RESUMO
The antinociceptive effect of nicotine administered intracereboventricularly (i.c.v.) or intrathecally (i.t) in several pain models was examined in the present study. We found that i.t. treatment with nicotine (from 5 to 20 g) dose-dependently blocked pain behavior revealed during the second phase, but not during the first phase in the formalin test. In addition, i.c.v. treatment with nicotine (from 0.1 to 10 microg) dose-dependently attenuated pain behavior revealed during both the first and second phases. In addition to the formalin test, nicotine administered i.c.v. or i.t. attenuated acetic acid-induced writhing response. Furthermore, i.c.v. or i.t. administration of nicotine did not cause licking, scratching and biting responses induced by substance P, glutamate, TNF-alpha (100 pg), IL-1beta (100 pg) and INF-gamma (100 pg) injectied i.t. The antinociception induced by supraspinally-administered nicotine appears to be more effective than that resulting from spinally administered nicotine. Our results suggest that nicotine administration induces antinociception by acting on the central nervous system and has differing antinociceptive profiles according to the various pain models.
Assuntos
Analgésicos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Dor/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Injeções Intraventriculares , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Dor/induzido quimicamente , Medição da Dor/efeitos dos fármacosRESUMO
We examined the effect of the subcutaneous (s.c.) pretreatment of formalin into both hind paws of mice on the antinociception induced by the intracerebroventricularly (i.c.v.) or intrathecally (i.t.) administration of beta-endorphin using the tail-flick test. Pretreatment with formalin (5%) for 5 h had no affect on the i.c.v. administered beta-endorphin-induced tail-flick response. However, pretreatment with formalin for 40 h attenuated the tail-flick inhibition induced by i.c.v. administered beta-endorphin. This antinociceptive tolerance to i.c.v. beta-endorphin continued up to 1 week, but to a lesser extent. Pretreatment with formalin for 5 and 40 h significantly reduced the i.t. beta-endorphin-induced inhibition of the tail-flick response, which continued up to 1 week. The s.c. formalin treatment increased the hypothalamic pro-opiomelanocortin (POMC) mRNA level at 2 h, but this returned to the basal level after 40 h. Our results suggest that the increase in the POMC mRNA level in the hypothalamus appears to be involved in the supraspinal or spinal beta-endorphin-induced antinociceptive tolerance in formalin-induced inflammatory pain.
Assuntos
Formaldeído , Medição da Dor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , beta-Endorfina/antagonistas & inibidores , beta-Endorfina/farmacologia , Animais , Northern Blotting , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Injeções Intraventriculares , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Pró-Opiomelanocortina/biossíntese , Pró-Opiomelanocortina/fisiologia , RNA Mensageiro/biossíntese , beta-Endorfina/administração & dosagemRESUMO
Kainic acid (KA) is a well-known excitatory and neurotoxic substance. In ICR mice, morphological damage of hippocampus induced by KA administered intracerebroventricularly (i.c.v.) was markedly concentrated on the hippocampal CA3 pyramidal neurons. In the present study, the possible role of adenosine receptors in hippocampal cell death induced by KA (0.1 microg) administered i.c.v. was examined. It has been shown that 3,7-dimethyl-1-propargylxanthine (DMPX; A2 adenosine receptors antagonist, 20 microg) reduced KA-induced CA3 pyramidal cell death. KA dramatically increased the phosphorylated extracellular signal-regulated kinase (p-ERK) immunoreactivities (IR) in dentate gyrus (DG) and mossy fibers. In addition, c-Jun, c-Fos, Fos-related antigen 1 (Fra-1) and Fos-related antigen 2 (Fra-2) protein levels were increased in hippocampal area in KA-injected mice. DMPX attenuated KA-induced p-ERK, c-Jun, Fra-1 and Fra-2 IR. However, 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (PACPX; A1 adenosine receptor antagonist, 20 microg) did not affect KA-induced p-ERK, c-Jun, Fra-1 and Fra-2 IR. KA also increased the complement receptor type 3 (OX-42) IR in CA3 region of hippocampus. DMPX, but not PACPX, blocked KA-induced OX-42 IR. Our results suggest that p-ERK and c-Jun may function as important regulators responsible for the hippocampal cell death induced by KA administered i.c.v. in mice. Activated microglia, which was detected by OX-42 IR, may be related to phagocytosis of degenerated neuronal elements by KA excitotoxicity. Furthermore, it is implicated that A2, but not A1, adenosine receptors appear to be involved in hippocampal CA3 pyramidal cell death induced by KA administered i.c.v. in mice.
Assuntos
Agonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Ácido Caínico/farmacologia , Neurônios/metabolismo , Receptores Purinérgicos P1/metabolismo , Teobromina/análogos & derivados , Animais , Morte Celular/fisiologia , Proteínas de Ligação a DNA/metabolismo , Agonistas de Aminoácidos Excitatórios/toxicidade , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/metabolismo , Antígeno 2 Relacionado a Fos , Hipocampo/citologia , Hipocampo/patologia , Ácido Caínico/toxicidade , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neurônios/citologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Teobromina/administração & dosagem , Teobromina/metabolismo , Fatores de Transcrição/metabolismo , Xantinas/administração & dosagem , Xantinas/metabolismoRESUMO
Effects of MK-801 (a NMDA receptor blocker) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione; a non-NMDA receptor blocker) on several neurotoxic responses induced by kainic acid (KA) were examined in ICR mice. In a lethality test, intracerebroventricular (i.c.v.) pretreatment of MK-801 (1 microg), but not CNQX (0.5 microg), attenuated the time to lethality induced by KA (0.5 microg) administered i.c.v. In the memory test (a passive avoidance test), MK-801, but not CNQX, prevented the memory loss induced by KA (0.1 microg). The damage induced by KA (0.1 microg) administered i.c.v. in the hippocampus was markedly concentrated in the CA3 pyramidal neurons. Both MK-801 and CNQX blocked the pyramidal cell death in CA3 hippocampal region induced by KA. In the immunocytochemical study, KA dramatically increased the phosphorylated ERK (p-ERK) and decreased the phosphorylated CREB (p-CREB) in the hippocmapus. Both MK-801 and CNQX attenuated, in part, the increased p-ERK and the decreased p-CREB induced by KA. In addition, both MK-801 and CNQX partially reduced the increased c-Fos and c-Jun protein expression in hippocampus induced by KA. Our results suggest that both NMDA and non-NMDA receptors are involved in supraspinally administered KA-induced pyramidal cell death in CA3 region of hippocampus in the mouse and the p-ERK and the dephosphorylation of CREB protein may play an important role in CA3 region cell death of the hippocampus induced by KA administered supraspinally. Furthermore, c-Fos and c-Jun proteins may serve as third messengers responsible for CA3 pyramidal cell death induced by supraspinally administered KA.
Assuntos
6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Maleato de Dizocilpina/farmacologia , Agonistas de Aminoácidos Excitatórios/toxicidade , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Ácido Caínico/toxicidade , Neurônios/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Northern Blotting , Western Blotting , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/metabolismo , Técnicas Imunoenzimáticas , Injeções Intraventriculares , Dose Letal Mediana , Masculino , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Sondas RNA , Receptores de AMPA/antagonistas & inibidores , Receptores de Glutamato/metabolismo , Receptores de Ácido Caínico/antagonistas & inibidores , Receptores de Ácido Caínico/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Taxa de SobrevidaRESUMO
In an immunohistochemical study, kainic acid (KA, 0.1 microg) administered intracerebroventricularly (i.c.v.) dramatically increased the expression of Ca2+/calmodulin-dependent protein kinase II (CaMK II) and the phosphorylation of CaMK II (p-CaMK II) in the CA3 hippocampal region of mice. Pre-treatment with cycloheximide (a protein synthesis inhibitor; 200 mg/kg) intraperitoneally prevented the expression of CaMK II and phosphorylation of CaMK II induced by KA. In addition, pre-treatment with MK-801 ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine; an NMDA receptor blocker, 1 microg, i.c.v.) or CNQX (6-cyano-7-nitroquinoxaline-2,3-dione; a non-NMDA receptor blocker, 0.5 microg, i.c.v.) attenuated the p-CaMK II, but not CaMK II, expression induced by KA. Our results suggest that KA administered supraspinally induces CaMK II and the phosphorylation of CaMK II expression in the CA3 hippocampal region, for which an on-going protein synthesis is needed. Furthermore, both NMDA and non-NMDA receptors appear to be involved in supraspinally administered KA-induced phosphorylation of CaMK II.
Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina/biossíntese , Proteínas Quinases Dependentes de Cálcio-Calmodulina/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Ácido Caínico/farmacologia , Neurônios/efeitos dos fármacos , Neurotoxinas/farmacologia , Receptores de Glutamato/efeitos dos fármacos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/enzimologia , Hipocampo/fisiopatologia , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neurônios/enzimologia , Fosforilação/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Receptores de Glutamato/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
In the present study, we examined the effect of cycloheximide on various pharmacological responses induced by kainic acid (KA) administered intracerebroventricularly (i.c.v.) in mice. In a passive avoidance test, a 20-min cycloheximide (200mg/kg, i.p.) pretreatment prevented the memory impairment induced by KA. The morphological damage induced by KA (0.1microg) in the hippocampus was markedly concentrated in the CA3 pyramidal neurons and cycloheximide effectively prevented the KA-induced pyramidal cell death in CA3 hippocampal region. In immunohistochemical study, KA dramatically increased the phosphorylation of extracellular signal-regulated protein kinase (p-ERK), c-Jun N-terminal kinase 1 (p-JNK1), and calcium/calmodulin-dependent protein kinase II (p-CaMK II). Cycloheximide attenuated the increased p-ERK, p-JNK1, and p-CaMK II levels induced by KA. Furthermore, cycloheximide inhibited the increased c-Fos and c-Jun protein expression levels induced by KA in the hippocampus. The activation of microglia was detected in KA-induced CA3 cell death region by immunostaining with a monoclonal antibody against the OX-42. Cycloheximide inhibited KA-induced increase of OX-42 immunoreactivity. Our results suggest that the increased expression of the c-Fos, c-Jun, and phosphorylation of ERK, JNK1, and CaMK II proteins may play important roles in the memory impairment and the cell death in CA3 region of the hippocampus induced by i.c.v. KA administration in mice. Furthermore, the activated microglia may be related to phagocytosis of degenerated neuronal elements induced by KA.
Assuntos
Antígenos CD , Antígenos de Neoplasias , Antígenos de Superfície , Proteínas Aviárias , Proteínas Sanguíneas , Cicloeximida/farmacologia , Hipocampo/efeitos dos fármacos , Ácido Caínico/antagonistas & inibidores , Inibidores da Síntese de Proteínas/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Basigina , Western Blotting , Morte Celular , Interações Medicamentosas , Espaço Extracelular , Hipocampo/anatomia & histologia , Hipocampo/metabolismo , Imuno-Histoquímica , Injeções Intraventriculares , Proteínas Quinases JNK Ativadas por Mitógeno , Ácido Caínico/farmacologia , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Tempo de Reação , Fatores de Tempo , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Antinociceptive profiles of decursinol were examined in ICR mice. Decursinol administered orally (from 5 to 200 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured by the tail-flick and hot-plate tests. In addition, decursinol attenuated dose-dependently the writhing numbers in the acetic acid-induced writhing test. Moreover, the cumulative response time of nociceptive behaviors induced by an intraplantar formalin injection was reduced by decursinol treatment during the both 1st and 2nd phases in a dose-dependent manner. Furthermore, the cumulative nociceptive response time for intrathecal (i.t.) injection of TNF-alpha (100 pg), IL-1 beta (100 pg), IFN-gamma (100 pg), substance P (0.7 microg) or glutamate (20 microg) was dose-dependently diminished by decursinol. Intraperitoneal (i.p.) pretreatment with yohimbine, methysergide, cyproheptadine, ranitidine, or 3,7-dimethyl-1-propargylxanthine (DMPX) attenuated inhibition of the tail-flick response induced by decursinol. However, naloxone, thioperamide, or 1,3-dipropyl-8-(2-amino-4-chloro-phenyl)-xanthine (PACPX) did not affect inhibition of the tail-flick response induced by decursinol. Our results suggests that decursinol shows an antinociceptive property in various pain models. Furthermore, antinociception of decursinol may be mediated by noradrenergic, serotonergic, adenosine A(2), histamine H(1) and H(2) receptors.
Assuntos
Analgésicos/farmacologia , Benzopiranos/administração & dosagem , Benzopiranos/farmacologia , Butiratos/administração & dosagem , Butiratos/farmacologia , Dor/tratamento farmacológico , Teobromina/análogos & derivados , Administração Oral , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Ciproeptadina/farmacologia , Relação Dose-Resposta a Droga , Ácido Glutâmico/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Interferon gama/farmacologia , Interleucina-1/farmacologia , Masculino , Metisergida/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Modelos Químicos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Piperidinas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Ranitidina/farmacologia , Receptores Adrenérgicos/metabolismo , Receptores Histamínicos/metabolismo , Receptores Purinérgicos P1/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Substância P/farmacologia , Teobromina/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Xantinas/farmacologia , Ioimbina/farmacologiaRESUMO
It has been reported that opioid receptor antagonist can induce antinociception in several nociceptive tests. In the intraplantar formalin pain model, however, opioid antagonist-induced antinociception, as well as its underlying mechanism, has not been well characterized. Therefore, in the mouse formalin test, we attempted to characterize the site of action and the possible opioid receptor subtypes. We found that naltrexone (a nonselective opioid antagonist) injected intraperitoneally (i.p., 1-20 mg/kg), intrathecally (i.t., 0.1-10 microg) and intracerebroventricularly (i.c.v., 0.1-10 microg) phase. Administration of beta-funaltrexamine (beta-FNA, 10-40 mg/kg i.p., 1.25-5 microg it or i.c.v.), naltrindole (1-10 mg/kg i.p., 1.25-5 microg it or i.c.v.) and nor-binaltorphimine (nor-BNI, 1-10 mg/kg i.p., 10-40 microg it or i.c.v.), which are selective mu-, delta- and kappa-opioid antagonists, respectively, also produced antinociception during the second phase. Additionally, we examined the involvement of the descending monoaminergic systems in the naltrexone-induced antinociception in the formalin test. Pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, a serotonergic neurotoxin, 20 microg i.t.), but not N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, a noradrenergic neurotoxin, 20 microg i.t.), reversed the naltrexone-induced antinociception during the second phase. Our results suggest that blockade of supraspinally or spinally located opioid receptors may play roles in the regulation of antinociception during the tonic painful stage. In addition, opioid receptors localized at the neuroterminal of the descending serotonergic, but not noradrenergic, inhibitory system in the spinal cord appear to be involved in opioid antagonist-induced antinociception during the second tonic phase of the formalin test.
Assuntos
Formaldeído , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes , Medição da Dor/efeitos dos fármacos , 5,7-Di-Hidroxitriptamina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzilaminas/farmacologia , Injeções Intraperitoneais , Injeções Intraventriculares , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidoresRESUMO
Effects of ginsenosides on nitric oxide (NO) production induced by lipopolysaccharide plus TNF-alpha (LNT) were examined in C6 rat glioma cells. Among several ginsenosides, ginsenoside Rd showed a complete inhibition against LNT-induced NO production. Ginsenoside Rd attenuated LNT-induced increased phosphorylation of ERK. Among several immediate early gene products, only Jun B and Fra-1 protein levels were increased by LNT, and ginsenoside Rd attenuated Jun B and Fra-1 protein levels induced by LNT. Furthermore, LNT increased AP-1 DNA binding activities, which were partially inhibited by ginsenoside Rd. Our results suggest that ginsenoside Rd exerts an inhibitory action against NO production via blocking phosphorylation of ERK, in turn, suppressing immediate early gene products such as Jun B and Fra-1 in C6 glioma cells.
Assuntos
Ginsenosídeos/farmacologia , Lipopolissacarídeos/farmacologia , Óxido Nítrico/antagonistas & inibidores , Inibidores da Síntese de Proteínas/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Western Blotting , Linhagem Celular Tumoral , Regulação Enzimológica da Expressão Gênica , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , Panax , Fosforilação , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , RNA Mensageiro/biossíntese , Ratos , Fator de Transcrição AP-1/metabolismoRESUMO
Platycodin D (PD), one of several triterpene saponins, was isolated from roots of Platycodon grandiflorum. We previously reported that intracerebroventricular (i.c.v.) administration of PD showed an antinociceptive effect as measured by the tail-flick assay. However, its exact role in the regulation of antinociception in the various types of pain models has not yet been characterized. Thus, we attempted to find antinociceptive profiles of PD in various pain models. PD administered intraperitoneally (i.p.), i.c.v. or intrathecally (i.t.) showed antinociceptive effects in dose-dependent manners as measured by the tail-flick, writhing and formalin tests. In the tail-flick test, PD at the low doses reached the peak after 15 minutes and returned to the control level after 60 minutes. However, higher doses of PD showed a strong antinociception at least for 1 hour. PD administered i.t. showed stronger antinociception than that induced by i.c.v. administration PD in both tail-flick and writhing tests. In the formalin test, PD administered i.p., i.c.v. or i.t. showed antinociceptive effects during both the first (direct nociceptive stimulation) and second (late inflammatory) phases. Pretreatment with naltrexone i.p., i.c.v. or i.t. did not affect PD-induced inhibition of the tail-flick response. Our results suggest that PD shows a strong antinociceptive effect on the tail-flick, writhing and formalin tests, acting on central nervous system. However, PD-induced antinociception may not be mediated by the opioid receptors.
Assuntos
Dor/tratamento farmacológico , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Campanulaceae/química , Ventrículos Cerebrais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos ICR , Medição da Dor , Saponinas/administração & dosagem , Cauda/fisiologia , Triterpenos/administração & dosagemRESUMO
To characterize the antinociceptive profiles of Angelica gigas NAKAI (ANG; Korean angelica), methanol extract from the dried roots of ANG was made and mice were administered orally at the various doses (from 0.25 to 3 g/kg). ANG produced the increased latencies of the tail-flick and hot-plate paw-licking responses in a dose-dependent manner. In acetic acid-induced writhing test, ANG dose-dependently decreased writhing numbers. Moreover, the cumulative response time of nociceptive behaviors induced by intraplantar formalin injection was reduced during both the 1st and the 2nd phases in a dose-dependent manner in ANG-treated mice. Furthermore, oral administration of ANG did not cause licking, scratching and biting responses induced by TNF-alpha (100 pg), IFN-gamma (100 pg) or IL-1beta (100 pg) injected intrathecally (i.t.), especially at higher dose (3 g/kg). Additionally, in ANG treated mice, the cumulative nociceptive response time for i.t. administration of substance P or capsaicin was dose-dependently diminished. Finally, nociceptive responses elicited by i.t. injection of glutamate (20 microg), N-methyl-D-aspartic acid (60 ng), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (13 ng) or kainic acid (12 ng) were decreased by oral administration of ANG. Our results suggest that ANG produces antinociception via acting on the central nervous system and shows antinociceptive profiles in various pain models, especially inflammatory pain.
Assuntos
Analgésicos/farmacologia , Angelica/química , Medição da Dor/efeitos dos fármacos , Dor/tratamento farmacológico , Administração Oral , Analgésicos/administração & dosagem , Animais , Capsaicina/farmacologia , Citocinas/farmacologia , Aminoácidos Excitatórios/farmacologia , Formaldeído , Temperatura Alta , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Dor/induzido quimicamente , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Equilíbrio Postural/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Substância P/farmacologiaRESUMO
Several studies have demonstrated that the nonselective opioid receptor antagonist naloxone produces a paradoxical antinociception in the formalin test. The opioid system is related to the serotonergic system for producing antinociception at the spinal level. Here we also asked whether systemic (i.p.) and intrathecal (i.t.) administrations of a nonselective serotonergic antagonist, methysergide, might produce paradoxical antinociception similar to naloxone in the mouse formalin test. A diluted formalin solution was injected into the mouse plantar region of the hind paw and the duration of licking responses was measured at periods of 0-5 min (1st phase) and 20-40 min (2nd phase) after formalin injection. Methysergide administered i.p. and i.t. showed an attenuated licking duration only in the 2nd phase. The effect observed in the 2nd phase was reversed in the 5,7-dihydroxytriptamine, but not N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine pretreated group of mice, suggesting that descending serotonergic, but not noradrenergic, systems are involved in the methysergide antinociception. To further investigate the mechanism by which methysergide inhibited the nociceptive behaviors induced by formalin, the antinociceptive effect of methysergide was also tested in substance P (i.t.) and excitatory amino acids (i.t.), such as glutamate, N-methyl-D-aspartic acid, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, and kainic acid, which are major components in the formalin-induced nociceptive transmission in the spinal cord pain models. The duration of nociceptive behaviors shown in these models was significantly shortened by i.p. and i.t. administration of methysergide. These results suggest that methysergide also produces a paradoxical antinociception in various pain models including the formalin test, similar to the results of naloxone.
Assuntos
Analgesia , Metisergida/uso terapêutico , Dor/tratamento farmacológico , Antagonistas da Serotonina/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Formaldeído/toxicidade , Injeções Intraperitoneais , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Dor/induzido quimicamenteRESUMO
In the present study, we examined the effects of ginsenoside Rd (G-Rd) and decursinol (DC) on various neurotoxic responses induced by kainic acid (KA) administered intracerebroventricularly ( i. c. v.) in ICR mice. Ginseng total saponin (GTS) inhibited the KA (0.5 microg)-induced lethal toxicity in a dose-dependent manner. Furthermore, G-Rd, a component of GTS, also attenuated the KA-induced lethal toxicity as well as DC pretreated orally for 30 min. In ICR mouse, neurotoxic damage induced by KA (0.1 microg) in the hippocampus was markedly concentrated in the CA3 pyramidal neurons. G-Rd and DC did not affect the pyramidal cell death in CA3 hippocampal region. In an immunohistochemical study, KA dramatically increased phospho-ERK and decreased phospho-CREB in the hippocampal area. G-Rd and DC attenuated, in part, the increased phospho-ERK and the decreased phospho-CREB protein levels. However, DC potentiated the increased c-Fos and c-Jun protein levels in the hippocampus induced by KA. Thus, our results suggest that the phosphorylation of ERK or the dephosphorylation of CREB protein may play a major role in the regulation of lethal toxicity induced by KA, whereas cell death in the hippocampal CA3 region induced by KA administered i. c. v. may not be directly mediated by ERK phosphorylation and CREB phosphorylation in the mouse.
Assuntos
Angelica , Benzopiranos/farmacologia , Butiratos/farmacologia , Ginsenosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Panax , Fitoterapia , Animais , Imuno-Histoquímica , Ácido Caínico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Preparações de Plantas/farmacologiaRESUMO
We have examined the effects of several ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, Rg1 and Rg3) administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on the nociceptive behavior induced by substance P (0.7 microg) injected i.t. Among the several ginsenosides studied, Rb2, Rc, Rd, and Re, but not Rb1, Rf, Rg1 and Rg3, treated i.c.v. (50 microg) attenuated the nociceptive behavior induced by substance P injected i.t. On the other hand, we found that i.t. treatment with 50 microg of Rb1, Rb2, Rd, or Rf effectively attenuated the nociceptive behavior induced by i.t. injected substance P. However, the i.t. treatment with the same doses of Rc, Re, Rg1 or Rg3 was not effective for antagonizing i.t. injected substance P-induced nociceptive behavior. Our results show that ginsenosides Rb2, Rc, Rd, or R2 injected supraspinally exert a antinociceptive effect in the substance P-induced pain model. Furthermore, Rb1, Rb2, Rd, or Rf treated spinally produce antinociception in the substance P-induced pain model.
Assuntos
Analgésicos/farmacologia , Ginsenosídeos/farmacologia , Dor/prevenção & controle , Panax , Fitoterapia , Extratos Vegetais/farmacologia , Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Ginsenosídeos/administração & dosagem , Ginsenosídeos/uso terapêutico , Injeções Intraventriculares , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Dor/induzido quimicamente , Medição da Dor/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Substância PRESUMO
Platycodin D administered intracerebroventricularly (i.c.v.) showed an antinociceptive effect in a dose-dependent manner as measured by the tail-flick assay. The antinociception induced by platycodin D was maintained at least 1 h. MK-801 [(+/-)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]cyclohepten-5,10-imine maleate], a competitive N-methyl- D-aspartic acid (NMDA) receptor antagonist, or CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), a non-NMDA receptor antagonist, muscimol (a GABA(A) receptor agonist), or baclofen (a GABA(B) receptor antagonist), or sulfated cholecystokinin (CCK-8 s; CCK A receptor agonist), injected i.c.v. significantly reduced the inhibition of the tail-flick response induced by platycodin D administered i.c.v. Additionally, intrathecal (i.t.) pretreatment with yohimbine (an alpha 2 -adrenergic receptor antagonist) or methysergide (a serotonin receptor antagonist) dose-dependently attenuated inhibition of the tail-flick response induced by i.c.v. administered platycodin D. However, naloxone (an opioid receptor antagonist) did not affect the inhibition of the tail-flick response induced by platycodin D. Our results suggest that platycodin D has an antinociceptive effect when it is administered supraspinally, and supraspinal GABA(A), GABA(B), NMDA and non-NMDA receptors are involved in platycodin D-induced antinociception. Furthermore, platycodin D administered supraspinally produces antinociception by stimulating descending noradrenergic and serotonergic, but not opioidergic, pathways.