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UNLABELLED: Neuropathic pain, often caused by nerve injury, is a major clinical challenge. Mechanisms that underlie neuropathic pain remain elusive and effective medications are limited. Numerous investigations of pain mechanisms have focused on alterations and phenotypic switches of the nociceptive transmitters and modulators, as well as on their receptors and downstream signaling pathways that have already exerted roles in the pain processes of mature nervous systems. We have demonstrated recently that nerve injury may elicit neuronal alterations that recapitulate events occurring during development. Signaling of the representative activated molecule Wnt thus becomes a trigger for the development of neuropathic pain and is a potential therapeutic target. We report that the transcriptional regulators YAP and TAZ, which orchestrate Wnt response via incorporation in the ß-catenin destruction complex, are key in the pathogenesis of neuropathic pain and may serve as an "ON-OFF" switch for neuropathic pain status in rats. Peripheral nerve injury causes rapid-onset and long-lasting nuclear accumulation of YAP/TAZ/ß-catenin in the spinal dorsal horn. Spinal inhibition or knock-down of either YAP or TAZ suppresses mechanical allodynia induced by nerve injury or the pain initiators lysophosphatidic acid and Wnt3a. Promoting the nuclear accumulation of YAP/TAZ leads to mechanical hypersensitivity in naive animals. Further, we discovered a new small molecule, dCTB, which targets YAP/TAZ/ß-catenin and can greatly suppress neuropathic pain and the associated neurochemical alterations. Our study reveals that YAP and TAZ are core mechanisms underlying the pathogenesis of neuropathic pain and are targets in the screening for potent analgesics for the treatment of neuropathic pain. SIGNIFICANCE STATEMENT: Mechanisms that underlie neuropathic pain remain elusive. We have demonstrated recently that nerve injury can activate Wnt signaling, which becomes a trigger for the development of neuropathic pain. We report that the transcriptional regulators YAP and TAZ, which orchestrate Wnt response via incorporation in the ß-catenin destruction complex, are key in the pathogenesis of neuropathic pain and may serve as an "ON-OFF" switch for neuropathic pain status. Further, we discovered a new small molecule, dCTB, which targets YAP/TAZ/ß-catenin and can greatly suppress neuropathic pain. Our study reveals that YAP and TAZ are core mechanisms underlying the pathogenesis of neuropathic pain and are targets in the screening of potent analgesics for the treatment of neuropathic pain.
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Proteínas Reguladoras de la Apoptosis/metabolismo , Neuralgia/prevención & control , Neuralgia/fisiopatología , Traumatismos de la Médula Espinal/fisiopatología , Médula Espinal/fisiopatología , Factores de Transcripción/metabolismo , Aciltransferasas , Animales , Masculino , Neuralgia/etiología , Dimensión del Dolor , Percepción del Dolor , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/complicaciones , Proteínas Señalizadoras YAPRESUMEN
The objective of this study was to explore the role of cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling in the development of bone cancer pain in rats. Female Sprague-Dawley rats (N=48) were divided randomly into four groups: sham (n=8), tumor cell implantation (TCI) (n=16), TCI+saline (n=8), and TCI+PKA inhibitor (n=16). Bone cancer-induced pain behaviors - thermal hyperalgesia and mechanical allodynia - were tested at postoperative days -3, -1, 1, 3, 5, 7, 10, and 14. A PKA inhibitor, Rp-cAMPS (1 mmol/l/20 µl), was injected intrathecally on postoperative days 3, 4, and 5 (early phase) or 7, 8, and 9 postoperative days (late phase). The expression of PKA mRNA in dorsal root ganglia (DRG) was detected by reverse transcription-PCR. The concentration of cAMP and activity of PKA in DRG and spinal cord were measured by enzyme-linked immunosorbent assay. TCI treatment induced significant pain behaviors, manifested as thermal hyperalgesia and mechanical allodynia. Spinal administration of the PKA inhibitor Rp-cAMPS during the early phase and late phase significantly delayed or reversed, respectively, TCI-induced thermal hyperalgesia and mechanical allodynia. TCI treatment also led to obvious tumor growth and bone destruction. The level of PKA mRNA in the DRG, as well as the concentration of cAMP and the activity of PKA, in both the DRG and spinal cord were significantly increased after TCI treatment (P<0.01). We conclude that the inhibition of the cAMP-PKA signaling pathway may reduce bone cancer pain.
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Neoplasias Óseas/fisiopatología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Ganglios Espinales/fisiopatología , Dolor/fisiopatología , Médula Espinal/fisiopatología , Animales , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Modelos Animales de Enfermedad , Ciclo Estral/fisiología , Femenino , Ganglios Espinales/efectos de los fármacos , Calor , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Trasplante de Neoplasias , Dolor/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Tionucleótidos/farmacología , Factores de Tiempo , TactoRESUMEN
OBJECTIVE: To explore the perioperative airway management for transoral surgical lysis in patients with irreducible atlantoaxial dislocation and posterior atlantoaxial or occipitocervical fixation. METHODS: Thirty patients undergoing surgical lysis through transoral approach with oral endotracheal intubation (OEI group) between September 2009 and June 2010 were recruited. And another 31 patients underwent transoral surgical lysis from December 2008 to August 2009 with percutaneous dilatational tracheostomy (PDT group). The time interval from artificial airway establishment to start of operation, the duration of nasogastric feeding, the incidence of respiratory complications and the postoperative length of hospital stay were compared between two groups. RESULTS: The time interval from artificial airway establishment to the start of operation in the OEI group was significantly shorter than that in the PDT group [(39 ± 15) vs (58 ± 16) min, P < 0.01]. The duration for nasogastric feeding in the OEI group was significantly shorter than that in the PDT group [(6.0 ± 1.2) vs (7.9 ± 0.3) days, P < 0.01]. And the postoperative length of hospital stay was also shorter in the OEI group than that in the PDT group [(9.5 ± 1.7) vs (11.8 ± 3.4) days, P < 0.01]. CONCLUSION: The management of perioperative airway with oral endotracheal intubation may avoid the complications of PDT, improve the utilizing efficiency of operating rooms and shorten the postoperative length of hospital stay.
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Manejo de la Vía Aérea , Fijación de Fractura/métodos , Orofaringe/cirugía , Atención Perioperativa , Adulto , Articulación Atlantoaxoidea/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Background: Treatment of diabetic neuropathic pain (DNP) continues to be a major challenge, and underlying mechanisms of DNP remain elusive. We investigated treatment effects of B vitamins on DPN- and DNP-associated alterations of neurochemical signaling in the nociceptive dorsal root ganglion (DRG) neurons and the spinal cord in rats. Methods: DNP was produced in male, adult, Sprague Dawley rats by single i.p. streptozotocin (STZ). Western blot analysis and immunohistochemistry were used to analyze protein expressions in DRG and ELISA to measure the proinflammatory cytokines in the spinal cord. Behaviorally expressed DNP was determined by measuring the sensitivity of hindpaw skin to mechanical and thermal stimulation. Results: There were 87.5% (77/88) rats which developed high blood glucose within 1-2 weeks following STZ injection. Of which, 70.13% (n = 54/77) animals exhibited DNP manifested as mechanical allodynia and/or thermal hyperalgesia. Intraperitoneal administration of vitamins B1/B6/B12 (100/100/2 mg/kg, one or multiple doses) significantly attenuated DNP without affecting the blood glucose. Expressions of P2X3 and TRPV1 in CGRP-positive and IB4-positive DRG neurons as well as the interleukin-1ß, tumor necrosis factor-α, and nerve growth factor in the lumbar spinal cord were greatly increased in DNP rats. Such DNP-associated neurochemical alterations were also greatly suppressed by the B-vitamin treatment. Conclusions: B-vitamin treatment can greatly suppress chronic DNP and DNP-associated increased activities of P2X3 and TRPV1 in DRG and the spinal proinflammatory cytokines, which may contribute to the pathogenesis of DNP. Systematic administration of B vitamins can be a strategy for DNP management in clinic.