RESUMEN
BACKGROUND: N-type Ca2+ channels (Ca(v)2.2) play an important role in the transmission of pain signals to the central nervous system. ω-Conotoxin (CTx)-MVIIA, also called ziconotide (Prialt®), effectively alleviates pain, without causing addiction, by blocking the pores of these channels. Unfortunately, CTx-MVIIA has a narrow therapeutic window and produces serious side effects due to the poor reversibility of its binding to the channel. It would thus be desirable to identify new analgesic blockers with binding characteristics that lead to fewer adverse side effects. RESULTS: Here we identify a new CTx, FVIA, from the Korean Conus Fulmen and describe its effects on pain responses and blood pressure. The inhibitory effect of CTx-FVIA on N-type Ca2+ channel currents was dose-dependent and similar to that of CTx-MVIIA. However, the two conopeptides exhibited markedly different degrees of reversibility after block. CTx-FVIA effectively and dose-dependently reduced nociceptive behavior in the formalin test and in neuropathic pain models, and reduced mechanical and thermal allodynia in the tail nerve injury rat model. CTx-FVIA (10 ng) also showed significant analgesic effects on writhing in mouse neurotransmitter- and cytokine-induced pain models, though it had no effect on acute thermal pain and interferon-γ induced pain. Interestingly, although both CTx-FVIA and CTx-MVIIA depressed arterial blood pressure immediately after administration, pressure recovered faster and to a greater degree after CTx-FVIA administration. CONCLUSIONS: The analgesic potency of CTx-FVIA and its greater reversibility could represent advantages over CTx-MVIIA for the treatment of refractory pain and contribute to the design of an analgesic with high potency and low side effects.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/efectos de los fármacos , Dolor/tratamiento farmacológico , omega-Conotoxinas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Calor , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , omega-Conotoxinas/aislamiento & purificaciónRESUMEN
We investigated effects of acetaminophen on LPS-induced hyperalgesia in various pain models. We examined the changes of pain behaviors induced by formalin injected subcutaneously (s.c.) in the hind paw, with substance P (SP) and glutamate injected inthrathecally (i.t.). Hyperalgesia was induced by LPS intraperitoneal injection 1 day prior to the pain test. LPS-induced hyperalgesia was exhibited in nociceptive behaviors induced by formalin s.c. (only in the second phase), SP and glutamate i.t. injection. APAP showed a dose-dependent antinociceptive effect on the saline- and LPS-pretreated group in the formalin and SP pain model. However, the analgesic effect of APAP was not observed in the glutamate pain model. To clarify the action site, APAP was administered i.t. or intracerebroventricularly (i.c.v.) 30 min prior to behavioral tests. The 2nd phase of formalin response was not only increased by LPS, but it also significantly attenuated by i.c.v. injections of APAP. However, the effect of APAP was observed only in the LPS-pretreatment, but not in the control group. These results suggest that LPS-induced hyperalgesia in the formalin 2nd phase may be involved in the SP-sensitive neuronal pathways, in which the hyperalgesic response elicited by LPS attenuated by APAP with supraspinal pain modulatory mechanisms.
Asunto(s)
Acetaminofén/farmacología , Analgésicos no Narcóticos/farmacología , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Lipopolisacáridos/farmacología , Dimensión del Dolor/efectos de los fármacos , Acetaminofén/administración & dosificación , Analgésicos no Narcóticos/administración & dosificación , Animales , Formaldehído , Ácido Glutámico/toxicidad , Hiperalgesia/psicología , Inyecciones Intraventriculares , Inyecciones Espinales , Inyecciones Subcutáneas , Masculino , Ratones , Ratones Endogámicos ICR , Sustancia PRESUMEN
Several ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, Rg1 and Rg3) are neuroprotective and antinociceptive agents. In this study, we assessed the effects of these ginsenosides following intracerebroventricular (i.c.v.) administration on the nociceptive behaviors induced by intrathecal injection of pro-inflammatory cytokines (tumor necrosis factor-a (TNF-alpha), interleukin-1 beta (IL-1 beta), and interferon-gamma (IFN-gamma)). The ginsenosides, Rb1, Rb2, Rc, Rd, Re, Rf and Rg1, significantly attenuated the nociceptive behavior induced by TNF-alpha, IL-1 beta, and IFN-gamma injection, but ginsenoside-Rg3 did not. These results suggest that several ginsenosides may regulate the nociceptive processing induced by pro-inflammatory cytokines.
Asunto(s)
Analgésicos/administración & dosificación , Conducta Animal/efectos de los fármacos , Citocinas/metabolismo , Ginsenósidos/administración & dosificación , Mediadores de Inflamación/metabolismo , Dolor/prevención & control , Animales , Citocinas/administración & dosificación , Modelos Animales de Enfermedad , Mediadores de Inflamación/administración & dosificación , Inyecciones Intraventriculares , Inyecciones Espinales , Interferón gamma/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Dolor/metabolismo , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The present study was performed to characterize the differential molecular mechanisms of morphine and beta-endorphin which are injected intracerebroventiricularly in mice. In the immunoblot assay, the increases of phosphorylated extracellular signal-regulated protein kinase (pERK) as well as phosphorylated calcium/calmodulin-dependent protein kinase IIalpha (pCaMK-IIalpha) expression induced by noxious stimuli were attenuated by intracerebroventricular (i.c.v.) beta-endorphin pretreatment in the hypothalamus, but not by i.c.v. morphine pretreatment. In addition to these immunoblot results, immunohistochemical study also showed that the attenuation of pERK or pCaMK-IIalpha immunoreactivity elicited by i.c.v. pretreatment of beta-endorphin mainly occurred in the paraventricular nucleus of the hypothalamus (PVN). We also investigated the effect of morphine and beta-endorphin on pERK and pCaMK-IIalpha expression in the locus coeruleus (LC). I.c.v. injection of morphine significantly increased pERK as well as pCaMK-IIalpha expression in the locus coeruleus, while beta-endorphin increased only pCaMK-IIalpha in the LC. In addition, beta-endorphin significantly attenuated pERK expression induced by SP i.t. injection. These results suggest that the antinociceptive effects of supraspinally administered morphine and beta-endorphin are involved with differentially intracellular signal transduction molecules-pERK, pCaMK-IIalpha in the PVN and the LC.
Asunto(s)
Analgésicos Opioides/farmacología , Química Encefálica/fisiología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/biosíntesis , Quinasas MAP Reguladas por Señal Extracelular/biosíntesis , Morfina/farmacología , Dolor/metabolismo , betaendorfina/farmacología , Analgésicos Opioides/administración & dosificación , Animales , Western Blotting , Química Encefálica/efectos de los fármacos , Formaldehído , Inmunohistoquímica , Inyecciones Intraventriculares , Inyecciones Espinales , Masculino , Ratones , Ratones Endogámicos ICR , Morfina/administración & dosificación , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/fisiología , Sustancia P , betaendorfina/administración & dosificaciónRESUMEN
The effect of stress mediators following the stress period and addition time is a controversial issue until now. Thus, we aim to clarify the differential effects of single restraint stress (SS) or repeated restraint stress (RS) on kainic acid (KA)-induced neuronal death especially as addressing not only the role of glucocorticoid (Gc) and its receptor but also the signal pathway leading to cAMP response element binding protein phosphorylation (pCREB) and its functional role during stress. In the present study, we found that although RS did not show any difference on serum Gc level and hippocampal Gc receptor level compared to SS, SS exacerbated KA-induced neuronal death in hippocampal CA3 region, but RS did not. Moreover, pre-treatment with RU 38486 (Gc receptor antagonist) abolished the effect of SS on KA-induced neuronal death without an effect on KA toxicity itself. Furthermore, RS aggravates KA-induced neuronal death when CREB phosphorylation was deprived by KN-93 (calcium/calmodulin-dependent protein kinase II inhibitor). However, other signal molecules inhibitors such as PD98059 (MEK1/2 inhibitor) and SP600125 (p-p38 inhibitor) have no effect on KA-induced neuronal death after RS although these signal molecule were increased during SS or RS. These findings suggest that pCREB expression via calcium/calmodulin-dependent protein kinase II phosphorylation during RS comprise one of the balancers against Gc induced by stress.