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1.
Life Sci ; 218: 89-95, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30580018

RESUMO

AIMS: To examine the effects of RQ-00434739, a novel selective TRPM8 antagonist, on deep body temperature (DBT) and normal bladder sensory function and overactivity and its associated facilitation of mechanosensitive primary bladder single-unit afferent activities (SAAs) induced by intravesical l-menthol or prostaglandin E2 (PGE2) instillation in rats. MAIN METHODS: The effect of RQ-00434739 on DBT was evaluated using intravenous administration of RQ-00434739 (1 mg/kg) or its vehicle under urethane anaesthesia. Cystometry (CMG) was performed on conscious and freely moving rats. SAAs were measured from the left L6 dorsal root under urethane anaesthesia, and the fibers were grouped as Aδ- or C-fiber based on their conduction velocity. For both CMG and SAA measurements, after baseline recording with saline instillation, further recording was performed with intravesical l-menthol (6 mM) or PGE2 (60 µM) instillation after pretreatment with intravenous RQ-00434739 (1 mg/kg) or its vehicle. KEY FINDINGS: RQ-00434739 did not significantly affect DBT. In CMG measurements, RQ-00434739 administration increased mean voided volume. Both l-menthol and PGE2 instillation decreased mean voided volume following vehicle pretreatment, whereas such effects were not observed following RQ-00434739 pretreatment. In SAA measurements, either l-menthol or PGE2 instillations increased SAAs of C-fibers, but not SAAs of Aδ-fibers, in the presence of vehicle. RQ-00434739 pretreatment significantly inhibited the l-menthol- and PGE2-induced activation of C-fiber SAAs. SIGNIFICANCE: The present results demonstrate that blockade of TRPM8 channels can inhibit the pathological activation of mechanosensitive C-fibers and suggest that RQ-00434739 may be a promising therapeutic drug candidate for bladder hypersensitive disorders without affecting DBT.


Assuntos
Vias Aferentes/efeitos dos fármacos , Regulação da Temperatura Corporal/efeitos dos fármacos , Dinoprostona/toxicidade , Neurônios Aferentes/efeitos dos fármacos , Canais de Cátion TRPM/antagonistas & inibidores , Doenças da Bexiga Urinária/prevenção & controle , Bexiga Urinária/efeitos dos fármacos , Animais , Células Cultivadas , Masculino , Neurônios Aferentes/metabolismo , Neurônios Aferentes/patologia , Ocitócicos/toxicidade , Ratos , Ratos Sprague-Dawley , Bexiga Urinária/inervação , Bexiga Urinária/metabolismo , Doenças da Bexiga Urinária/induzido quimicamente , Doenças da Bexiga Urinária/metabolismo
2.
Diabetes ; 61(12): 3084-93, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22826028

RESUMO

Brown rice is known to improve glucose intolerance and prevent the onset of diabetes. However, the underlying mechanisms remain obscure. In the current study, we investigated the effect of brown rice and its major component, γ-oryzanol (Orz), on feeding behavior and fuel homeostasis in mice. When mice were allowed free access to a brown rice-containing chow diet (CD) and a high-fat diet (HFD), they significantly preferred CD to HFD. To reduce hypothalamic endoplasmic reticulum (ER) stress on an HFD, mice were administered with 4-phenylbutyric acid, a chemical chaperone, which caused them to prefer the CD. Notably, oral administration of Orz, a mixture of major bioactive components in brown rice, also improved glucose intolerance and attenuated hypothalamic ER stress in mice fed the HFD. In murine primary neuronal cells, Orz attenuated the tunicamycin-induced ER stress. In luciferase reporter assays in human embryonic kidney 293 cells, Orz suppressed the activation of ER stress-responsive cis-acting elements and unfolded protein response element, suggesting that Orz acts as a chemical chaperone in viable cells. Collectively, the current study is the first demonstration that brown rice and Orz improve glucose metabolism, reduce hypothalamic ER stress, and, consequently, attenuate the preference for dietary fat in mice fed an HFD.


Assuntos
Dieta Hiperlipídica , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Preferências Alimentares/efeitos dos fármacos , Oryza/metabolismo , Fenilpropionatos/farmacologia , Animais , Western Blotting , Peso Corporal/efeitos dos fármacos , Células Cultivadas , Ingestão de Alimentos/efeitos dos fármacos , Teste de Tolerância a Glucose , Camundongos , Camundongos Endogâmicos C57BL , Fenilbutiratos/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Triglicerídeos/metabolismo
3.
J Pharmacol Exp Ther ; 328(2): 671-9, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18981288

RESUMO

Inhibition of H(+),K(+)-ATPase is accepted as the most effective way of controlling gastric acid secretion. However, current acid suppressant therapy for gastroesophageal reflux disease, using histamine H(2) receptor antagonists and proton pump inhibitors, does not fully meet the needs of all patients because of their mechanism of action. This study sought to characterize the in vitro and in vivo pharmacology of a novel acid pump antagonist, N-(2-Hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), and to compare it with other acid suppressants. Porcine, canine, and human recombinant gastric H(+),K(+)-ATPase activities were measured by ion-leaky and ion-tight assay. The affinities for a range of receptors, ion channels, and enzymes were determined to analyze selectivity profile. Acid secretion in Ghosh-Schild rats and Heidenhain pouch dogs were measured by titrating perfusate and gastric juice samples. PF-03716556 demonstrated 3-fold greater inhibitory activity than 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine (revaprazan), the only acid pump antagonist that has been available on the market, in ion-tight assay. The compound did not display any species differences, exhibiting highly selective profile including the canine kidney Na(+),K(+)-ATPase. Kinetics experiments revealed that PF-03716556 has a competitive and reversible mode of action. More rapid onset of action than 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-sulfinyl}-benzimidazole (omeprazole) and 3-fold greater potency than revaprazan were observed in Ghosh-Schild rats and Heidenhain pouch dogs. PF-03716556, a novel acid pump antagonist, could improve upon or even replace current pharmacological treatment for gastroesophageal reflux disease.


Assuntos
Aminopiridinas/uso terapêutico , Benzopiranos/uso terapêutico , Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Aminopiridinas/farmacologia , Animais , Antiulcerosos/farmacologia , Antiulcerosos/uso terapêutico , Benzopiranos/farmacologia , Modelos Animais de Doenças , Cães , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Omeprazol/farmacologia , Omeprazol/uso terapêutico , Inibidores da Bomba de Prótons/farmacologia , Ratos , Ratos Sprague-Dawley , Estômago/fisiopatologia , Suínos
4.
Biochem Biophys Res Commun ; 365(2): 344-8, 2008 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-17996730

RESUMO

GPR35, previously an orphan G-protein coupled receptor, is a receptor for kynurenic acid. Here we examine the distribution of GPR35 in the rat dorsal root ganglion (DRG) and the effects of its selective activation. GPR35 was expressed predominantly by small- to medium-diameter neurons of the DRG. Many of these same neurons also expressed the transient receptor potential vanilloid 1 channel, a nociceptive neuronal marker. The GPR35 agonists kynurenic acid and zaprinast inhibited forskolin-stimulated cAMP production by cultured rat DRG neurons. Inhibition required G(i/o) proteins as the effect was completely abolished by pretreatment with pertussis toxin. This is the first study to report the expression and function of GPR35 in rat nociceptive DRG neurons. We propose that GPR35 modulates nociception and that continued study of this receptor will provide additional insight into the role of kynurenic acid in pain perception.


Assuntos
Gânglios Espinais/metabolismo , Ácido Cinurênico/administração & dosagem , Células do Corno Posterior/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Células Cultivadas , Gânglios Espinais/efeitos dos fármacos , Células do Corno Posterior/efeitos dos fármacos , Ratos
5.
Regul Pept ; 146(1-3): 80-7, 2008 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-17870192

RESUMO

Motilin, a 22-amino acid peptide hormone secreted by endocrine cells of the intestinal mucosa, plays an important role in the regulation of gastrointestinal motility. The actions of motilin agonists have been extensively investigated in dogs due to physiological similarities between the dog and human alimentary tracts. The amino acid sequence of the dog motilin receptor, however, was previously unknown. We have cloned a cDNA from dog stomach corresponding to the motilin receptor. The deduced protein shared 71% and 72% sequence identity with the human and rabbit motilin receptors, respectively. Expression of the dog motilin receptor in CHO cells promoted the typical cellular responses to the agonists, motilin and erythromycin. The rank order of potency determined for these agonists was similar to that found for the human motilin receptor, with motilin being more potent than erythromycin. Immunohistochemistry of the dog stomach revealed that the motilin receptor was localized in neuronal cell bodies and fibers. This is the first study detailing the cloning, expression, and functional characterization of the dog motilin receptor. Determination of the full sequence and functional properties of the dog motilin receptor will provide useful information enabling us to interpret previous and future studies of motilin agonists in dogs.


Assuntos
Receptores dos Hormônios Gastrointestinais/genética , Receptores de Neuropeptídeos/genética , Estômago/química , Sequência de Aminoácidos , Animais , Sequência de Bases , Linhagem Celular , Células Cultivadas , Clonagem Molecular , DNA Complementar/genética , Cães , Mucosa Gástrica/metabolismo , Humanos , Dados de Sequência Molecular , RNA Mensageiro/biossíntese , Coelhos , Receptores dos Hormônios Gastrointestinais/análise , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores de Neuropeptídeos/análise , Receptores de Neuropeptídeos/metabolismo , Alinhamento de Sequência
6.
J Neurosci Methods ; 165(1): 49-54, 2007 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17597226

RESUMO

Sensory information is conveyed to the central nervous system by primary afferent neurons within dorsal root ganglia (DRG), which synapse onto neurons of the dorsal horn of the spinal cord. This synaptic connection is central to the processing of both sensory and pain stimuli. Here, we describe a model system to monitor synaptic transmission between DRG neurons and dorsal horn neurons that is compatible with high-throughput screening. This co-culture preparation comprises DRG and dorsal horn neurons and utilizes Ca(2+) imaging with the indicator dye Fura-2 to visualize synaptic transmission. Addition of capsaicin to co-cultures stimulated DRG neurons and led to activation of dorsal horn neurons as well as increased intracellular Ca(2+) concentrations. This effect was dose-dependent and absent when DRG neurons were omitted from the culture. NMDA receptors are a critical component of synapses between DRG and dorsal horn neurons as MK-801, a use-dependent non-competitive antagonist, prevented activation of dorsal horn neurons following capsaicin treatment. This model system allows for rapid and efficient analysis of noxious stimulus-evoked Ca(2+) signal transmission and provides a new approach both for investigating synaptic transmission in the spinal cord and for screening potential analgesic compounds.


Assuntos
Cálcio/metabolismo , Diagnóstico por Imagem/métodos , Gânglios Espinais/metabolismo , Células do Corno Posterior/metabolismo , Transmissão Sináptica/fisiologia , Vias Aferentes/fisiologia , Animais , Técnicas de Cocultura , Corantes Fluorescentes , Fura-2 , Ratos
7.
J Pharmacol Exp Ther ; 322(2): 686-94, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17495127

RESUMO

The prostaglandin (PG) EP(4) receptor subtype is expressed by peripheral sensory neurons. Although a potential role of EP(4) receptor in pain has been suggested, a limited number of selective ligands have made it difficult to explore the physiological functions of EP(4) or its potential as a new analgesic target. Here, we describe the in vitro and in vivo pharmacology of a novel EP(4) receptor antagonist, N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) phenyl]ethyl}amino) carbonyl]-4-methylbenzenesulfonamide (CJ-023,423). In vitro, CJ-023,423 inhibits [(3)H]PGE(2) binding to both human and rat EP(4) receptors with K(i) of 13 +/- 4 and 20 +/- 1 nM, respectively. CJ-023,423 is highly selective for the human EP(4) receptor over other human prostanoid receptor subtypes. It also inhibits PGE(2)-evoked elevation in intracellular cAMP at the human and rat EP(4) receptors with pA(2) of 8.3 +/- 0.03 and 8.2 +/- 0.2 nM, respectively. In vivo, oral administration of CJ-023,423 significantly reduces thermal hyperalgesia induced by intraplantar injection of PGE(2) (ED(50) = 12.8 mg/kg). CJ-023,423 is also effective in models of acute and chronic inflammatory pain. CJ-023,423 significantly reduces mechanical hyperalgesia in the carrageenan model. Furthermore, CJ-023,423 significantly reverses complete Freund's adjuvant-induced chronic inflammatory pain response. Taken together, the present data indicate that CJ-023,423, a highly potent and selective antagonist of both human and rat EP(4) receptors, produces antihyperalgesic effects in animal models of inflammatory pain. Thus, specific blockade of the EP(4) receptor signaling may represent a novel therapeutic approach for the treatment of inflammatory pain.


Assuntos
Analgésicos/farmacologia , Hiperalgesia/tratamento farmacológico , Receptores de Prostaglandina E/antagonistas & inibidores , Sulfonamidas/farmacologia , Analgésicos/química , Analgésicos/metabolismo , Animais , Ligação Competitiva , Carragenina/toxicidade , Linhagem Celular , Células Cultivadas , AMP Cíclico/metabolismo , Dinoprostona/metabolismo , Dinoprostona/farmacologia , Relação Dose-Resposta a Droga , Adjuvante de Freund/toxicidade , Gânglios Espinais/citologia , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Masculino , Estrutura Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Dor/induzido quimicamente , Dor/tratamento farmacológico , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E/genética , Receptores de Prostaglandina E/metabolismo , Receptores de Prostaglandina E Subtipo EP4 , Sulfonamidas/química , Sulfonamidas/metabolismo , Fatores de Tempo , Transfecção
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