RESUMEN
The proliferation of neural stem cells (NSCs) is precisely regulated by extracellular environmental factors. In situ hypoxia, one of the key factors involved in the regulation of NSC characteristics, has attracted increasing amounts of attention. Numerous studies have demonstrated that hypoxia can significantly promote the formation of neurospheres and the proliferation of NSCs in vitro and that intermittent hypoxia can promote the proliferation of endogenous NSCs in vivo. In this article, the effects of different concentrations of oxygen on NSC proliferation and differentiation both in vivo and in vitro are reviewed, and the potential applications of hypoxia-preconditioned NSCs, as well as research progress and challenges in the treatment of central nervous system diseases, are further summarized. Here, the critical role of oxygen in the neurogenesis of NSCs is emphasized, and insights into the use of hypoxia to regulate NSC characteristics are provided.
Asunto(s)
Hipoxia de la Célula , Proliferación Celular , Células-Madre Neurales , Neurogénesis , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Humanos , Animales , Diferenciación Celular , Oxígeno/metabolismo , Oxígeno/farmacologíaRESUMEN
Opioid analgesics are widely used to treat acute, postoperative, and chronic pain. However, opioid receptor activation can result in severe respiratory depression. In this study, we demonstrated that Tandospirone (TS), a selective serotonin-1A receptor partial agonist, is effective against opioid-induced respiratory depression. Fentanyl was used to establish a respiratory depression model in rodents. We observed the effects of TS on respiratory depression in rats by using plethysmographic recordings and arterial oxygen saturation. In addition, we evaluated the effects of TS on fentanyl-induced sedation and analgesia by using the loss of righting reflex (LORR) and hot-plate tests, respectively. Rats (n = 5) were treated with TS or saline 5 min prior to fentanyl administration. TS [2 mg/kg, intravenous (i.v.)] dose-dependently attenuated fentanyl-induced respiratory depression versus saline + fentanyl group. Furthermore, pre-treatment with TS (2 mg/kg, i.v.) increased arterial oxygen saturation to 76.5 ± 2.0% at 5 min after fentanyl injection, compared with 35.9 ± 2.5% in saline pre-treated rats (P < 0.001), whereas the time to induction of LORR (P > 0.99) and duration of LORR (P = 0.95) did not differ between the "TS + fentanyl" and "saline + fentanyl" group. The antinociceptive effect of fentanyl was not affected by the administration of TS (P = 0.99) in mice (n = 10). In conclusion, we found that TS, a novel non-benzodiazepine anxiolytic/antidepressant drug, could attenuate severe fentanyl-induced respiratory depression and did not affect the analgesic/sedative effect of fentanyl. The clinical application of TS could significantly improve pain management.
Asunto(s)
Analgésicos Opioides/toxicidad , Fentanilo/toxicidad , Isoindoles/uso terapéutico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Insuficiencia Respiratoria/tratamiento farmacológico , Agonistas de Receptores de Serotonina/uso terapéutico , Animales , Femenino , Isoindoles/administración & dosificación , Masculino , Ratones , Nocicepción , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Insuficiencia Respiratoria/etiología , Agonistas de Receptores de Serotonina/administración & dosificaciónRESUMEN
BACKGROUND: Methamphetamine (METH) is one of the most widely abused illicit substances worldwide; unfortunately, its addiction mechanism remains unclear. Based on accumulating evidence, changes in gene expression and chromatin modifications might be related to the persistent effects of METH on the brain. In the present study, we took advantage of METH-induced behavioral sensitization as an animal model that reflects some aspects of drug addiction and examined the changes in gene expression and histone acetylation in the prefrontal cortex (PFC) of adult rats. METHODS: We conducted mRNA microarray and chromatin immunoprecipitation (ChIP) coupled to DNA microarray (ChIP-chip) analyses to screen and identify changes in transcript levels and histone acetylation patterns. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were performed to analyze the differentially expressed genes. We then further identified alterations in ANP32A (acidic leucine-rich nuclear phosphoprotein-32A) and POU3F2 (POU domain, class 3, transcription factor 2) using qPCR and ChIP-PCR assays. RESULTS: In the rat model of METH-induced behavioral sensitization, METH challenge caused 275 differentially expressed genes and a number of hyperacetylated genes (821 genes with H3 acetylation and 10 genes with H4 acetylation). Based on mRNA microarray and GO and KEGG enrichment analyses, 24 genes may be involved in METH-induced behavioral sensitization, and 7 genes were confirmed using qPCR. We further examined the alterations in the levels of the ANP32A and POU3F2 transcripts and histone acetylation at different periods of METH-induced behavioral sensitization. H4 hyperacetylation contributed to the increased levels of ANP32A mRNA and H3/H4 hyperacetylation contributed to the increased levels of POU3F2 mRNA induced by METH challenge-induced behavioral sensitization, but not by acute METH exposure. CONCLUSIONS: The present results revealed alterations in transcription and histone acetylation in the rat PFC by METH exposure and provided evidence that modifications of histone acetylation contributed to the alterations in gene expression caused by METH-induced behavioral sensitization.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Expresión Génica/efectos de los fármacos , Histonas/metabolismo , Metanfetamina/farmacología , Corteza Prefrontal/efectos de los fármacos , Acetilación/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Trastornos Relacionados con Sustancias/metabolismoRESUMEN
Gamma-aminobutyric acid, type A (GABAA) receptors are complex heterogeneous pentamers with various drug binding sites. Several lines of evidence suggest that benzodiazepines modulate certain GABAA receptors in a flumazenil-insensitive manner, possibly via binding sites other than the classical ones. However, GABAA receptor subtypes that contain non-classical benzodiazepine binding sites are not systemically studied. The present study investigated the high-concentration effects of three benzodiazepines and their sensitivity to flumazenil on different recombinant (α1ß2, α2ß2, α3ß2, α4ß2, α5ß2 and α1ß3) and native neuronal GABAA receptors using the whole-cell patch-clamp electrophysiology technique. The classical benzodiazepine diazepam (200 µmol/L) and midazolam (200 µmol/L) produced flumazenil-insensitive effects on α1ß2 receptor, whereas the imidazopyridine zolpidem failed to modulate the receptor. Flumazenil-insensitive effects of diazepam were also observed on the α2ß2, α3ß2 and α5ß2, but not α4ß2 receptors. Unlike ß2-containing receptors, the α1ß3 receptor was insensitive to diazepam. Moreover, the diazepam (200 µmol/L) effects on some cortical neurons could not be fully antagonized by flumazenil (200 µmol/L). These findings suggested that the non-classical (flumazenil-insensitive) benzodiazepine effects depended on certain receptor subtypes and benzodiazepine structures and may be important for designing of subtype- or binding site- specific drugs.
RESUMEN
Vesicular glutamate transporter 2 (VGLUT2)-which uptakes glutamate into presynaptic vesicles-is a fundamental component of the glutamate neurotransmitter system. Although several lines of evidence from genetically modified mice suggest a possible association of VGLUT2 with neuropathic pain, the specific role of VGLUT2 in the spinal cord during neuropathic pain, and its regulatory mechanism remain elusive. In this study, we report that spared nerve injury induced an upregulation of VGLUT2 in the spinal cord, and intrathecal administration of small hairpin RNAs (shRNA) against VGLUT2 before or after surgery attenuated mechanical allodynia, and pathologically-enhanced glutamate release. Meanwhile, nerve injury activated the Wnt1/ß-catenin signaling pathway in a quick-onset and sustained manner, and blocking the Wnt1 signaling with a Wnt1 targeting antibody attenuated neuropathic pain. In naïve mice, administration of a Wnt agonist or Wnt1 increased spinal VGLUT2 protein levels. Moreover, intrathecal administration of the Wnt/ß-catenin inhibitor, XAV939 attenuated mechanical allodynia, and this effect was concurrent with that of VGLUT2 downregulation. Pretreatment with VGLUT2 shRNAs abolished the allodynia induced by the Wnt agonist or Wnt1. These findings reveal a novel mechanism wherein there is Wnt1/ß-catenin-dependent VGLUT2 upregulation in neuropathic pain, thus potentiating the development of new therapeutic strategies in pain management.
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Neuralgia/fisiopatología , Proteína 2 de Transporte Vesicular de Glutamato/biosíntesis , Vía de Señalización Wnt/efectos de los fármacos , Animales , Ácido Glutámico/metabolismo , Hiperalgesia/tratamiento farmacológico , Inmunohistoquímica , Inyecciones Espinales , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/uso terapéutico , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Regulación hacia Arriba , beta Catenina/metabolismoRESUMEN
Analgesics and sedative hypnotics in clinical use often give rise to significant side effects, particularly respiratory depression. For emergency use, specific antagonists are currently administered to counteract respiratory depression. However, antagonists are often short-lasting and eliminate drug generated analgesia. To resolve this issue, novel positive AMPA modulators, LCX001, was tested to alleviate respiratory depression triggered by different drugs. The acetic acid writhing and hot-plate test were conducted to evaluate analgesic effect of LCX001. Binding assay, whole-cell recording, live cell imaging, and Ca2+ imaging were used to clarify mechanism and impact of LCX001 on respiratory protection. Results showed that LCX001 effectively rescued and prevented opioid (fentanyl and TH-030418), propofol, and pentobarbital-induced respiratory depression by strengthening respiratory frequency and minute ventilation. The acetic acid writhing test and hot-plate test revealed potent anti-nociceptive efficacy of LCX001, in contrast to other typical ampakines that did not affect analgesia. Furthermore, LCX001 potentiated [3H]AMPA and L-glutamate binding affinity to AMPA receptors, and facilitated glutamate-evoked inward currents in HEK293 cells stably expressing GluA2(R). LCX001 had a typical positive modulatory impact on AMPAR-mediated function. Importantly, application of LCX001 generated a significant increase in GluA2(R) surface expression, and restrained opioid-induced abnormal intracellular Ca2+ load, which might participate in breathing modulation. Our study improves therapeutic interventions for the treatment of drug induced respiratory depression, and increases understanding of potential mechanism of AMPA receptor modulators.
RESUMEN
Vesicular glutamate transporters (VGLUTs) transport glutamate into synaptic vesicles prior to exocytotic release. The expression pattern of VGLUT2 and studies of genetically modified mice have revealed that VGLUT2 contributes to neuropathic pain. We previously showed that VGLUT2 is upregulated in supraspinal regions including the thalamus in mice following spared nerve injury (SNI), and blocking VGLUTs using the VGLUT inhibitor CSB6B attenuated mechanical allodynia. To further evaluate the role of VGLUT2 in neuropathic pain, in this study, we developed a lentiviral vector expressing small hairpin RNAs (shRNAs) against mouse VGLUT2, which was injected into the ventral posterolateral (VPL) nucleus of the thalamus in the presence or absence of SNI. The administration of VGLUT2 shRNAs result in downregulation of VGLUT2 mRNA and protein expression, and decreased extracellular glutamate release in primary cultured neurons. We also showed that VGLUT2 shRNAs attenuated SNI-induced mechanical allodynia, in accordance with knockdown of VGLUT2 in the VPL nucleus in mice. Accordingly, our study supports the essential role of supraspinal VGLUT2 in neuropathic pain in adult mice and, thereby, validates VGLUT2 as a potential target for neuropathic pain therapy.
Asunto(s)
Regulación hacia Abajo , Hiperalgesia/genética , Neuralgia/genética , Núcleos Talámicos Ventrales/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/genética , Animales , Ácido Glutámico/metabolismo , Hiperalgesia/metabolismo , Hiperalgesia/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuralgia/metabolismo , Neuralgia/patología , Neuronas/metabolismo , ARN Interferente Pequeño/genética , Núcleos Talámicos Ventrales/patologíaRESUMEN
BACKGROUND: We previously reported that YQA31 is a dopamine D3 receptor antagonist with modest 5-HT1A receptor affinity and that it exhibits antipsychotic properties in animal models of schizophrenia. However, the contributions of D3 and 5-HT1A receptors in the anti-psychotic effects of YQA31 are not clear. The current study evaluated the role of these two receptors in the effect of YQA31 on the hyperactivity and novel object recognition deficit in mice. METHODS: We used dopamine D3 receptor knockout mice and 5-HT1A receptor antagonist WAY100635 pretreatment, respectively, to investigate the involvement of these receptors in the effects of YQA31. The anti-psychotic effects were tested by inducing hyperlocomotion with methamphetamine or MK-801 and by inducing novel object recognition deficit with MK-801, which are the animal models to represent a positive symptom and a cognitive disorder. RESULTS: YQA31 significantly inhibited MK-801-induced hyperlocomotion and novel object recognition deficit in WT mice, which was significantly inhibited by dopamine D3 receptor knockout. The 5-HT1A receptor antagonist, WAY100635, also blocked the effect of YQA31 in MK-801-induced novel object recognition deficit but not hyperlocomotion. The effect of YQA31 on methamphetamine-induced hyperlocomotion was not reversed by either dopamine D3 receptor knockout or WAY100635 pretreatment. CONCLUSIONS: These results demonstrate the different roles of dopamine D3 and 5-HT1A receptors in the anti-psychotic effects of YQA31. Both dopamine D3 and 5-HT1A receptors contributed to the effects of YQA31 on the inhibition of MK-801-induced novel object recognition deficit, and the dopamine D3 receptor mediated the inhibiting effect of YQA31 on hyperlocomotion induced by MK-801.
Asunto(s)
Antipsicóticos/farmacología , Benzotiazoles/farmacología , Piperazinas/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptores de Dopamina D3/efectos de los fármacos , Animales , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Hipercinesia/tratamiento farmacológico , Masculino , Metanfetamina/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Piridinas/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Dopamina D3/genética , Receptores de Dopamina D3/metabolismo , Reconocimiento en Psicología/efectos de los fármacosRESUMEN
Opioid analgesics remain the first choice for the treatment of moderate to severe pain, but they are also notorious for their respiratory depression and addictive effects. This study focused on the pharmacology of a novel opioid receptor mixed agonist DPI-125 and attempted to elucidate the relationship between the δ-, µ- and κ-receptor potency ratio and respiratory depression and abuse liability. Five diarylmethylpiperazine compounds (DPI-125, DPI-3290, DPI-130, KUST202 and KUST13T02) were selected for this study. PKA fluorescence redistribution assays in CHO cells individually expressing δ-, µ- or κ-receptors were used to measure the agonist potency. The respiratory safety profiles were estimated in rats by the ratio of ED50 (pCO2 increase)/ED50 (antinociception). The abuse liability of DPI-125 was evaluated with a self-administration model in rhesus monkeys. The observed agonist potencies of DPI-125 for δ-, µ- and κ-opioid receptors were 4.29±0.36, 11.10±3.04, and 16.57±4.14 nmol/L, respectively. The other four compounds were also mixed agonists with varying potencies. DPI-125 exhibited a high respiratory safety profile, clearly related to its high δ-receptor potency. The ratio of the EC50 potencies for the µ- and δ-receptors was found to be positively correlated with the respiratory safety ratio. DPI-125 has similar potencies for µ- and κ-receptors, which is likely the reason for its reduced abuse potential. Our results demonstrate that the opioid receptor mixed agonist DPI-125 is safer and less addictive than traditional µ-agonist analgesics. These findings suggest that the development of δ>µâ¼κ opioid receptor mixed agonists is feasible, and such compounds could represent a promising class of potent analgesics with wider therapeutic windows.
Asunto(s)
Analgesia , Analgésicos Opioides/farmacología , Dolor/tratamiento farmacológico , Piperazinas/farmacología , Insuficiencia Respiratoria/tratamiento farmacológico , Tiofenos/farmacología , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/química , Animales , Células CHO , Cricetulus , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Conformación Molecular , Dimensión del Dolor , Piperazinas/administración & dosificación , Piperazinas/química , Ratas , Ratas Wistar , Receptores Opioides delta/agonistas , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas , Relación Estructura-Actividad , Tiofenos/administración & dosificación , Tiofenos/químicaRESUMEN
The use of opioid drugs for pain relief can induce life-threatening respiratory depression. Although naloxone effectively counteracts opioid-induced respiratory depression, it diminishes the efficacy of analgesia. Our studies indicate that ampakines, in particular, a brain-targeted compound XD-8-17C, are able to reverse respiratory depression without affecting analgesia at relatively low doses. Mice and rats were subcutaneously or intravenously injected with the opioid agonist TH-030418 to induce moderate or severe respiratory depression. XD-8-17C was intravenously administered before or after TH-030418. The effect of XD-8-17C on opioid-induced respiratory depression was evaluated in terms of the opioid-induced acute death rate, arterial blood gas analysis and pulmonary function tests. In addition, the hot-plate test was conducted to investigate whether XD-8-17C influenced opioid-induced analgesia. Pre-treatment with XD-8-17C significantly reduced opioid-induced acute death, and increased the median lethal dose of TH-030418 by 4.7-fold. Blood gas analysis and pulmonary function tests demonstrated that post-treatment with XD-8-17C alleviated respiratory depression, as indicated by restoration of arterial blood gas (pO2, sO2, cK+) and lung function parameters (respiratory frequency, minute ventilation) to the normal range. The hot-plate test showed that XD-8-17C had no impact on the antinociceptive efficacy of morphine. The ability of XD-8-17C to reverse opioid-induced respiratory depression has the potential to increase the safety and convenience of opioid treatment. These findings contribute to the discovery of novel therapeutic agents that protect against opioid-induced respiratory depression without loss of analgesia.
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Analgésicos Opioides/efectos adversos , Encéfalo/efectos de los fármacos , Oxadiazoles/farmacología , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/tratamiento farmacológico , Animales , Análisis de los Gases de la Sangre , Encéfalo/metabolismo , Femenino , Masculino , Ratones , Oxadiazoles/uso terapéutico , Ratas , Insuficiencia Respiratoria/sangreRESUMEN
Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was down-regulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.
Asunto(s)
Agmatina/farmacología , Líquido Extracelular/efectos de los fármacos , Ácido Glutámico/metabolismo , Hipocampo , Morfina/farmacología , Narcóticos/farmacología , Adaptación Fisiológica/efectos de los fármacos , Análisis de Varianza , Animales , Regulación hacia Abajo/efectos de los fármacos , Interacciones Farmacológicas , Técnicas Electroquímicas , Líquido Extracelular/metabolismo , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de TiempoRESUMEN
OBJECTIVE: To investigate the protective effects of tea polyphenols (TP) against myocardial ischemia/reperfusion (IR) injuries and explore the possible mechanisms. METHODS: Langendorff-perfused rat hearts were subjected to ischemia for 30 min followed by reperfusion for another 30 min. Myocardial function indices were measured by a left ventricular cannula via a pressure transducer connected to the polygraph in isolated Langendorff hearts and energy metabolism was measured using (31)P nuclear magnetic resonance (NMR) spectroscopy. Whole-cell atch-clamp technique was used to record calcium inward current (I(Ca-L)) in cultured rat cardiac myocytes. RESULTS: Compared with the control hearts, the ex vivo rat hearts with 2.5 mg/L TP treatment showed significantly increased left ventricular developed pressure (LVDP), maximal rise rate of LVDP (+dp/d(tmax)), maximal fall rate of LVDP (-dp/dt(max)), and coronary flow (CF) (P<0.05). During both cardiac ischemia and reperfusion phase, ATP and PCr levels were elevated significantly in TP-treated hearts compared with those in the control hearts (P<0.05). In cultured rat cardiac myocytes, ICa-L was remarkably decreased by TP at the doses of 2.5 and 5.0 mg/L (P<0.01). CONCLUSION: Our results support a possible protective role of TP against myocardial IR injury by improving myocardial energy metabolism and inhibiting I(Ca-L) in the cardiac myocytes.
Asunto(s)
Calcio/metabolismo , Metabolismo Energético , Daño por Reperfusión Miocárdica , Miocitos Cardíacos/efectos de los fármacos , Polifenoles/farmacología , Animales , Canales de Calcio/metabolismo , Células Cultivadas , Corazón/efectos de los fármacos , Técnicas In Vitro , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Ratas , Té/químicaRESUMEN
Disturbance of glutamate homeostasis is a well-characterized mechanism of neuropathic pain. Vesicular glutamate transporters (VGLUTs) determine glutamate accumulation in synaptic vesicles and their roles in neuropathic pain have been suggested by gene-knockout studies. Here, we investigated the spatio-temporal changes in VGLUT expression during the development of neuropathic pain in wild-type rats. Spared nerve injury (SNI) induced mechanical allodynia from postoperative day 1 to at least day 14. Expression of VGLUT1 and VGLUT2 in dorsal root ganglia and spinal cord was examined by western blot analyses on different postoperative days. We observed that VGLUT2 were selectively upregulated in crude vesicle fractions from the ipsilateral lumbar enlargement on postoperative days 7 and 14, while VGLUT1 was transiently downregulated in ipsilateral DRG (day 4) and contralateral lumbar enlargement (day 1). Upregulation of VGLUT2 was not accompanied by alterations in vesicular expression of synaptotagmin or glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Thus, VGLUTs expression, especially VGLUT2, is regulated following peripheral nerve injury. Temporal regulation of VGLUT2 expression in spinal cord may represent a novel presynaptic mechanism contributing to injury-induced glutamate imbalance and associated neuropathic pain.
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Ganglios Espinales/metabolismo , Neuralgia/metabolismo , Neuropatía Ciática/metabolismo , Médula Espinal/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/biosíntesis , Proteína 2 de Transporte Vesicular de Glutamato/biosíntesis , Animales , Expresión Génica , Masculino , Neuralgia/genética , Nervio Peroneo/lesiones , Nervio Peroneo/metabolismo , Ratas , Ratas Sprague-Dawley , Neuropatía Ciática/genética , Nervio Sural/lesiones , Nervio Sural/metabolismo , Nervio Tibial/lesiones , Nervio Tibial/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/genética , Proteína 2 de Transporte Vesicular de Glutamato/genéticaRESUMEN
AIM: To investigate the potential effects of Y-QA31, a novel dopamine D3 receptor antagonist, as an antipsychotic drug. METHODS: A panel of radioligand-receptor binding assays was performed to identify the affinities of Y-QA31 for different G protein-coupled receptors. [(35)S]GTPγS-binding assays and Ca(2+) imaging were used to assess its intrinsic activities. The antipsychotic profile of Y-QA31 was characterized in mouse models for the positive symptoms and cognitive deficits of schizophrenia and extrapyramidal side effects with haloperidol and clozapine as positive controls. RESULTS: In vitro, Y-QA31 is a dopamine D3 receptor antagonist that is 186-fold more potent at the D3 receptor than at the D2 receptor. Y-QA31 also exhibits 5-HT1A receptor partial agonist and α1A adrenoceptor antagonist activities with medium affinity, whereas it exhibits very little affinity for other receptors (100-fold lower than for the D3 receptor). In vivo, Y-QA31 (10-40 mg/kg, po) significantly inhibited MK-801-induced hyperlocomotion and methamphetamine-induced prepulse inhibition disruption in a dose-dependent manner. Y-QA31 also inhibited the avoidance response and methamphetamine-induced hyperlocomotion with potency lower than haloperidol. Y-QA31 was effective in alleviating the MK-801-induced disruption of novel object recognition at a low dose (1 mg/kg, po). Moreover, Y-QA31 itself did not affect spontaneous locomotion or induce cataleptic response until its dose reached 120 mg/kg. CONCLUSION: Y-QA31 is a selective D3R antagonist that exhibits antipsychotic effects in some animal models with positive symptoms and cognitive disorder and less extrapyramidal side effects.
Asunto(s)
Antipsicóticos/uso terapéutico , Benzotiazoles/uso terapéutico , Piperazinas/uso terapéutico , Receptores de Dopamina D3/antagonistas & inhibidores , Esquizofrenia/tratamiento farmacológico , Animales , Antipsicóticos/química , Benzotiazoles/química , Locomoción/efectos de los fármacos , Masculino , Ratones , Modelos Animales , Piperazinas/química , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Dopamina D3/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Agonistas del Receptor de Serotonina 5-HT1/química , Agonistas del Receptor de Serotonina 5-HT1/uso terapéuticoRESUMEN
AIM: We have reported that a selective dopamine D3 receptor antagonist YQA14 attenuates cocaine reward and relapse to drug-seeking in mice. In the present study, we investigated whether YQA14 could inhibit methamphetamine (METH)-induced locomotor sensitization and conditioned place preference (CPP) in mice. METHODS: Locomotor activity was monitored in mice treated with METH (1 mg/kg, ip) daily on d 4-13, followed by a challenge with METH (0.5 mg/kg) on d 21. CPP was examined in mice that were administered METH (1 mg/kg) or saline alternately on each other day for 8 days (METH conditioning). YQA14 was injected intraperitoneally 20 min prior to METH or saline. RESULTS: Both repetitive (daily on d 4-13) and a single injection (on the day of challenge) of YQA14 (6.25, 12.5 and 25 mg/kg) dose-dependently inhibited the acquisition and expression of METH-induced locomotor sensitization. However, repetitive injection of YQA14 (daily during the METH conditioning) did not alter the acquisition of METH-induced CPP, whereas a single injection of YQA14 (prior to CPP test) dose-dependently attenuated the expression of METH-induced CPP. In addition, the repetitive injection of YQA14 dose-dependently facilitated the extinction and decreased the reinstatement of METH-induced CPP. CONCLUSION: Brain D3 receptors are critically involved in the reward and psychomotor-stimulating effects of METH. Thus, YQA14 deserves further study as a potential medication for METH addiction.
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Conducta Adictiva/tratamiento farmacológico , Benzoxazoles/uso terapéutico , Estimulantes del Sistema Nervioso Central/farmacología , Metanfetamina/farmacología , Piperazinas/uso terapéutico , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Conducta Adictiva/metabolismo , Conducta Adictiva/fisiopatología , Benzoxazoles/administración & dosificación , Benzoxazoles/farmacología , Estimulantes del Sistema Nervioso Central/administración & dosificación , Locomoción/efectos de los fármacos , Masculino , Metanfetamina/administración & dosificación , Ratones , Piperazinas/administración & dosificación , Piperazinas/farmacología , Receptores de Dopamina D3/metabolismoRESUMEN
Incarvillea sinensis is a Bignoniaceae plant used to treat rheumatism and relieve pain in traditional Chinese medicine. As a major component of I. sinensis, incarvillateine has shown analgesic activity in mice formalin tests. Using a series of animal models, this study further evaluated the effects of incarvillateine against acute, inflammatory, and neuropathic pain. Incarvillateine (10 or 20 mg/kg, i.p.) dose-dependently attenuated acetic acid-induced writhing, but did not affect thermal threshold in the hot plate test. In a Complete Freund's Adjuvant model, incarvillateine inhibited both thermal hyperalgesia and paw edema, and increased interleukin-1ß levels. Additionally, incarvillateine attenuated mechanical allodynia induced by spared nerve injury or paclitaxel, whereas normal mechanical sensation was not affected. Incarvillateine did not affect locomotor activity and time on the rotarod at analgesic doses, and no tolerance was observed after 7 consecutive daily doses. Moreover, incarvillateine-induced antinociception was attenuated by theophylline, 1,3-dipropyl-8-cyclopentylxanthine, and 3,7-dimethyl-1-propargylxanthine, but not naloxone, indicating that the effects of incarvillateine on chronic pain were related to the adenosine system, but not opioid system. These results indicate that incarvillateine is a novel analgesic compound that is effective against inflammatory and neuropathic pain, and that its effects are associated with activation of the adenosine system.
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Adenosina/metabolismo , Alcaloides/farmacología , Analgésicos/farmacología , Bignoniaceae/química , Monoterpenos/farmacología , Alcaloides/química , Alcaloides/uso terapéutico , Analgésicos/química , Analgésicos/uso terapéutico , Animales , Antineoplásicos Fitogénicos/toxicidad , Bignoniaceae/metabolismo , Modelos Animales de Enfermedad , Edema/inducido químicamente , Edema/prevención & control , Adyuvante de Freund/química , Hiperalgesia/etiología , Hiperalgesia/prevención & control , Interleucina-1beta/metabolismo , Medicina Tradicional China , Ratones , Monoterpenos/química , Monoterpenos/uso terapéutico , Actividad Motora/efectos de los fármacos , Paclitaxel/toxicidad , Dimensión del Dolor/efectos de los fármacos , Teobromina/análogos & derivados , Teobromina/farmacología , Teofilina/farmacología , Xantinas/farmacologíaRESUMEN
Vesicular glutamate transporters (VGLUTs) control the storage and release of glutamate, which plays a critical role in pain processing. The VGLUT2 isoform has been found to be densely distributed in the nociceptive pathways in supraspinal regions, and VGLUT2-deficient mice exhibit an attenuation of neuropathic pain; these results suggest a possible involvement of VGLUT2 in neuropathic pain. To further examine this, we investigated the temporal changes in VGLUT2 expression in different brain regions as well as changes in glutamate release from thalamic synaptosomes in spared nerve injury (SNI) mice. We also investigated the effects of a VGLUT inhibitor, Chicago Sky Blue 6B (CSB6B), on pain behavior, c-Fos expression, and depolarization-evoked glutamate release in SNI mice. Our results showed a significant elevation of VGLUT2 expression up to postoperative day 1 in the thalamus, periaqueductal gray, and amygdala, followed by a return to control levels. Consistent with the changes in VGLUT2 expression, SNI enhanced depolarization-induced glutamate release from thalamic synaptosomes, while CSB6B treatment produced a concentration-dependent inhibition of glutamate release. Moreover, intracerebroventricular administration of CSB6B, at a dose that did not affect motor function, attenuated mechanical allodynia and c-Fos up-regulation in pain-related brain areas during the early stages of neuropathic pain development. These results demonstrate that changes in the expression of supraspinal VGLUT2 may be a new mechanism relevant to the induction of neuropathic pain after nerve injury that acts through an aggravation of glutamate imbalance.
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Encéfalo/metabolismo , Encéfalo/patología , Neuralgia/patología , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo , Animales , Colorantes/farmacología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Ácido Glutámico/metabolismo , Hiperalgesia/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Neuralgia/fisiopatología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Médula Espinal/metabolismo , Médula Espinal/patología , Estadísticas no Paramétricas , Sinaptosomas/metabolismo , Sinaptosomas/patología , Nervio Tibial/lesiones , Nervio Tibial/fisiopatología , Azul de Tripano/farmacología , Proteína 2 de Transporte Vesicular de Glutamato/antagonistas & inhibidoresRESUMEN
Stimulation of the µopioid receptor activates extracellular signalregulated kinase (ERK), however, the mechanism by which this occurs remains to be elucidated. Phosphatidylethanolaminebinding protein (PEBP) has been reported to act as a negative regulator of the ERK cascade (RafMEKERK) by binding to Raf1 kinase. In the present study, the role of PEBP in µopioid receptormediated ERK activation was investigated in Chinese hamster ovary/µ cells and SHSY5Y cells, as well as in human embryonic kidney 293 cells expressing other types of G proteincoupled receptors. The acute activation of µopioid receptors by morphine or (DAla2, MePhe4, Gly5ol) enkephalin induced a rapid activation of ERK. Prolonged morphine treatment did not affect the phosphorylation level of ERK compared with control cells, but the phosphorylation level of ERK decreased markedly when cells were precipitated with naloxone following chronic morphine treatment. For the phosphorylation of PEBP, no change was identified under the designated drug treatment and exposure duration. A total of two other types of G proteincoupled receptors, including Gscoupled dopamine D1 receptors and Gqcoupled adrenergic α1A receptors were also investigated and only the activation of adrenergic α1A receptors induced an upregulated phosphorylation of PEBP, which was protein kinase C activity dependent. Thus, PEBP did not have a significant role in µopioid receptormediated regulation of ERK.
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Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas de Unión a Fosfatidiletanolamina/metabolismo , Receptores Opioides mu/metabolismo , Analgésicos Opioides/farmacología , Animales , Células CHO , Línea Celular Tumoral , Cricetinae , Cricetulus , Expresión Génica , Humanos , Indoles/farmacología , Maleimidas/farmacología , Morfina/farmacología , Proteínas de Unión a Fosfatidiletanolamina/genética , Fosforilación , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Dopamina D1/metabolismoRESUMEN
Improved utilization of continuous or intermittent opioid administration in pain treatment necessitates a comparison of the antinociceptive effect and tolerance of these two treatment methods. More importantly, the effect of treatment method on subsequent opioid consumption has not been directly compared, although it is widely assumed that continuous opioid treatment may produce lower addictive liability relative to intermittent opioid treatment. In this study, we compared the antinociceptive effect and tolerance of morphine in rats that received repeated injection (10 mg/kg twice daily for 7 days) or continuous infusion (20 mg/kg daily for 7 days) subcutaneously and the self-administration of intravenous morphine in these rats after 7 days of withdrawal. Both intermittent and continuous morphine treatment produced antinociceptive tolerance, but the exhibition of tolerance differed. Moreover, intermittent morphine pretreatment facilitated subsequent morphine self-administration, whereas continuous morphine pretreatment produced minimal effects, as shown by comparable levels of active responses and morphine consumption between continuous morphine and saline-treated rats. These results suggest that the administration method of opioid should be selected according to the specific pain situation and that continuous opioid administration or long-acting therapy may be advantageous, producing less influence on drug-taking behavior than intermittent administration of short-acting drugs.