etanercept or infliximab treatment after induction of AIA significantly reduced both macrophage infiltration and VCAM-1 expression. It also decreased mechanical hyperalgesia at the inflamed joint although the joint inflammation itself was barely attenuated, and it reduced mechanical hyperalgesia at the non-inflamed contralateral knee joint. Thus, bilateral segment-specific infiltration of macrophages into DRGs is part of an unilateral inflammatory process in peripheral tissue and it may be involved in the generation of hyperalgesia in particular on the non-inflamed side.
Assuntos
Artrite Experimental/complicações , Gânglios Espinais , Hiperalgesia/etiologia , Macrófagos/patologia , Limiar da Dor/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Fator 3 Ativador da Transcrição/metabolismo , Animais , Anticorpos/uso terapêutico , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Modelos Animais de Doenças , Ectodisplasinas/metabolismo , Feminino , Adjuvante de Freund/efeitos adversos , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Gânglios Espinais/fisiopatologia , Traumatismos do Joelho/etiologia , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/fisiologia , Ratos , Fator de Necrose Tumoral alfa/imunologia , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
OBJECTIVE: The reduction of pain in the course of antiinflammatory therapy can result from an attenuation of the inflammatory process and/or from the neutralization of endogenous mediators of inflammation that act directly on nociceptive neurons. The purpose of this study was to investigate whether analgesic effects of the neutralization of tumor necrosis factor alpha (TNFalpha) are due to an attenuation of inflammation or whether direct neuronal effects significantly contribute to pain relief in the course of therapy. METHODS: Locomotor and pain-related behavior and histology were assessed in rats with chronic antigen-induced arthritis (AIA) in the knee joint, and the rats were treated with systemic saline, etanercept, or infliximab. The expression of TNF receptors (TNFRs) in dorsal root ganglia was measured using immunohistochemical analysis and polymerase chain reaction. Action potentials were recorded from afferent Adelta fibers and C fibers of the medial knee joint nerve, and etanercept and infliximab were injected intraarticularly into normal or inflamed knee joints (AIA or kaolin/carrageenan-induced inflammation). RESULTS: In rats with AIA, both etanercept and infliximab significantly decreased inflammation-induced locomotor and pain-related behavior, while joint swelling was only weakly attenuated and histomorphology still revealed pronounced inflammation. A large proportion of dorsal root ganglion neurons showed TNFRI- and TNFRII-like immunoreactivity. Intraarticular injection of etanercept reduced the responses of joint afferents to mechanical stimulation of the inflamed joint starting 30 minutes after injection, but had no effect on responses to mechanical stimulation of the uninflamed joint. CONCLUSION: Overall, these data show the pronounced antinociceptive effects of TNFalpha neutralization, thus suggesting that reduction of the effects of TNFalpha on pain fibers themselves significantly contributes to pain relief.