RESUMEN
OBJECT: Ninjurin2 (nerve injury induced protein 2, NINJ2) is a molecule which mediates cell-to-cell and cell-to-extracellular matrix interactions in the nervous system. Clinical study shows NINJ2 is associated with the development of postherpetic neuralgia. However, it is lack of direct evidence that NINJ2 participated in neuropathic pain. In this study, we aim to investigate the role of NINJ2 in the development of neuropathic pain in spared sciatic nerve injury rats and the underlying mechanism. METHOD: Spared sciatic nerve injury (SNI) models were established. The level of NINJ2 and p-p65 (a NF-κB family member) were measured in SNI rats by western blots and immunofluorescent staining. Lentivirus encoding small interfering RNA targeting NINJ2 (RNAi) was intrathecally injected into rats. Then the change of pain behavior of rats induced by NINJ2 RNAi was tested by Von-Frey hairs. The change of p-p65 in the spinal cord in rats after NINJ2 RNAi treatment was also measured by western blots. inhibitor of p-p65-induced change of TNF-α, IL-1ß, and IL-6 levels were measured by ELISA. RESULTS: NINJ2 and p-p65 were increased in the spinal cord of SNI rats on the 3, 7, 14th days after modeling. NINJ2 were mainly expressed in neurons, and co-located with p-p65 in the spinal dorsal horn. When down regulating the level of NINJ2 by RNAi, the development of pain in SNI rats was partially blocked. Phosphorylation of p65 was also inhibited by NINJ2 RNAi. Blocking the phosphorylation of NF-κB pathway could inhibit the increase of TNF-α, IL-1ß, and IL-6 in the spinal cord of SNI rats. CONCLUSION: NINJ2 protein was increased in the spinal cord of SNI rats. It participated in the development of nerve injury-induced neuropathic pain by activating neuroinflammation in the spinal cord via NF-κB pathway. This study provides a new target to investigate the mechanism of neuropathic pain.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/inmunología , Neuralgia/inmunología , Enfermedades Neuroinflamatorias/inmunología , Nervio Ciático/lesiones , Factor de Transcripción ReIA/inmunología , Animales , Moléculas de Adhesión Celular Neuronal/genética , Masculino , Ratas Sprague-Dawley , Nervio Ciático/inmunología , Médula Espinal/inmunologíaRESUMEN
Chemokines are important regulators of immune, inflammatory, and neuronal responses in peripheral and central pain pathway. The aim of this study was to investigate whether chemokine (C-X-C motif) ligand 13 (CXCL13) and its receptor (C-X-C chemokine receptor type 5, CXCR5) involve in the development of bone cancer pain (BCP) and the regulation of morphine analgesia in rats. The change of pain behaviors in BCP rats were measured by testing paw withdrawal threshold (PWT). The levels of CXCL13, CXCR5 and signal pathway proteins (p-p38, p-ERK and p-AKT etc.) in the spinal cord were measured via western blots. The expression of CXCL13 and CXCR5 in spinal cord was increased in BCP rats. The BCP rats showed decrease of PWTs, which was relieved by CXCR5i. Intrathecally injection of murine recombinant CXCL13 (mrCXCL13) decreased the PWTs of BCP rats and opposed morphine-induced analgesia in BCP rats. In BCP rats, the signal pathway proteins (p38, ERK and AKT) in the spinal cord were activated. CXCL13 and morphine had contrary effect on the phosphorylation of these proteins. MrCXCL13 directly increased the levels of p-p38, p-ERK and p-AKT in BCP rats. However, morphine decreased the levels of these proteins in BCP rats. While blocking the activation of p-p38, p-ERK and p-AKT, morphine analgesia was enhanced. These results suggest CXCL13 participated in bone cancer pain and opposed morphine analgesia via p38, ERK and AKT pathways. It may be a target to enhance pain management in cancer pain patients.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Dolor en Cáncer/tratamiento farmacológico , Quimiocina CXCL13/administración & dosificación , Morfina/administración & dosificación , Médula Espinal/efectos de los fármacos , Analgesia/métodos , Animales , Neoplasias Óseas/metabolismo , Dolor en Cáncer/metabolismo , Método Doble Ciego , Femenino , Inyecciones Espinales , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Médula Espinal/metabolismoAsunto(s)
Corteza Cerebral/metabolismo , Electroacupuntura/métodos , Epilepsia/terapia , Glucosa/metabolismo , Núcleos Talámicos Anteriores/fisiología , Corteza Cerebral/diagnóstico por imagen , Epilepsia/diagnóstico por imagen , Epilepsia/patología , Humanos , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Tomografía Computarizada de Emisión de Fotón Único , Resultado del TratamientoAsunto(s)
Estimulación Eléctrica/métodos , Epilepsia/terapia , Núcleo Tegmental Pedunculopontino/fisiología , Animales , Epilepsia/complicaciones , Humanos , Proteínas Luminiscentes , Ratones , Músculo Esquelético/fisiología , Vías Nerviosas/fisiología , Neuronas/metabolismo , Núcleo Tegmental Pedunculopontino/citología , Triptófano Hidroxilasa/metabolismo , Tirosina 3-Monooxigenasa/metabolismoAsunto(s)
Corteza Cerebral/metabolismo , Estimulación Encefálica Profunda/normas , Electroacupuntura , Epilepsia/metabolismo , Epilepsia/terapia , Melanocortinas/metabolismo , Transducción de Señal/fisiología , Animales , Modelos Animales de Enfermedad , Epilepsia/genética , Humanos , Receptor de Melanocortina Tipo 4RESUMEN
Previously, we showed that activation of the spinal CXCL9, 10/CXCR3 pathway mediated bone cancer pain (BCP) in rats. However, the cellular mechanism involved is poorly understood. Here, we found that the activated CXCR3 was co-localized with either neurons, microglia, and astrocytes in the spinal cord, or non-peptidergic-, peptidergic-, and A-type neurons in the dorsal root ganglion. The inoculation of Walker-256 mammary gland carcinoma cells into the rat's tibia induced a time-dependent phosphorylation of Akt and extracellular signal-regulated kinase (ERK1/2) in the spinal cord, and CXCR3 was necessary for the phosphorylation of Akt and ERK 1/2. Meanwhile, CXCR3 was co-localized with either pAkt or pERK1/2. Blockage of either Akt or ERK1/2 prevented or reversed the mechanical allodynia in BCP rats. Furthermore, there was cross-activation between PI3K/Akt and Raf/MEK/ERK pathway under the BCP condition. Our results demonstrated that the activation of spinal chemokine receptor CXCR3 mediated BCP through Akt and ERK 1/2 kinase, and also indicated a crosstalk between PI3K/Akt and Raf/MEK/ERK signaling pathways under the BCP condition.
Asunto(s)
Neoplasias Óseas/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Dolor/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores CXCR3/metabolismo , Animales , Western Blotting , Neoplasias Óseas/complicaciones , Modelos Animales de Enfermedad , Femenino , Hiperalgesia/metabolismo , Inmunohistoquímica , Dolor/etiología , Ratas , Ratas Wistar , Receptor Cross-Talk/fisiologíaRESUMEN
The etiology of postoperative pain may be different from antigen-induced inflammatory pain and neuropathic pain. However, central neural plasticity plays a key role in incision pain. It is also known that phosphatidylinositol 3-kinase (PI3K) and protein kinase B/Akt (PKB/Akt) are widely expressed in laminae I-IV of the spinal horn and play a critical role in spinal central sensitization. In the present study, we explored the role of PI3K and Akt in incision pain behaviors. Plantar incision induced a time-dependent activation of spinal PI3K-p110γ and Akt, while activated Akt and PI3K-p110γ were localized in spinal neurons or microglias, but not in astrocytes. Pre-treatment with PI3K inhibitors, wortmannin or LY294002 prevented the activation of Akt brought on by plantar incision in a dose-dependent manner. In addition, inhibition of spinal PI3K signaling pathway prevented pain behaviors (dose-dependent) and spinal Fos protein expression caused by plantar incision. These data demonstrated that PI3K signaling mediated pain behaviors caused by plantar incision in mice.