RESUMEN
BACKGROUND: Isotalatizidine is a representative C19-diterpenoid alkaloid extracted from the lateral roots of Aconitum carmichaelii, which has been widely used to treat various diseases on account of its analgesic, anti-inflammatory, anti-rheumatic, and immunosuppressive properties. The aim of this study was to evaluate the analgesic effect of isotalatizidine and its underlying mechanisms against neuropathic pain. METHODS: A chronic constrictive injury (CCI)-induced model of neuropathic pain was established in mice, and the limb withdrawal was evaluated by the Von Frey filament test following isotalatizidine or placebo administration. The signaling pathways in primary or immortalized microglia cells treated with isotalatizidine were analyzed by Western blotting and immunofluorescence. RESULTS: Intrathecal injection of isotalatizidine attenuated the CCI-induced mechanical allodynia in a dose-dependent manner. At the molecular level, isotalatizidine selectively increased the phosphorylation of p38 and ERK1/2, in addition to activating the transcription factor CREB and increasing dynorphin A production in cultured primary microglia. However, the downstream effects of isotalatizidine were abrogated by the selective ERK1/2 inhibitor U0126-EtOH or CREB inhibitor of KG-501, but not by the p38 inhibitor SB203580. The results also were confirmed in in vivo experiments. CONCLUSION: Taken together, isotalatizidine specifically activates the ERK1/2 pathway and subsequently CREB, which triggers dynorphin A release in the microglia, eventually leading to its anti-nociceptive action.
Asunto(s)
Aconitina/análogos & derivados , Analgésicos/farmacología , Dinorfinas/biosíntesis , Microglía/efectos de los fármacos , Neuralgia/metabolismo , Aconitina/farmacología , Animales , Dolor Crónico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Dinorfinas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Microglía/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
A subpopulation of neurons located within the arcuate nucleus, colocalizing kisspeptin, neurokinin B, and dynorphin (Dyn; termed KNDy neurons), represents key mediators of pulsatile GnRH secretion. The KNDy model of GnRH pulse generation proposes that Dyn terminates each pulse. However, it is unknown where and when during a pulse that Dyn is released to inhibit GnRH secretion. Dyn acts via the κ opioid receptor (KOR), and KOR is present in KNDy and GnRH neurons in sheep. KOR, similar to other G protein-coupled receptors, are internalized after exposure to ligand, and thus internalization can be used as a marker of endogenous Dyn release. Thus, we hypothesized that KOR will be internalized at pulse termination in both KNDy and GnRH neurons. To test this hypothesis, GnRH pulses were induced in gonad-intact anestrous ewes by injection of neurokinin B (NKB) into the third ventricle and animals were euthanized at times of either pulse onset or termination. NKB injections produced increased internalization of KOR within KNDy neurons during both pulse onset and termination. In contrast, KOR internalization into GnRH neurons was seen only during pulse termination, and only in GnRH neurons within the mediobasal hypothalamus (MBH). Overall, our results indicate that Dyn is released onto KNDy cells at the time of pulse onset, and continues to be released during the duration of the pulse. In contrast, Dyn is released onto MBH GnRH neurons only at pulse termination and thus actions of Dyn upon KNDy and GnRH cell bodies may be critical for pulse termination.
Asunto(s)
Dinorfinas/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Neuronas/metabolismo , Receptores Opioides kappa/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/citología , Núcleo Arqueado del Hipotálamo/metabolismo , Dinorfinas/efectos de los fármacos , Femenino , Hipotálamo/citología , Hipotálamo/metabolismo , Kisspeptinas/metabolismo , Neuroquinina B/metabolismo , Neuroquinina B/farmacología , Neuronas/efectos de los fármacos , Receptores Opioides kappa/efectos de los fármacos , OvinosRESUMEN
The dynorphin opioid peptides control glutamate neurotransmission in the hippocampus. Alcohol-induced dysregulation of this circuit may lead to impairments in spatial learning and memory. This study examines whether changes in the hippocampal dynorphin and glutamate systems are related, and contribute to impairment of spatial learning and memory in a rat model of cognitive deficit associated with alcohol binge drinking. Hippocampal dynorphins (radioimmunoassay) and glutamate (in vivo microdialysis) were analyzed in Wistar rats exposed to repeated moderate-dose ethanol bouts that impair spatial learning and memory in the Water Maze Task (WMT). The highly selective, long-acting κ-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was administered systemically or into the hippocampal CA3 region to test a role of dynorphins in alcohol-induced dysregulations in glutamate neurotransmission and behavior in the WMT. The ethanol treatment impaired learning and memory, upregulated dynorphins and increased glutamate overflow in the CA3 region. Administration of nor-BNI after cessation of ethanol exposure reversed ethanol-induced changes in glutamate neurotransmission in animals exposed to ethanol and normalized their performance in the WMT. The findings suggest that impairments of spatial learning and memory by binge-like ethanol exposure are mediated through the KOR activation by upregulated dynorphins resulting in elevation in glutamate levels. Selective KOR antagonists may correct alcohol-induced pathological processes, thus representing a novel pharmacotherapy for treating of ethanol-related cognitive deficits.
Asunto(s)
Región CA3 Hipocampal/efectos de los fármacos , Depresores del Sistema Nervioso Central/farmacología , Dinorfinas/efectos de los fármacos , Etanol/farmacología , Ácido Glutámico/efectos de los fármacos , Memoria/efectos de los fármacos , Animales , Región CA3 Hipocampal/metabolismo , Dinorfinas/metabolismo , Ácido Glutámico/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Aprendizaje por Laberinto , Memoria/fisiología , Microdiálisis , Naltrexona/análogos & derivados , Antagonistas de Narcóticos , Radioinmunoensayo , Ratas , Ratas Wistar , Receptores Opioides kappa/antagonistas & inhibidores , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
Accumulating evidence supports the value of 5-HT1A receptor (5-HT1AR) agonists for dyskinesias that arise with long-term L-DOPA therapy in Parkinson's disease (PD). Yet, how 5-HT1AR stimulation directly influences the dyskinetogenic D1 receptor (D1R)-expressing striatonigral pathway remains largely unknown. To directly examine this, one cohort of hemiparkinsonian rats received systemic injections of Vehicle + Vehicle, Vehicle + the D1R agonist SKF81297 (0.8 mg/kg), or the 5-HT1AR agonist ±8-OH-DPAT (1.0 mg/kg) + SKF81297. Rats were examined for changes in abnormal involuntary movements (AIMs), rotations, striatal preprodynorphin (PPD), and glutamic acid decarboxylase (GAD; 65 and 67) mRNA via RT-PCR. In the second experiment, hemiparkinsonian rats received intrastriatal pretreatments of Vehicle (aCSF), ±8-OH-DPAT (7.5 mM), or ±8-OH-DPAT + the 5-HT1AR antagonist WAY100635 (4.6 mM), followed by systemic Vehicle or SKF81297 after which AIMs, rotations, and extracellular striatal glutamate and nigral GABA efflux were measured by in vivo microdialysis. Results revealed D1R agonist-induced AIMs were reduced by systemic and intrastriatal 5-HT1AR stimulation while rotations were enhanced. Although ±8-OH-DPAT did not modify D1R agonist-induced increases in striatal PPD mRNA, the D1R/5-HT1AR agonist combination enhanced GAD65 and GAD67 mRNA. When applied locally, ±8-OH-DPAT alone diminished striatal glutamate levels while the agonist combination increased nigral GABA efflux. Thus, presynaptic 5-HT1AR stimulation may attenuate striatal glutamate levels, resulting in diminished D1R-mediated dyskinetic behaviors, but maintain or enhance striatal postsynaptic factors ultimately increasing nigral GABA levels and rotational activity. The current findings offer a novel mechanistic explanation for previous results concerning 5-HT1AR agonists for the treatment of dyskinesia.
Asunto(s)
Agonistas de Dopamina/farmacología , Actividad Motora/efectos de los fármacos , Neostriado/efectos de los fármacos , Receptor de Serotonina 5-HT1A , Receptores de Dopamina D1/agonistas , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Sustancia Negra/efectos de los fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Conducta Animal/efectos de los fármacos , Benzazepinas/farmacología , Dinorfinas/efectos de los fármacos , Dinorfinas/metabolismo , Discinesia Inducida por Medicamentos , Glutamato Descarboxilasa/efectos de los fármacos , Glutamato Descarboxilasa/metabolismo , Trastornos Parkinsonianos , Piperazinas/farmacología , Precursores de Proteínas/efectos de los fármacos , Precursores de Proteínas/metabolismo , Piridinas/farmacología , Ratas , Antagonistas del Receptor de Serotonina 5-HT1/farmacologíaRESUMEN
It is well documented that neonatal neurosteroid administration influences brain development. In our previous studies, administration of pregnenolone, the precursor of neurosteroids, during the neonatal period altered the activity of dopamine (DA) in the striatum. Furthermore, neonatal treatment with pregnenolone or dehydroepiandrosterone (DHEA) increased synapse-related protein synapsin I as well as neuropeptide Y (NPY) in the hippocampus. The present study examined the effects of neonatal treatment with pregnenolone or DHEA on synapsin I, DA transporter (DAT), dynorphin A, and NPY in the striatum and the core and shell of the nucleus accumbens at post-puberty. Administration of pregnenolone or DHEA during the neonatal period increased immunodensity of synapsin I in the dorsomedial or ventrolateral striatum. DAT immunodensity in the striatum and the nucleus accumbens core as well as dynorphin A immunodensity in the nucleus accumbens core were increased in DHEA-treated but not in pregnenolone-treated rats. In addition, the size, but not numbers, of NPY-positive cells in the nucleus accumbens core was increased in pregnenolone- and DHEA-treated rats. The results suggest that neurosteroid levels during the neonatal period have larger impact on synaptic formation, development of DA and NPY systems in the nigrostriatal rather than the mesolimbic pathway.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Deshidroepiandrosterona/farmacología , Proteínas del Tejido Nervioso/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Pregnenolona/farmacología , Adyuvantes Inmunológicos/farmacología , Animales , Animales Recién Nacidos , Cuerpo Estriado/crecimiento & desarrollo , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Dinorfinas/efectos de los fármacos , Dinorfinas/metabolismo , Inmunohistoquímica , Proteínas del Tejido Nervioso/metabolismo , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/crecimiento & desarrollo , Vías Nerviosas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuropéptido Y/efectos de los fármacos , Neuropéptido Y/metabolismo , Núcleo Accumbens/crecimiento & desarrollo , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-Dawley , Sinapsinas/efectos de los fármacos , Sinapsinas/metabolismo , Tiempo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
The hippocampal formation (HF) is involved in modulating learning related to drug abuse. While HF-dependent learning is regulated by both endogenous opioids and estrogen, the interaction between these two systems is not well understood. The mossy fiber (MF) pathway formed by dentate gyrus (DG) granule cell axons is involved in some aspects of learning and contains abundant amounts of the endogenous opioid peptide dynorphin (DYN). To examine the influence of ovarian steroids on DYN expression, we used quantitative light microscopic immunocytochemistry to measure DYN levels in normal cycling rats as well as in two established models of hormone-treated ovariectomized (OVX) rats. Rats in estrus had increased levels of DYN-immunoreactivity (ir) in the DG and certain CA3 lamina compared with rats in proestrus or diestrus. OVX rats exposed to estradiol for 24 h showed increased DYN-ir in the DG and CA3, while those with 72 h estradiol exposure showed increases only in the DG. Six hours of estradiol exposure produced no change in DYN-ir. OVX rats chronically implanted with medroxyprogesterone also showed increased DYN-ir in the DG and CA3. Next, dual-labeling electron microscopy (EM) was used to evaluate the subcellular relationships of estrogen receptor (ER) alpha-, ERbeta and progestin receptor (PR) with DYN-labeled MFs. ERbeta-ir was in some DYN-labeled MF terminals and smaller terminals, and had a subcellular association with the plasmalemma and small synaptic vesicles. In contrast, ERalpha-ir was not in DYN-labeled terminals, although some DYN-labeled small terminals synapsed on ERalpha-labeled dendritic spines. PR labeling was mostly in CA3 axons, some of which were continuous with DYN-labeled terminals. These studies indicate that ovarian hormones can modulate DYN in the MF pathway in a time-dependent manner, and suggest that hormonal effects on the DYN-containing MF pathway may be directly mediated by ERbeta and/or PR activation.
Asunto(s)
Dinorfinas/efectos de los fármacos , Dinorfinas/metabolismo , Estradiol/farmacología , Hormonas Esteroides Gonadales/farmacología , Hipocampo/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Animales , Ciclo Estral/fisiología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Hormonas Esteroides Gonadales/clasificación , Hipocampo/metabolismo , Microscopía Inmunoelectrónica , Fibras Musgosas del Hipocampo/efectos de los fármacos , Fibras Musgosas del Hipocampo/fisiología , Ovariectomía , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/clasificación , Receptores de Estrógenos/ultraestructura , Factores de TiempoRESUMEN
Different studies have supported neuroprotective effects of Corticotropin-releasing hormone (CRH) against various excitotoxic and oxidative insults in vitro. However, the physiological mechanisms involved in this protection remain largely unknown. The present study was undertaken to determine the impact of CRH administration (at concentrations ranging from 200 fmol to 2 nmol) before and at delayed time intervals following potassium cyanide (KCN)-induced insult in rat primary cortical neurons. A second objective aimed to determine whether kappa and delta opioid receptor (KOR and DOR) blockade, using nor-binaltorphimine and naltrindole respectively (10 microM), could alter CRH-induced cellular protection. Our findings revealed that CRH treatments before or 3 and 8 h following KCN insult conferred significant protection against cortical injury, an effect blocked in cultures treated with alpha-helical CRH (9-41) prior to KCN administration. In addition, KOR and DOR blockade significantly reduced CRH-induced neuronal protection observed 3 but not 8 h post-KCN insult. Using western blotting, we demonstrated increased dynorphin, enkephalin, DOR and KOR protein expression in CRH-treated primary cortical neurons, and immunocytochemistry revealed the presence of opioid peptides and receptors in cortical neurons. These findings suggest protective effects of CRH against KCN-induced neuronal damage, and the contribution of the opioid system in modulating CRH actions.
Asunto(s)
Hormona Liberadora de Corticotropina/administración & dosificación , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Animales , Isquemia Encefálica , Muerte Celular/efectos de los fármacos , Células Cultivadas , Dinorfinas/efectos de los fármacos , Dinorfinas/metabolismo , Encefalinas/metabolismo , Indoles/metabolismo , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Proteínas del Tejido Nervioso/metabolismo , Cianuro de Potasio/toxicidad , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/metabolismoRESUMEN
RATIONALE: Nicotine displays rewarding and aversive effects, and while dopamine has been linked with nicotine's reward, the neurotransmitter(s) involved with aversion remains speculative. The kappa-dynorphinergic system has been associated with negative motivational and affective states, and whether dynorphin (Dyn) contributes to the behavioral pharmacology of nicotine is a pertinent question. OBJECTIVE: We determined whether administration of a single dose of nicotine alters the biosynthesis of Dyn in the striatum of mice. RESULTS: Nicotine free base, 1 mg/kg, sc, induced a biphasic, protracted increase of striatal Dyn, an initial rise by 1 h, which declined to control levels by 2 h, and a subsequent increase, between 6 and 12 h, lasting over 24 h. At 1 h, the nicotine effect was dose dependent, with doses>or=0.5 mg/kg inducing a response. Prodynorphin mRNA increased by 30 min for over 24 h, and in situ hybridization demonstrated elevated signal in caudate/putamen and nucleus accumbens. The nicotinic antagonist mecamylamine prevented the Dyn response, and a similar effect was observed with D1- and D2-like dopamine receptor antagonists, SCH 23390, sulpiride, and haloperidol. The glutamate NMDA receptor antagonist MK-801 reversed the nicotine-induced increase of Dyn, while the AMPA antagonist NBQX had a marginal effect. CONCLUSIONS: We interpret our findings to indicate that acute nicotine enhances the synthesis and release of striatal Dyn. We propose that nicotine influences Dyn primarily through dopamine release and that glutamate plays a modulatory role. A heightened dynorphinergic tone may contribute to the aversive effects of nicotine in naive animals and first-time tobacco smokers.
Asunto(s)
Dinorfinas/efectos de los fármacos , Encefalinas/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Precursores de Proteínas/efectos de los fármacos , Animales , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Dinorfinas/metabolismo , Encefalinas/metabolismo , Masculino , Ratones , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Precursores de Proteínas/metabolismo , Putamen/efectos de los fármacos , Putamen/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de TiempoRESUMEN
The monoamine uptake inhibitor BTS 74 398 induces ipsilateral circling in 6-hydroxydopamine (6-OHDA) lesioned rats without induction of abnormal motor behaviours associated with L-dopa administration. We examined whether this was reflected in the expression of peptide mRNA in the direct and indirect striatal output pathways.6-OHDA lesioning of the nigrostriatal pathway increased striatal expression of PPE-A mRNA and decreased levels of PPT mRNA with PPE-B mRNA expression remaining unchanged. Acute L-dopa administration normalised PPE-A mRNA and elevated PPT mRNA while PPE-B mRNA expression remained unchanged. Acute administration of BTS 74 398 did not alter striatal peptide mRNA levels. Following chronic treatment with L-dopa, PPE-A mRNA expression in the lesioned striatum continued to be normalised and PPT mRNA was increased compared to the intact side. PPE-B mRNA expression was also markedly increased relative to the non-lesioned striatum. Chronic BTS 74 398 administration did not alter mRNA expression in the 6-OHDA lesioned striatum although small increases in PPT mRNA expression in the intact and sham lesioned striatum were observed. The failure of BTS 74 398 to induce changes in striatal neuropeptide mRNA correlated with its failure to induce abnormal motor behaviours or behavioural sensitisation but does not explain how it produces a reversal of motor deficits. An action in another area of the brain appears likely and may explain the subsequent failure of BTS 74 398 and related compounds to exert anti-parkinsonian actions in man.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Clorobencenos/administración & dosificación , Cuerpo Estriado/efectos de los fármacos , Ciclobutanos/administración & dosificación , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Adrenérgicos/toxicidad , Animales , Conducta Animal/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dinorfinas/biosíntesis , Dinorfinas/efectos de los fármacos , Encefalinas/biosíntesis , Encefalinas/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Hibridación in Situ , Levodopa/administración & dosificación , Masculino , Oxidopamina/toxicidad , ARN Mensajero/análisis , Ratas , Ratas Wistar , Sustancia P/biosíntesis , Sustancia P/efectos de los fármacos , TiempoRESUMEN
Previous studies showed that opioid drugs-oxycodone-6-oxime and 14-methoxy-5-methyl-dihydromorphinone (14-methoxymetopon)-produced less respiratory depressive effect and slower rate of tolerance and dependence, respectively. It was also reported that morphine decreased the prodynorphin gene expression in the rat hippocampus, striatum and hypothalamus. In this study, we determined the prodynorphin gene expression and dynorphin levels in selected brain regions of opioid tolerant rats. We found that in the striatum morphine decreased, while oxycodone-6-oxime increased and 14-methoxymetopon did not alter the prodynorphin gene expression. In the nucleus accumbens, morphine and oxycodone-6-oxime did not change, while 14-methoxymetopon increased the prodynorphin gene expression. In the hippocampus both oxycodone-6-oxime and 14-methoxymetopon enhanced, whereas morphine did not alter the prodynorphin gene expression. In the rat striatum only oxycodone-6-oxime increased dynorphin levels significantly in accordance with the prodynorphin mRNA changes. In the hippocampus both opioid agonists increased the dynorphin levels significantly similarly to the augmented prodynorphin gene expression. In ventral tegmental area only 14-methoxymetopon increased dynorphin levels significantly. In nucleus accumbens and the temporal-parietal cortex the changes in the prodynorphin gene expression and the dynorphin levels did not correlate. Since the endogenous prodynorphin system may play a modulatory role in the development of opioid tolerance, the elevated supraspinal dynorphin levels appear to be partly responsible for the reduced degree of tolerance induced by the investigated opioids.
Asunto(s)
Encéfalo/efectos de los fármacos , Dinorfinas/efectos de los fármacos , Encefalinas/efectos de los fármacos , Derivados de la Morfina/administración & dosificación , Narcóticos/administración & dosificación , Oxicodona/administración & dosificación , Precursores de Proteínas/efectos de los fármacos , Animales , Northern Blotting , Tolerancia a Medicamentos/fisiología , Dinorfinas/biosíntesis , Encefalinas/biosíntesis , Encefalinas/genética , Expresión Génica/efectos de los fármacos , Masculino , Precursores de Proteínas/biosíntesis , Precursores de Proteínas/genética , ARN Mensajero/análisis , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
The antinociceptive response of mice to the amino acid L-arginine (L-ARG) has been attributed to either an opioid mechanism or a non-opioid but nitric oxide (NO)-dependent mechanism. Earlier it was reported that the mechanism of nitrous oxide-induced antinociception involved opioid components and was also dependent on brain NO. This study was designed to determine whether the antinociceptive effects of L-ARG and the NO donor 3-morpholinosydnoimine (SIN-1) might be mediated by brain mechanisms similar to those that are responsible for nitrous oxide (N(2)O) antinociception. L-ARG and SIN-1 were administered to mice intracerebroventricularly (i.c.v.), and antinociception was assessed using the acetic acid abdominal constriction test. Both L-ARG and SIN-1 caused dose-related antinociceptive effects that were blocked by naloxone and norbinaltorphimine. The antinociceptive effects of both SIN-1 and L-ARG were also blocked to a greater extent by i.c.v. administration of a rabbit antiserum against rat dynorphin 1-13 than an antiserum against methionine-enkephalin, suggesting that the SIN-1 and L-ARG effects may be related to stimulated release of dynorphin. The antinociceptive effect of L-ARG was antagonized by an inhibitor of neuoronal NO synthase enzyme, indicating that L-ARG had to be converted to NO for its antinociceptive action. These findings indicate that the mechanisms of antinociceptive action of L-ARG and SIN-1 are both mediated by dynorphin and dependent on NO.
Asunto(s)
Analgésicos/administración & dosificación , Arginina/administración & dosificación , Encéfalo/efectos de los fármacos , Dinorfinas/efectos de los fármacos , Molsidomina/análogos & derivados , Donantes de Óxido Nítrico/administración & dosificación , Animales , Dinorfinas/metabolismo , Inhibidores Enzimáticos/farmacología , Inyecciones Intraventriculares , Masculino , Ratones , Molsidomina/administración & dosificación , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dimensión del DolorRESUMEN
The molecular mechanisms involved in the reversion of levodopa-induced motor fluctuations by the adenosine A2A antagonist 8-(3-chlorostryryl) caffeine (CSC) were investigated in rats with a 6-hydroxydopamine (6-OHDA)-induced lesion and compared with the ones achieved by the kappa-opioid agonist, U50,488. Animals were treated with levodopa (50 mg/kg/day) for 22 days and for one additional week with levodopa + CSC (5 mg/kg/day), levodopa + U50,488 (1 mg/kg/day), or levodopa + vehicle. The reversion of the decrease in the duration of levodopa-induced rotations by CSC, but not by U50,488, was maintained until the end of the treatment and was associated with a further increase in levodopa-induced preprodynorphin mRNA in the lesioned striatum, being higher in the ventromedial striatum. The increase in striatal preprodynorphin expression, particularly in the ventromedial striatum, may be related to the reversion of levodopa-induced motor fluctuations in the CSC-treated animals, suggesting a role of the direct striatal output pathway activity in the ventromedial striatum in the pathophysiology of motor fluctuations.
Asunto(s)
Cafeína/análogos & derivados , Cuerpo Estriado/efectos de los fármacos , Dinorfinas/biosíntesis , Discinesias/fisiopatología , Levodopa/efectos adversos , Trastornos Parkinsonianos/fisiopatología , Precursores de Proteínas/biosíntesis , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Adenosina/antagonistas & inhibidores , Adrenérgicos/toxicidad , Animales , Cafeína/farmacología , Cuerpo Estriado/metabolismo , Dinorfinas/efectos de los fármacos , Discinesias/etiología , Encefalinas/biosíntesis , Encefalinas/efectos de los fármacos , Inmunohistoquímica , Hibridación in Situ , Masculino , Oxidopamina/toxicidad , Trastornos Parkinsonianos/tratamiento farmacológico , Precursores de Proteínas/efectos de los fármacos , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Receptores Opioides kappa/agonistasRESUMEN
Opiates are commonly used to treat moderate to severe pain and can be used over prolonged periods in states of chronic pain such as those associated with cancer. In addition, to analgesic actions, studies show that opiate administration can paradoxically induce hyperalgesia. At the pre-clinical level, such hyperalgesia is associated with numerous pronociceptive neuroplastic changes within the primary afferent fibers and the spinal cord. In rodents, sustained opiate administration also induces antinociceptive tolerance. The mechanisms by which prolonged opiate exposure induces hyperalgesia and the relationship of this state to antinociceptive tolerance remain unclear. The present study was aimed at determining whether sustained opiate-induced hyperalgesia, associated neuroplasticity and antinociceptive tolerance are the result of specific opiate interaction at opiate receptors. Enantiomers of oxymorphone, a mu opioid receptor agonist, were administered to rats by spinal infusion across 7 days. Sustained spinal administration of (-)-oxymorphone, but not its inactive enantiomer (+)-oxymorphone or vehicle, upregulated spinal dynorphin content, produced thermal and tactile hypersensitivity, and produced antinociceptive tolerance. These results indicate that these pronociceptive actions of sustained opiate administration require specific interaction with opiate receptors and are unlikely to be the result of accumulation of potentially excitatory metabolic products. While the precise mechanisms, which may account for these pronociceptive changes remain to be unraveled, the present data point to plasticity initiated by opiate receptor interaction.
Asunto(s)
Hiperalgesia/inducido químicamente , Narcóticos/efectos adversos , Dolor/inducido químicamente , Receptores Opioides/agonistas , Vías Aferentes/efectos de los fármacos , Vías Aferentes/metabolismo , Vías Aferentes/fisiopatología , Animales , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/fisiopatología , Modelos Animales de Enfermedad , Esquema de Medicación , Tolerancia a Medicamentos/fisiología , Dinorfinas/efectos de los fármacos , Dinorfinas/metabolismo , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Isomerismo , Masculino , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Nociceptores/fisiopatología , Oximorfona/efectos adversos , Dolor/metabolismo , Dolor/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Ratas , Ratas Sprague-Dawley , Receptores Opioides/metabolismo , Receptores Opioides mu/efectos de los fármacos , Receptores Opioides mu/metabolismo , Raíces Nerviosas Espinales/efectos de los fármacos , Raíces Nerviosas Espinales/metabolismo , Raíces Nerviosas Espinales/fisiopatología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
The prodynorphin system is implicated in the neurochemical mechanism of psychostimulants. Exposure to different drugs of abuse can induce neuroadaptations in the brain and affect opioid gene expression. The present study aims to examine the possibility of a common neurobiological substrate in drug addiction processes. We studied the effects of single and repeated 3,4-methylenedioxy-N-methylamphetamine ('Ecstasy') on the gene expression of the opioid precursor prodynorphin, and on the levels of peptide dynorphin A in the rat brain. Acute (8 mg/kg, intraperitoneally) 3,4-methylenedioxy-N-methylamphetamine markedly raised, two hours later, prodynorphin mRNA levels in the prefrontal cortex, and in the caudate putamen, whereas it decreased gene expression in the ventral tegmental area. Chronic (8 mg/kg, intraperitoneally, twice a day for 7 days) 3,4-methylenedioxy-N-methylamphetamine increased prodynorphin mRNA in the nucleus accumbens, hypothalamus and caudate putamen and decreased it in the ventral tegmental area. Dynorphin A levels increased after chronic treatment in the ventral tegmental area and decreased after acute treatment in the nucleus accumbens, prefrontal cortex and hypothalamus. These findings confirm the role of the dynorphinergic system in mediating the effects of drugs of abuse, such as 3,4-methylenedioxy-N-methylamphetamine, in various regions of the rat brain, which may be important sites for the opioidergic mechanisms activated by addictive drugs.
Asunto(s)
Encéfalo/efectos de los fármacos , Dinorfinas/efectos de los fármacos , Encefalinas/efectos de los fármacos , Alucinógenos/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Precursores de Proteínas/efectos de los fármacos , Animales , Northern Blotting , Dinorfinas/metabolismo , Encefalinas/metabolismo , Expresión Génica/efectos de los fármacos , Masculino , Precursores de Proteínas/metabolismo , ARN Mensajero/análisis , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Our previous study proved that the hypothalamic paraventricular nucleus (PVH) plays an important role in acupuncture analgesia. The neuropeptides involving in the PVH regulation of acupuncture analgesia was investigated in the rat. The changes of pain threshold, which was induced by electrical acupuncture of "Zusanli" points (St. 36), were measured as acupuncture analgesia. Microinjection of l-glutamate sodium into the PVH, which only excites the PVH neurons, could dose-dependently enhance the acupuncture analgesia, but microinjection of l-glutamate sodium into the area nearby the PVH did not alter acupuncture analgesia. Removing pituitary did not influence this effect of l-glutamate sodium. Microinjection of l-glutamate sodium into the PVH only increased the arginine vasopressin (AVP), not oxytocin (OXT), leucine enkephaline (L-Ek), beta-endorphine (beta-Ep) and dynorphinA(1-13) (DynA(1-13)) concentrations in the PVH perfuse liquid using radioimmunoassay. Intraventricular injection of anti-arginine vasopressin serum (AAVPS) could completely reverse the effect of microinjection of l-glutamate sodium into the PVH enhancing acupuncture analgesia. Intraventricular injection of naloxone, one opiate peptide antagonist, partly attenuated this effect of l-glutamate sodium, and intraventricular of anti-oxytocin serum (AOXTS) did not change this effect of l-glutamate sodium. The results suggested that l-glutamate sodium induces the PVH enhancing acupuncture analgesia only through AVP, not OXT and endogenous opiate peptides in central nervous system.
Asunto(s)
Analgesia por Acupuntura , Arginina Vasopresina/metabolismo , Ácido Glutámico/administración & dosificación , Péptidos Opioides/metabolismo , Umbral del Dolor/fisiología , Núcleo Hipotalámico Paraventricular/fisiología , Animales , Dinorfinas/efectos de los fármacos , Dinorfinas/metabolismo , Electroacupuntura , Encefalina Leucina/efectos de los fármacos , Encefalina Leucina/metabolismo , Inyecciones Intraventriculares , Masculino , Microinyecciones , Naloxona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oxitocina/metabolismo , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Fragmentos de Péptidos/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
The formalin test was used to elicit acute and chronic pain in rats, and antisense oligodeoxynucleotide (AS-ODN) was used as a tool to modulate the expression of nociceptive behavioral and neurochemical responses. AS-ODN complementary to c-Fos mRNA was administered intrathecally (i.t.) 4 h before formalin injection in the experimental group. Normal saline or reverse AS-ODN was pre-administered i.t. at the same time in two control groups (saline and reverse AS-ODN). The results showed that the acute phase of nociceptive behavior showed no change by AS-ODN administration, whereas the tonic phase of nociceptive licking and biting behavior was significantly suppressed by AS-ODN as compared with the saline or the reverse AS-ODN group, respectively (p < .05 and p < .01). At the same time, both Fos-like immunoreactive (FLI) neurons and density of dynorphin-like immunoreactivities (DLI) were decreased significantly (p < .05 and p < .01) in the AS-ODN group as compared with that in two control groups. The results indicate that the long-lasting nociceptive responses elicited by sustained noxious inputs are based on the up-regulation of c-Fos gene expression, which in turn induces the upregulation of Dyn A production. It is proposed that intensified Dyn A production in the dorsal horn may be pivotal for the appearance of chronic pain.
Asunto(s)
Conducta Animal/efectos de los fármacos , Dinorfinas/efectos de los fármacos , Oligodesoxirribonucleótidos Antisentido/administración & dosificación , Umbral del Dolor/efectos de los fármacos , Fragmentos de Péptidos/efectos de los fármacos , Células del Asta Posterior/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Conducta Animal/fisiología , Dinorfinas/genética , Dinorfinas/metabolismo , Femenino , Formaldehído , Inyecciones Espinales , Masculino , Dolor/inducido químicamente , Umbral del Dolor/fisiología , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Células del Asta Posterior/metabolismo , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/genética , ARN Mensajero/análisis , ARN Mensajero/efectos de los fármacos , Ratas , Ratas Wistar , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Marked fluctuation of dopamine concentration in the striatum following long-term L-DOPA administration contributes to the development of L-DOPA-induced motor complications including L-DOPA-induced dyskinesias and wearing-off in patients with Parkinson's disease. We have shown that pretreatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A (5-hydroxytryptamine) receptor agonist, alleviates fluctuation of dopamine levels in the dopamine-denervated striatum of 6-hydroxydopamine-lesioned (hemiparkinsonian) rats after L-DOPA treatment. To determine whether co-administration of 8-OH-DPAT with L-DOPA prevents L-DOPA-induced motor complications, we examined rotation behavior and levels of messenger RNAs coding for dynorphin and glutamic acid decarboxylase in the striatum of 6-hydroxydopamine-lesioned rats treated with L-DOPA alone or L-DOPA + 8-OH-DPAT, twice daily, for 2 weeks. Co-administration of 8-OH-DPAT inhibited an increase of rotation behavior to L-DOPA and L-DOPA-induced increases in levels of messenger RNAs coding for dynorphin and glutamic acid decarboxylase in the dopamine-denervated striatum, both of which are established indices of L-DOPA-induced motor complications. These results suggest that pharmaceutical products that stimulate 5-HT1A receptors could prove useful in prevention of the development of L-DOPA-induced motor complications in patients with Parkinson's disease.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/administración & dosificación , Antiparkinsonianos/administración & dosificación , Discinesia Inducida por Medicamentos/prevención & control , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Agonistas de Receptores de Serotonina/administración & dosificación , Animales , Antiparkinsonianos/efectos adversos , Conducta Animal , Cuerpo Estriado , Modelos Animales de Enfermedad , Quimioterapia Combinada , Dinorfinas/efectos de los fármacos , Dinorfinas/metabolismo , Femenino , Glutamato Descarboxilasa/efectos de los fármacos , Glutamato Descarboxilasa/metabolismo , Hibridación in Situ , Levodopa/efectos adversos , Ratas , Ratas WistarRESUMEN
Epilepsy is a significant health problem. Despite the widespread use of both classic and newer pharmacological agents that target ion channels, amino acid transmission or receptors, there are numerous examples of mono- or polytherapy being ineffective. Seizures that are secondary to CNS infections are among the most refractory medically, and thus insult-specific agents are desirable. Recently, the study of the neuropharmacological actions of dynorphin in CNS viral injury has yielded new insights into epileptogenesis and epilepsy treatment. The opioid neuropeptide dynorphin modulates neuronal excitability in vitro in hippocampal slices and potentiates endogenous anti-ictal (i.e. protective) processes in animal models and humans. This work has renewed interest in the role of dysregulation of dynorphin in the pathogenesis of refractory seizures, including encephalitic seizures. The important role of dynorphin in epilepsy is also supported by new models of symptomatic epilepsies based on viral-induced seizures.
Asunto(s)
Enfermedades del Sistema Nervioso Central/complicaciones , Dinorfinas/fisiología , Epilepsia , Hipocampo/fisiología , Convulsiones , Animales , Enfermedades del Sistema Nervioso Central/virología , Modelos Animales de Enfermedad , Dinorfinas/efectos de los fármacos , Dinorfinas/metabolismo , Epilepsia/tratamiento farmacológico , Epilepsia/etiología , Epilepsia/fisiopatología , Hipocampo/metabolismo , Humanos , Ratas , Convulsiones/tratamiento farmacológico , Convulsiones/etiología , Convulsiones/virologíaRESUMEN
The clinical management of neuropathic pain is particularly challenging. Current therapies for neuropathic pain modulate nerve impulse propagation or synaptic transmission; these therapies are of limited benefit and have undesirable side effects. Injuries to peripheral nerves result in a host of pathophysiological changes associated with the sustained expression of abnormal pain. Here we show that systemic, intermittent administration of artemin produces dose- and time-related reversal of nerve injury-induced pain behavior, together with partial to complete normalization of multiple morphological and neurochemical features of the injury state. These effects of artemin were sustained for at least 28 days. Higher doses of artemin than those completely reversing experimental neuropathic pain did not elicit sensory or motor abnormalities. Our results indicate that the behavioral symptoms of neuropathic pain states can be treated successfully, and that partial to complete reversal of associated morphological and neurochemical changes is achievable with artemin.