RESUMO
The Chronic Constriction Injury of the Infraorbital Nerve (CCI-ION) is a well-established model to study facial sensory changes related to trigeminal neuropathic pain. CCI-ION induces heat hypersensitivity that resolves within 2-3 weeks and a delayed mechanical hypersensitivity that emerges during the second week post-injury. The role of descending facilitatory pain pathways from the rostro ventromedial medulla (RVM) in mediating the heat and tactile hypersensitivity was examined. CCI-ION induced heat hypersensitivity observed 5days post-surgery was reversed by systemic, but not RVM lidocaine. CCI-ION-induced tactile hypersensitivity observed 15days post-surgery was reversed by systemic lidocaine and attenuated by RVM lidocaine. CCI-ION-induced spontaneous pain was determined using conditioned place preference (CPP) to pain relief at each time-point. At day 5 post-CCI-ION, neither systemic nor RVM lidocaine induced CPP. However, at 15days post-CCI-ION, CPP was observed to the chamber paired with RVM lidocaine, but not systemic lidocaine. These data indicate that CCI-ION induced heat hypersensitivity is not dependent on descending facilitatory pain pathways 5-days post-injury whereas descending facilitatory pain pathways mediate tactile allodynia and spontaneous pain 15days post-CCI-ION. This suggests that CCI-ION induces early peripheral sensitization followed by development of central sensitization that mediates spontaneous pain and contributes to mechanical hypersensitivity.
Assuntos
Hiperalgesia/fisiopatologia , Bulbo/fisiopatologia , Vias Neurais/fisiopatologia , Neuralgia do Trigêmeo/fisiopatologia , Animais , Modelos Animais de Doenças , Temperatura Alta , Masculino , Ratos , Ratos Wistar , TatoRESUMO
OBJECTIVE AND DESIGN: This study attempted to clarify the roles of endothelins and mechanisms associated with ETA/ETB receptors in mouse models of colitis. MATERIALS AND METHODS: Colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 1.5 mg/animal) or dextran sulfate sodium (DSS, 3%). After colitis establishment, mice received Atrasentan (ETA receptor antagonist, 10 mg/kg), A-192621 (ETB receptor antagonist, 20 mg/kg) or Dexamethasone (1 mg/kg) and several inflammatory parameters were assessed, as well as mRNA levels for ET-1, ET-2 and ET receptors. RESULTS: Atrasentan treatment ameliorates TNBS- and DSS-induced colitis. In the TNBS model was observed reduction in macroscopic and microscopic score, colon weight, neutrophil influx, IL-1ß, MIP-2 and keratinocyte chemoattractant (KC) levels, inhibition of adhesion molecules expression and restoration of IL-10 levels. However, A192621 treatment did not modify any parameter. ET-1 and ET-2 mRNA was decreased 24 h, but ET-2 mRNA was markedly increased at 48 h after TNBS. ET-2 was able to potentiate LPS-induced KC production in vitro. ETA and ETB receptors mRNA were increased at 24, 48 and 72 h after colitis induction. CONCLUSIONS: Atrasentan treatment was effective in reducing the severity of colitis in DSS- and TNBS-treated mice, suggesting that ETA receptors might be a potential target for inflammatory bowel diseases.
Assuntos
Colite/imunologia , Antagonistas do Receptor de Endotelina A/farmacologia , Endotelina-2/imunologia , Pirrolidinas/farmacologia , Animais , Atrasentana , Células Cultivadas , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Citocinas/imunologia , Sulfato de Dextrana , Selectina E/imunologia , Antagonistas do Receptor de Endotelina A/uso terapêutico , Antagonistas do Receptor de Endotelina B/farmacologia , Endotelina-1/genética , Endotelina-1/imunologia , Endotelina-2/genética , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Masculino , Camundongos Endogâmicos BALB C , Infiltração de Neutrófilos/efeitos dos fármacos , Selectina-P/imunologia , Peroxidase/imunologia , Pirrolidinas/uso terapêutico , RNA Mensageiro/metabolismo , Receptor de Endotelina A/genética , Receptor de Endotelina A/imunologia , Receptor de Endotelina B/genética , Receptor de Endotelina B/imunologia , Ácido TrinitrobenzenossulfônicoRESUMO
BACKGROUND: This study evaluated the involvement of tumour necrosis factor α (TNF-α) in orofacial thermal and mechanical hyperalgesia induced by an inflammatory stimulus or by chronic constriction of the infraorbital nerve (CION) using etanercept (Eta), a TNF-receptor fusion protein that inhibits TNF-α action. METHODS: Animals were treated with Eta (0.5 and 5.0 mg/kg, s.c.) or dexamethasone (Dex, 0.5, 1.0 and 2.0 mg/kg, s.c.) and orofacial thermal (cold and heat) and mechanical hyperalgesia induced by an inflammatory stimulus (carrageenan, Cg 50 and 100 µg/lip) or by chronic CION, a model of neuropathic pain in the orofacial region was evaluated. Treatments with Dex or Eta were carried out before Cg or before or after CION. RESULTS: Eta or Dex abolished inflammatory thermal and mechanical hyperalgesia. Also, each drug, when given at the day of the surgery and the subsequent day, was effective to abolish thermal and mechanical hyperalgesia induced by CION, assessed on day 4 and on day 13 after the surgery, respectively. However, Eta, but not Dex, given after the CION, abolished thermal and mechanical hyperalgesia and reduced TNF-α level in the trigeminal ganglion. CONCLUSIONS: These results suggest that TNF-α has an important role in cold, heat and mechanical hyperalgesia induced by inflammation or neuropathy in the orofacial region and this may contribute for the establishment of new therapeutic strategies to treat orofacial pain.