RESUMEN
In the present study, we examined nociceptive behaviors on various pain models after the pretreatment of kainic acid intracerebroventricularly. We found that intracerebroventricular administration of kainic acid shows significant neuronal damage on the hippocampal CA3 region in the brain slices stained with cresyl violet. Compared to the control group, intracerebroventricular pretreatment of kainic acid significantly attenuated nocifensive behaviors induced by intraplantar formalin (only in the 2nd phase), intrathecal glutamate, TNF-alpha or IL-1beta. However, nocifensive behaviors induced by intraperitoneal acetic acid (writhing test), intrathecal substance P or IFN-gamma were not affected by the pretreatment of kainic acid. These results suggest that (1) KA-induced alterations of nocifensive behaviors are related to the neuronal death of the hippocampal formation, especially CA3 pyramidal neurons and (2) nocifensive behaviors induced by formalin, acetic acid, SP, glutamate, and pro-inflammatory cytokines were modulated in a different manner.
Asunto(s)
Conducta Animal/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Ácido Kaínico/farmacología , Dolor/metabolismo , Animales , Conducta Animal/fisiología , Citocinas/administración & dosificación , Citocinas/farmacología , Agonistas de Aminoácidos Excitadores/administración & dosificación , Ácido Glutámico/administración & dosificación , Ácido Glutámico/farmacología , Hipocampo/citología , Ácido Kaínico/administración & dosificación , Masculino , Ratones , Neuronas/citología , Neuronas/metabolismo , Neuronas/patología , Dolor/inducido químicamente , Dimensión del Dolor , Sustancia P/administración & dosificación , Sustancia P/farmacologíaRESUMEN
In the present study, we investigated the role of phosphorylated calcium/calmodulin-dependent protein kinase II (pCaMK-II) and phosphorylated extracellular signal-regulated protein kinase (pERK) in nociceptive processing at the spinal and supraspinal levels in the formalin subcutaneous induced mouse pain model. In the immunoblot assay, subcutaneous (s.c.) injection with formalin increased the pERK and pCaMK-IIalpha level in the spinal cord, and an immunohistochemical study showed that the increase of pERK and pCaMK-IIalpha immunoreactivity mainly occurred in the laminae I and II areas of the spinal dorsal horn. At the supraspinal level, although pERK was not changed in the hippocampus induced by formalin s.c. injection, pCaMK-IIalpha was increased in the hippocampus and hypothalamus by s.c. formalin injection, and an increase of pCaMK-IIalpha immunoreactivity mainly occurred in the pyramidal cells and the stratum lucidum/radiatum layer of the CA3 region of hippocampus and paraventricular nucleus of the hypothalamus. Moreover, pERK immunoreactivity in the hypothalamic paraventricular nucleus was also increased. The second phase of nociceptive behavior induced by formalin administered either i.t. or intracerebroventricularly (i.c.v.) was attenuated by PD98059 (ERK inhibitor) as well as KN-93(a CaMK-II inhibitor). On the other hand, the first phase of nociceptive behavior induced by formalin s.c. injection was not affected by i.t. KN-93. Our results suggest that pERK and pCaMK-II located at both the spinal cord and supraspinal levels are an important regulator during the nociceptive processes induced by formalin administered s.c. respectively.
Asunto(s)
Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Sistema Nervioso Central/enzimología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Vías Nerviosas/enzimología , Dolor/enzimología , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Proteínas Quinasas Dependientes de Calcio-Calmodulina/antagonistas & inhibidores , Sistema Nervioso Central/citología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Hipocampo/citología , Hipocampo/metabolismo , Masculino , Ratones , Vías Nerviosas/citología , Dolor/fisiopatología , Dimensión del Dolor , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/metabolismo , Fosforilación , Células del Asta Posterior/citología , Células del Asta Posterior/metabolismo , Regulación hacia Arriba/fisiologíaRESUMEN
In the present study, we investigated the role of pERK in nociceptive processing at the spinal and supraspinal levels in the substance P (SP)-induced mouse pain model. In the immunoblot assay, intrathecal (it) injection with SP increased pERK level at the spinal cord and an immunohistochemical study showed that increase of pERK immunoreactivity mainly occurred in the lamina I and II areas of the spinal dorsal horn. At the supraspinal level, pERK was increased in hippocampus and hypothalamus by i.t. SP injection, and an increase of pERK immunoreactivity mainly occurred in the dentate gyrus and CA3 region of hippocampus and paraventricular nucleus on hypothalamus. The nociceptive behavior induced by Sub P administered either i.t. or intracerebroventricularly (i.c.v.) was attenuated by PD98059 (a MEK 1/2 inhibitor) in a dose-dependent manner. Our results suggest that pERK located at both spinal cord and supraspinal levels plays as an important regulator during the nociceptive process activated by SP administered it.
Asunto(s)
Encéfalo/enzimología , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Dolor/enzimología , Médula Espinal/enzimología , Sustancia P/metabolismo , Animales , Encéfalo/efectos de los fármacos , Giro Dentado/efectos de los fármacos , Giro Dentado/enzimología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Inmunohistoquímica , Inyecciones Intraventriculares , Inyecciones Espinales , Masculino , Ratones , Ratones Endogámicos ICR , Proteína Quinasa 3 Activada por Mitógenos/efectos de los fármacos , Dolor/inducido químicamente , Dolor/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/enzimología , Fosforilación/efectos de los fármacos , Células del Asta Posterior/efectos de los fármacos , Células del Asta Posterior/enzimología , Médula Espinal/efectos de los fármacos , Sustancia P/farmacologíaRESUMEN
In the present study, we investigated the role of phosphorylated calcium/calmodulin-dependent protein kinase-II (pCaMK-II) in nociceptive processing at the spinal and supraspinal levels in the substance P (SP)-induced mouse pain model. In the immunoblot assay, intrathecal (i.t.) injection with SP increased the pCaMK-II level in the spinal cord, and an immunohistochemical study showed that the increase of pCaMK-II immunoreactivity mainly occurred in the laminae I and II areas of the spinal dorsal horn. At the supraspinal level, pCaMK-II was increased in the hippocampus and hypothalamus by i.t. SP injection, and an increase of pCaMK-II immunoreactivity mainly occurred in the pyramidal cells and the stratum lucidum/radiatum layer of the CA3 region of hippocampus and paraventricular nucleus of the hypothalamus. Moreover, pCaMK-II immunoreactivity in the locus coelureus of the brain stem was also increased. The nociceptive behavior induced by SP administered either i.t. or intracerebroventricularly (i.c.v.) was attenuated by KN-93 (a CaMK-II inhibitor). Our results suggest that pCaMK-II located at both spinal cord and supraspinal levels is an important regulator during the nociceptive processes induced by SP administered i.t.