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1.
Dig Dis Sci ; 59(10): 2417-22, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24801687

RESUMO

BACKGROUND AND AIMS: Ilaprazole is a novel proton pump inhibitor that has been marketed as an oral therapy for acid-related diseases in China and Korea. This study aimed to compare the gastroprotective effects of intravenous and enteral ilaprazole in rat models. METHODS: The rats were divided into 7-8 groups receiving vehicle, esomeprazole, and different doses of intravenous and enteral ilaprazole. The rats were then exposed to indomethacin (30 mg/kg, i.g.), or water-immersion stress and gastric lesions were examined. The effects of different treatments on histamine (10 µmol/kg/h)-induced acid secretion were also observed. RESULTS: Intravenous ilaprazole exhibited high antiulcer activity in a dose-dependent manner. Ilaprazole at a dose of 3 mg/kg decreased ulcer number and index to the same extent as 20 mg/kg esomeprazole. Moreover, the potency of intravenous ilaprazole is superior to that of intragastric ilaprazole. In anesthetized rats, the inhibitory effect of intravenous ilaprazole on histamine-induced acid secretion is faster and longer-lasting than that of intraduodenal ilaprazole. CONCLUSION: Intravenous ilaprazole is more potent than oral ilaprazole against indomethacin- or stress-induced gastric lesions, with faster and longer inhibition of acid secretion.


Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/administração & dosagem , 2-Piridinilmetilsulfinilbenzimidazóis/uso terapêutico , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/uso terapêutico , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Histamina/farmacologia , Indometacina/toxicidade , Masculino , Ratos , Ratos Sprague-Dawley , Estômago/efeitos dos fármacos , Estômago/patologia , Estresse Fisiológico
2.
Yao Xue Xue Bao ; 45(4): 436-41, 2010 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-21355207

RESUMO

Human rhinoviruses (HRVs) are the causative pathogens in more than half of viral upper respiratory tract infections. Currently, no antiviral agents that are active against HRVs are available for clinical use. Because only higher primates are susceptible to HRVs, the screening of new drug is most commonly based on the cell line model. In this study, isolated rabbit airway smooth muscles (ASM) tissue model has been established, and the airway responsiveness with different treatment has been examined. Relative to control tissues, the maximal constrictor (Tmax) response to ACh increased significantly 150% in ASM inoculated with HRV, and relaxation to isoproterenol has been attenuated to 63%. And the abnormal responsiveness can be inhibited in presence of pretreatment with several new compounds which have been exhibited effective anti-HRV activity on cell lines. The results demonstrate that the established ASM model will be applied to screening the anti-HRVs drugs.


Assuntos
Antivirais/farmacologia , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/fisiopatologia , Rhinovirus , Traqueia/fisiopatologia , Acetilcolina/farmacologia , Animais , Efeito Citopatogênico Viral/efeitos dos fármacos , Células HeLa , Humanos , Isoproterenol/farmacologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/virologia , Piperidinas/farmacologia , Piridazinas/farmacologia , Coelhos , Traqueia/efeitos dos fármacos , Traqueia/virologia
3.
Eur J Pharmacol ; 599(1-3): 18-23, 2008 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-18845140

RESUMO

Agmatine, an endogenous ligand for imidazoline I(1) receptor, has previously been shown to prevent opioid tolerance in rats and mice, but the cellular mechanisms remain unknown. In the present study, the effects of agmatine activation on imidazoline I(1) receptor on the desensitization, down-regulation and internalization of micro opioid receptor were investigated. Two cell lines, CHO cells transfected micro opioid receptor (CHO-micro cells) and co-transfected micro opioid receptor and imidazoline I(1) receptor antisera-selected protein (IRAS) (CHO-micro/IRAS cells), were used. In both CHO-micro cells and CHO-micro/IRAS cells, agmatine (0.01-10 microM) did not affect the desensitization of micro opioid receptor induced by [d-Ala(2), N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) (10 microM) treatment for 30 min. However, agmatine (0.1-100 nM) co-pretreatment with DAMGO (1 microM) for 12 h concentration-dependently inhibited DAMGO-induced down-regulation of micro opioid receptor in CHO-micro/IRAS cells, but not in CHO-micro cells. Efaroxan, the I(1)/alpha(2)-adrenoceptors mix antagonist, completely reversed the inhibitory effect of agmatine, suggesting the participation of imidazoline I(1) receptor. In addition, agmatine (1-100 nM) inhibited DAMGO-induced internalization of micro opioid receptor in CHO-micro/IRAS cells, which was reversed by efaroxan as well. While treatment with DAMGO (1 microM) or co-treatment with agmatine (1-100 nM) for 12 h failed to affect the mRNA level of micro opioid receptor. Taken together, these results indicate that the inhibitory effect of agmatine on tolerance in vitro might be related to attenuation of the internalization and down-regulation of micro opioid receptor via activation of imidazoline I(1) receptor.


Assuntos
Agmatina/metabolismo , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Receptores de Imidazolinas/efeitos dos fármacos , Receptores Opioides mu/efeitos dos fármacos , Agmatina/administração & dosagem , Animais , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Tolerância a Medicamentos/fisiologia , Receptores de Imidazolinas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores Opioides mu/metabolismo , Transfecção
4.
Eur J Pharmacol ; 593(1-3): 62-7, 2008 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-18657533

RESUMO

Our previous studies have shown that agmatine inhibited morphine-induced conditioned place preference and locomotor sensitization in rats. In the present study, we further investigated the effects of agmatine on the discriminative stimulating effects produced by morphine in rats. Agmatine, at the dose range of 10-80 mg/kg (i.g.), neither induced drug discrimination, nor substituted for morphine stimulus in rats that were previously treated with morphine, suggesting that agmatine itself has no psychomotor-stimulating potential. However, pretreatment with agmatine (40, 80 mg/kg, i.g.) significantly inhibited the acquisition, but not expression, of morphine-induced drug discrimination as assessed by the correct nose-poke response. Further, chronic administration of agmatine (40, 80 mg/kg/day x 12 days, i.g., 25 min prior to morphine) also significantly accelerated the extinction of the discrimination induced by morphine. These data suggest that agmatine inhibits the acquisition and accelerates the extinction of morphine-induced discrimination, supporting possible use of agmatine in the treatment of opioid dependence.


Assuntos
Agmatina/farmacologia , Discriminação Psicológica/efeitos dos fármacos , Morfina/antagonistas & inibidores , Morfina/farmacologia , Entorpecentes/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Interpretação Estatística de Dados , Aprendizagem por Discriminação/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Esquema de Reforço , Transtornos Relacionados ao Uso de Substâncias/psicologia
5.
Eur J Pharmacol ; 586(1-3): 130-8, 2008 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-18374913

RESUMO

ZC88 is a novel non-peptide N-type voltage-sensitive calcium channel blocker synthesized by our institute. In the present study, the oral analgesic activity of ZC88 in animal models of acute and neuropathic pain, and functional interactions between ZC88 and morphine in terms of analgesia, tolerance and dependence were investigated. In mice acetic acid writhing tests, ZC88 (10-80 mg/kg) administered by oral route showed significant antinociceptive effects in a dose-dependent manner. The ED50 values of ZC88 were 14.5 and 14.3 mg/kg in male and female mice, respectively. In sciatic nerve chronic constriction injury rats, mechanical allodynia was ameliorated by oral administration of ZC88 at doses of 14, 28 and 56 mg/kg, suggesting ZC88 relieved allodynic response of neuropathic pain. When concurrently administered with morphine, ZC88 (20-80 mg/kg) dose-dependently potentiated morphine analgesia and attenuated morphine analgesic tolerance in hot-plate tests. ZC88 also prevented chronic exposure to morphine-induced physical dependence and withdrawal, but not morphine-induced psychological dependence in conditioned place preference model. These results suggested that ZC88, a new non-peptide N-type calcium channel blocker, had notable oral analgesia and anti-allodynia for acute and neuropathic pain. ZC88 might be used in pain relief by either application alone or in combination with opioids because it enhanced morphine analgesia while prevented morphine-induced tolerance and physical dependence.


Assuntos
Analgésicos Opioides/farmacologia , Analgésicos , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/efeitos dos fármacos , Dependência de Morfina/tratamento farmacológico , Morfina/farmacologia , Piperidinas/farmacologia , Ácido Acético , Animais , Condicionamento Operante/efeitos dos fármacos , Tolerância a Medicamentos , Camundongos , Dependência de Morfina/psicologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/tratamento farmacológico , Dor/etiologia , Medição da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/complicações , Estimulação Física , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Neuropatia Ciática/tratamento farmacológico
6.
Eur J Pharmacol ; 587(1-3): 155-62, 2008 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-18455724

RESUMO

Our previous studies demonstrated that subcutaneous injection of agmatine inhibits tolerance to and physiological dependence on morphine in mice and rats. In the present study we further evaluated the effects of intragastric (i.g.) administration of agmatine on morphine-induced physiological dependence in mice, rats, beagle dogs and rhesus monkeys. When agmatine (5-40 mg/kg, i.g.) was co-administered with morphine during the development of morphine-induced physiological dependence, it inhibited the abstinent syndrome precipitated by naloxone in mice, rats and beagle dogs. In addition, agmatine (40 mg/kg, i.g.) inhibited the abstinent syndrome precipitated by naloxone in mice when it was administered on the test day. In naloxone precipitated and naturally abstinent morphine dependent model in rhesus monkeys, agmatine (40 or 80 mg/kg, i.g.) inhibited the development of physiological dependence when it was co-administered with morphine. After the development of morphine dependence, agmatine (80 mg/kg, i.g.) inhibited the naturally abstinent syndrome during the 7-d abstinent period. All these results suggested that intragastric administration of agmatine inhibits morphine-induced physiological dependence in animal models.


Assuntos
Agmatina/farmacologia , Analgésicos Opioides , Dependência de Morfina/prevenção & controle , Morfina , Agmatina/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Intubação Gastrointestinal , Macaca mulatta , Masculino , Camundongos , Dependência de Morfina/psicologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos Wistar , Síndrome de Abstinência a Substâncias/psicologia
7.
Neurosci Lett ; 448(2): 221-5, 2008 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-18973795

RESUMO

Acute administration of opioids produces analgesia, while chronic administration induces tolerance and dependence. Aquaporin 4 (AQP4) is most strongly expressed in astrocytes throughout central nervous system, and plays an important role in some pathophysiological processes in brain. However, whether AQP4 modulates opioid analgesia, tolerance and dependence or not remains unknown. In the present study, the effects of AQP4 deficiency on morphine analgesia, tolerance and physical dependence were investigated. (1) In hot-plate tests, ED(50) values of morphine analgesia were 3.77 and 3.96 mg/kg in male and female AQP4 knockout mice, which were lower than that in wild-type mice (5.23 and 5.20mg/kg in males and females). (2) Repeated treatment with morphine resulted in analgesic tolerance to morphine in wild-type mice, whereas the morphine tolerance was attenuated in AQP4 knockout mice treated as the same schedule. (3) After repeated morphine administration, naloxone precipitation induced significant abstinent jumping in wild-type mice, whereas naloxone-induced abstinent jumping was not observed in AQP4 knockout mice. This suggested that AQP4 deficiency inhibited the development of morphine physical dependence. (4) Repeated morphine administration down-regulated cerebral glutamate transporter 1 (GLT-1) expression in wild-type mice. However, the down-regulation of GLT-1 expression diminished in AQP4 knockout mice. Taken together, these results demonstrated that AQP4 deficiency potentiated morphine analgesia, attenuated morphine tolerance and physical dependence. The suppression of down-regulation of cerebral GLT1 expression might mediate the attenuation of AQP4 deficiency to morphine tolerance and dependence.


Assuntos
Analgésicos Opioides/farmacologia , Aquaporina 4/deficiência , Aquaporina 4/fisiologia , Dependência de Morfina/fisiopatologia , Morfina/farmacologia , Analgésicos Opioides/administração & dosagem , Análise de Variância , Animais , Aquaporina 4/genética , Western Blotting , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Transportador 2 de Aminoácido Excitatório/metabolismo , Feminino , Temperatura Alta , Masculino , Camundongos , Camundongos Knockout , Morfina/administração & dosagem , Naloxona/farmacologia , Dor/tratamento farmacológico , Dor/fisiopatologia , Medição da Dor , Síndrome de Abstinência a Substâncias/fisiopatologia , Sensação Térmica/efeitos dos fármacos , Sensação Térmica/fisiologia
8.
Eur Neuropsychopharmacol ; 17(12): 790-9, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17604969

RESUMO

The effects of agmatine on morphine-induced locomotion sensitization and morphine-induced changes in extracellular striatal dopamine (DA) and DA metabolites were studied. The locomotor response to morphine challenge (3 mg/kg, s.c.) was enhanced in rats 3 days after repeated morphine administration, indicating development of locomotion sensitization. In vivo microdialysis demonstrated a significant increase in striatal basal levels of the DA metabolites DOPAC and HVA, but not in DA itself, and an increase in DA response to morphine challenge in rats 3 days after withdrawal. Agmatine (1, 10, 80 mg/kg) inhibited morphine-induced locomotion sensitization and the changes in DA noted above. Idazoxan attenuated the effects of agmatine on locomotion, suggesting that the effects are mediated by imidazoline receptors. In addition, repeated morphine also increased the expression of tyrosine hydroxylase mRNA in the VTA after 4 days of morphine pretreatment, while decreasing the expression of dynorphin mRNA at 3 days after withdrawal. Agmatine inhibited morphine-induced changes in dynorphin, but not in tyrosine hydroxylase mRNA expression. These data suggest that agmatine, likely by activating imidazoline receptors, inhibits morphine-induced locomotion sensitization and morphine-induced changes in extracellular DA and in dynorphin expression. Thus, agmatine deserves further study as an anti-opioid medication.


Assuntos
Agmatina/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Locomoção/efeitos dos fármacos , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Antagonistas Adrenérgicos alfa/farmacologia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Dinorfinas/genética , Dinorfinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Homovanílico/metabolismo , Idazoxano/farmacologia , Masculino , Ratos , Ratos Wistar , Fatores de Tempo
9.
Eur J Pharmacol ; 548(1-3): 21-8, 2006 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-16962578

RESUMO

The present study investigated the effects of agmatine action on imidazoline I1 receptor antisera-selected protein (IRAS), a candidate for imidazoline I1 receptor, on prolonged morphine-induced adaptations of calcium signal and long-lasting alterations in gene expression to further elucidate the role of IRAS in opioid dependence. Two cell lines, Chinese hamster ovary cells expressing mu opioid receptor alone (CHO-mu) and expressing mu opioid receptor and IRAS together (CHO-mu/IRAS), were used. After chronic treatment with morphine for 48 h, naloxone induced a significant elevation of intracellular calcium concentration ([Ca2+]i) in CHO-mu and CHO-mu/IRAS cells. Agmatine (0.01-3 microM) concentration-dependently inhibited the naloxone-precipitated [Ca2+]i elevation when co-pretreated with morphine in CHO-mu/IRAS, but not in CHO-mu. Efaroxan, an imidazoline I1 receptor-preferential antagonist, completely reversed the effect of agmatine in CHO-mu/IRAS. Agmatine (1-10 microM) administration after chronic morphine exposure for 48 h partially decreased the [Ca2+]i elevation in CHO-mu/IRAS which was entirely antagonized by efaroxan, but not in CHO-mu. In addition, agmatine (1 microM) co-pretreated with morphine attenuated the naloxone-precipitated increases of cAMP-responsive element binding protein and extracellular signal-regulated kinase 1/2 phosphorylations and c-Fos expression in CHO-mu/IRAS. These effects were blocked by efaroxan as well. Taken together, these results indicate that the agmatine-IRAS action system attenuates the up-regulations of Ca2+ signal and its downstream gene expression in morphine-dependent model in vitro, providing additional evidence to support the contribution of IRAS to opioid dependence.


Assuntos
Agmatina/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Morfina/farmacologia , Transtornos Relacionados ao Uso de Opioides/metabolismo , Receptores de Droga/metabolismo , Animais , Células CHO , Proteína de Ligação a CREB/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Cricetinae , Cricetulus , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Receptores de Imidazolinas , Naloxona/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo
10.
Biochem Pharmacol ; 70(7): 1079-87, 2005 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16112088

RESUMO

Agmatine, an endogenous ligand for the I1-imidazoline receptor, has previously been shown to prevent morphine dependence in rats and mice. To investigate the role of imidazoline receptor antisera-selected protein (IRAS), a strong candidate for I1R, in morphine dependence, two CHO cell lines were created, in which mu opioid receptor (MOR) was stably expressed alone (CHO-mu) or MOR and IRAS were stably co-expressed (CHO-mu/IRAS). After 48 h administration of morphine (10 microM), naloxone induced a cAMP overshoot in both cell lines, suggesting cellular morphine dependence had been produced. Agmatine (0.1-2.5 microM) concentration-dependently inhibited the naloxone-precipitated cAMP overshoot when co-pretreated with morphine in CHO-mu/IRAS, but not in CHO-mu. Agmatine at 5-100 microM also inhibited the cAMP overshoot in CHO/mu and CHO-mu/IRAS. Efaroxan, an I1R-preferential antagonist, completely blocked the effect of agmatine on the cAMP overshoot at 0.1-2.5 microM in CHO-mu/IRAS, while partially reversing the effects of agmatine at 5-100 microM. L-type calcium channel blocker nifedipine entirely mimicked the effects of agmatine at high concentrations on forskolin-stimulated cAMP formation in CHO-mu and naloxone-precipitated cAMP overshoot in morphine-pretreated CHO-mu. Therefore, IRAS, in the co-transfected CHO-mu/IRAS cell line, appears necessary for low concentrations of agmatine to cause attenuation of cellular morphine dependence. An additional effect of agmatine at higher concentrations seems to relate to both transfected IRAS and some naive elements in CHO cells, and L-type voltage-gated calcium channels are not ruled out. This study suggests that IRAS mediates agmatine's high affinity effects on cellular morphine dependence and may play a role in opioid dependence.


Assuntos
Agmatina/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Morfina/farmacologia , Animais , Células CHO , Cricetinae , AMP Cíclico/metabolismo , Maleato de Dizocilpina/farmacologia , Imidazóis/farmacologia , Receptores de Imidazolinas , NG-Nitroarginina Metil Éster/farmacologia , Naloxona/farmacologia , Nifedipino/farmacologia , Óxido Nítrico Sintase/metabolismo
11.
Eur J Pharmacol ; 515(1-3): 99-106, 2005 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-15899480

RESUMO

Our previous studies demonstrated the ability of exogenous agmatine to inhibit tolerance to and physical dependence on morphine in mice, rats and monkeys. The present study further evaluated the effect of agmatine on the psychological dependence induced by morphine in conditioned place preference assay. Agmatine (0.75-20 mg/kg, s.c.) co-administered with morphine during the conditioning sessions completely abolished the acquisition of morphine-induced conditioned place preference in rats, which was associated with activation of imidazoline receptors. Agmatine (0.75-10 mg/kg, s.c.) administered on the test day inhibited the expression of the place preference. After 30 days of extinction of conditioned place preference, agmatine 2.5 and 40 mg/kg inhibited the priming effect of morphine 0.5 mg/kg on the place preference. Furthermore, agmatine inhibited the increased expression of FosB in the nucleus accumbens caused by chronic morphine. All these results suggest that agmatine could inhibit morphine-induced psychological dependence and relapses by affecting the expression of transcription factor FosB.


Assuntos
Agmatina/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Morfina/farmacologia , Animais , Comportamento de Escolha/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Imuno-Histoquímica , Masculino , Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Ratos , Ratos Wistar , Fatores de Transcrição/biossíntese
12.
Pharmacol Biochem Behav ; 77(2): 345-9, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14751463

RESUMO

The present study was designed to examine the effect of agmatine, the decarboxylated product of L-arginine by L-arginine decarboxylase, on convulsion in the mouse maximal electroshock (MES) test and mouse glutamate-induced convulsant test. MES convulsion and glutamate convulsion were respectively induced by an electrical stimulation (110 V, 0.3 s, 8 Hz) and by intracerebroventricular injection of glutamate (0.5 M, pH 7.4, 5microl). The results were expressed as the tonic and clonic time of convulsion in MES or percentage of mice with tonic hind-limb extension in glutamate-induced convulsant assay. Agmatine given intracerebroventricularly (2-16 mg/kg) or subcutaneously (10-160 mg/kg) significantly shortened the tonic and clonic times of convulsion in a dose-dependent manner in the mouse MES test. Glutamate (0.5 M, 5microl icv per mouse) induced an obvious convulsive response indicated by tonic hind-limb extension in mice, and agmatine (2-16 mg/kg icv) decreased the rate of mice with tonic hind-limb extension like NMDA receptor antagonist MK-801. The anticonvulsive effect of agmatine (80 mg/kg sc) on both the tonic and clonic times of convulsion lasted for more than 4 h after administration in the mouse MES test, which was twice that of barbital. Taken together, the results implicate that agmatine has obvious anticonvulsive effects, and its possible mechanism might be related to the antagonism of the function of NMDA receptors.


Assuntos
Agmatina/farmacologia , Anticonvulsivantes , Antagonistas de Aminoácidos Excitatórios/farmacologia , Animais , Maleato de Dizocilpina/farmacologia , Eletrochoque , Ácido Glutâmico/toxicidade , Injeções Intraventriculares , Masculino , Camundongos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Convulsões/induzido quimicamente , Convulsões/fisiopatologia
13.
CNS Neurosci Ther ; 19(1): 12-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23051665

RESUMO

BACKGROUND: Glutamate homeostasis plays a critical role in mediating the addiction-related behaviors. Therefore, preventing the disruption or reestablishing of it is a novel strategy for the treatment of addiction. Glutamate transporters are responsible for clearing extracellular glutamate and maintaining glutamate homeostasis. Our previous work demonstrated that aquaporin-4 (AQP4) deficiency attenuated morphine dependence, but the mechanisms are unclear. According to the recent evidence that AQP4 might form a functional complex with glutamate transporter-1 (GLT-1), this study focused on whether AQP4 participates in the modulation of GLT-1 and glutamate homeostasis in morphine-dependent mice. RESULTS: We found that AQP4 knockout prevented the down-regulations of GLT-1 expression and glutamate clearance when mice were repeatedly treated with morphine. Further study revealed that inhibition of GLT-1 by dihydrokainic acid (DHK) initiated morphine dependence in AQP4 knockout mice. In addition, AQP4 knockout abolished both decreases and increases in the extracellular glutamate levels in the prefrontal cortex during repeated morphine treatment and naloxone-precipitated withdrawal. CONCLUSION: AQP4 deficiency suppresses the down-regulation of GLT-1, and the disruption of glutamate homeostasis caused by repeated exposure to morphine, pointing to a strategy for maintaining glutamate homeostasis and thereby treating addiction through the modulation of AQP4 function and expression.


Assuntos
Aquaporina 4/deficiência , Regulação para Baixo/genética , Transportador 2 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Homeostase/genética , Dependência de Morfina/genética , Dependência de Morfina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Transportador 2 de Aminoácido Excitatório/genética , Homeostase/efeitos dos fármacos , Ácido Caínico/análogos & derivados , Ácido Caínico/uso terapêutico , Camundongos , Camundongos Knockout , Microdiálise , Morfina/administração & dosagem , Dependência de Morfina/tratamento farmacológico , Dependência de Morfina/patologia , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Trítio/metabolismo
14.
Eur J Pharmacol ; 650(1): 200-5, 2011 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-20950603

RESUMO

It has been proved that agmatine inhibits opioid dependence, yet the neural mechanism remains unclear. In the present study, the effect of agmatine on the neuroadaptation of glutamate neurotransmission induced by morphine dependence, including changes of the extracellular glutamate level and glutamate receptors in the nucleus accumbens was investigated. We found that agmatine (2.5-20mg/kg, s.c.) inhibited development of morphine dependence, which was consistent with our previous report. In rats repeatedly treated with morphine, the glutamate level in the nucleus accumbens dialysate was markedly increased after naloxone-precipitated withdrawal. When agmatine (20mg/kg, s.c.) was co-pretreated with morphine or was applied before naloxone-precipitated withdrawal, this elevation of the extracellular glutamate level was inhibited. In the synaptosome model, repeated morphine treatment and naloxone precipitation induced an increase in glutamate release, while agmatine (20mg/kg, s.c.) co-pretreated with morphine reversed the increase of glutamate release. However, neither morphine or agmatine treatment alone nor morphine and agmatine co-administration had any influence on [3H]-glutamate uptake. It indicated that the elevation of the glutamate level in the nucleus accumbens might be caused by the increase of glutamate release of synaptosome in the withdrawal conditions of morphine-dependent rat. Furthermore, agmatine concomitant treatment with morphine entirely abolished the up-regulation of the NR1 subunit of N-methyl-d-aspartate (NMDA) receptors in the nucleus accumbens in repeated morphine-treated rats. Taken together, the present study demonstrated that agmatine could modulate the neuroadaptations of glutamate transmission in the nucleus accumbens in the case of morphine dependence, including modulating extracellular glutamate concentration and NMDA receptor expression.


Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Agmatina/farmacologia , Ácido Glutâmico/metabolismo , Morfina/efeitos adversos , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Transporte Biológico/efeitos dos fármacos , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Microdiálise , Dependência de Morfina/prevenção & controle , Neurônios/citologia , Neurônios/metabolismo , Núcleo Accumbens/citologia , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo
15.
Eur J Pharmacol ; 612(1-3): 1-8, 2009 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-19356733

RESUMO

Moxonidine and rilmenidine are classical imidazoline I(1) receptor agonists, and used as anti-hypertension drugs in clinical practice. Agmatine is an imidazoline I(1) receptor endogenous ligand as well as its agonist, but more and more evidences suggest it has no influence on blood pressure. In the present study we compared the effects of moxonidine, rilmenidine and agmatine in the development of morphine dependence, and investigated the role of imidazoline I(1) receptor in the effects of these agents. Chinese hamster ovary cells co-expressing mu opioid receptor and imidazoline receptor antisera-selected protein (IRAS), the strong candidate for imidazoline I(1) receptor, were used as the cell line. cAMP overshoot, which represents an opioid dependent state in vitro, was measured to study the effects on morphine dependence. siRNA against IRAS was carried out to investigate the role of imidazoline I(1) receptor. Moxonidine and rilmenidine (0.01-10 microM) were ineffective on cAMP level in the cells when given alone, and failed to inhibit chronic morphine exposure, naloxone-precipitated cAMP overshoot when co-pretreated with morphine. Agmatine (0.01-10 microM) by itself was ineffective but co-pretreated with morphine concentration-dependently inhibited chronic morphine exposure, naloxone-precipitated cAMP overshoot in the cells. Furthermore, we found that the inhibitory effect of agmatine (100 nM and 1 microM) on cAMP overshoot was significantly reduced by siRNA against IRAS. This study indicates that agmatine can inhibit the development of morphine dependence in vitro, whereas moxonidine and rilmenidine have no the effect. Imidazoline I(1) receptor plays an important role in agmatine inhibiting morphine dependence.


Assuntos
Agmatina/farmacologia , Anti-Hipertensivos/farmacologia , Imidazóis/farmacologia , Receptores de Imidazolinas/agonistas , Dependência de Morfina/metabolismo , Oxazóis/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/análise , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Rilmenidina , Fatores de Tempo , Transfecção
16.
Pharmacol Biochem Behav ; 92(4): 676-82, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19328824

RESUMO

Our previous studies showed that agmatine inhibits morphine-induced conditioned place preference, locomotor sensitization and drug discrimination in rats. In the present study, we investigated the effects of agmatine on intravenous morphine self-administration in rats. At a dose of 80 mg/kg/infusion, agmatine did not substitute for intravenous morphine (0.5 mg/kg/infusion) self-administration, suggesting that agmatine itself has no reinforcing effect. However, pretreatment with agmatine (40 or 80 mg/kg, i.g.) significantly inhibited the acquisition of intravenous morphine self-administration as assessed by the nose-poke response and morphine intake. The mean number of days required to meet the acquisition criteria for intravenous morphine self-administration was significantly prolonged. After acquisition of intravenous morphine self-administration, chronic administration of agmatine (40 or 80 mg/kg x 30 days, bid, i.g.) during the extinction period significantly prevented the re-acquisition of intravenous morphine self-administration. The ability of agmatine to inhibit the acquisition and re-acquisition of intravenous morphine self-administration suggests a possible use of agmatine in the treatment of opioid dependence.


Assuntos
Agmatina/administração & dosagem , Morfina/administração & dosagem , Animais , Modelos Animais de Doenças , Extinção Psicológica/efeitos dos fármacos , Infusões Intravenosas , Masculino , Entorpecentes/administração & dosagem , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Autoadministração , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/psicologia
17.
J Cell Biochem ; 98(6): 1615-28, 2006 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16598778

RESUMO

Imidazoline receptor antisera-selected protein (IRAS) is considered as a candidate for the I1-imidazoline receptor (I1R), but the signaling pathway mediated by IRAS remains unknown. In our study, the signal transduction pathways of IRAS were investigated in CHO cells stably expressing IRAS (CHO-IRAS), and compared to the native I1R signaling pathways. Rilmenidine or moxonidine (10 nM-100 microM), I1R agonists, failed to stimulate [35S]-GTPgammaS binding in CHO-IRAS cell membrane preparations, suggesting that G protein may not be involved in IRAS signaling pathway. However, incubation of CHO-IRAS with rilmenidine or moxonidine for 5 min could induce an upregulation of phosphatidylcholine-selective phospholipase C (PC-PLC) activity, and an increase in the accumulation of diacylglycerol (DAG), the hydrolysate of PC-PLC, in a concentration-dependent manner. The elevated activation of PC-PLC by rilmenidine or moxonidine (100 nM) could be blocked by efaroxan, a selective I1R antagonist. Cells treated with rilmenidine or moxonidine showed an increased level of extracellular signal-regulated kinase (ERK) phosphorylation in a concentration-dependent manner, which could be reversed by efaroxan or D609, a selective PC-PLC inhibitor. These results suggest that the signaling pathway of IRAS in response to I1R agonists coupled with the activation of PC-PLC and its downstream signal transduction molecule, ERK. These findings are similar to those in the signaling pathways of native I1R, providing some new evidence for the relationship between I1R and IRAS.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Fosfolipases Tipo C/metabolismo , Animais , Células CHO , Membrana Celular/metabolismo , Cricetinae , Diglicerídeos/metabolismo , Relação Dose-Resposta a Droga , Guanosina Trifosfato/metabolismo , Imidazóis/farmacologia , Receptores de Imidazolinas , Ligantes , Oxazóis/farmacologia , Rilmenidina , Transdução de Sinais
18.
Acta Pharmacol Sin ; 26(5): 616-22, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15842783

RESUMO

AIM: To assess the inhibitory effect of agmatine on tumor growth in vivo and tumor cell proliferation in vitro. METHODS: The transplanted animal model, [3H]thymidine incorporation assay,3-[4,5-dimethythiazol-2-yl]-2,5-diphenyltetrazolium assay, and lactate dehydrogenase (LDH) release assay were performed. RESULTS: Agmatine, at doses of 5-40 mg/kg, suppressed the S180 sarcoma tumor growth dose-dependently in mice in vivo and the highest inhibitory ratio reached 31.3% in Kunming mice and 50.0% in Balb/c mice, respectively. Similar results were obtained in the transplanted B16 melanoma tumor model. Agmatine (1-1000 micromol/L) was able to attenuate the proliferation of cultured MCF-7 human breast cancer cells in vitro in a concentration-dependent manner and the highest inhibitory ratio reached 50.3% in the [3H]thymidine incorporation assay. Additionally, in the LDH release assay, spermine (20 micromol/L) and spermidine (20 micromol/L) increased the LDH release significantly, but agmatine (1-1000 micromol/L) did not, indicating that the inhibitory effect of agmatine on the proliferation of MCF was not related to cellular toxicity. In the [3H]thymidine incorporation assay, putrescine (12.5-100.0 micromol/L) could reverse the inhibitory effect of agmatine on the proliferation of MCF concentration-dependently, suggesting that the inhibitory effect of agmatine on the proliferation of MCF might be associated with a decreased level of the intracellular polyamines pool. CONCLUSION: Agmatine had significant inhibitory effect on transplanted tumor growth in vivo and proliferation of tumor cells in vitro, and the mechanism might be a result of inducing decrease of intracellular polyamine contents.


Assuntos
Agmatina/farmacologia , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Poliaminas/metabolismo , Sarcoma 180/patologia , Agmatina/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Humanos , L-Lactato Desidrogenase/metabolismo , Masculino , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Putrescina/farmacologia
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