RESUMEN
In this study, we attempted to clarify a role of prostaglandin (PG) I2 and its specific receptor, IP in the pathogenesis of irritable bowel syndrome (IBS) using a maternal separation (MS)-induced IBS model. Administration of beraprost (BPS), a specific IP agonist, improved visceral hypersensitivity and depressive state with decreased serum CRF level in the IBS rats. To clarify the mechanism of the effect of BPS, we performed serum metabolome analysis and 1-methylnicotinamide (1-MNA) was identified as a possible candidate for a clue metabolite of pathogenesis of IBS. The serum 1-MNA levels revealed inverse correlation to the level of visceral sensitivity, and positive correlation to a depression marker, immobilizing time. Administration of 1-MNA induced visceral hypersensitivity and depression with increased levels of serum CRF. Since fecal 1-MNA is known for a marker of dysbiosis, we examined the composition of fecal microbiota by T-RFLP analysis. The proportion of clostridium cluster XI, XIVa and XVIII was significantly changed in MS-induced IBS rats treated with BPS. Fecal microbiota transplant of BPS-treated rats improved visceral hypersensitivity and depression in IBS rats. These results suggest for the first time that PGI2-IP signaling plays an important role in IBS phenotypes such as visceral hypersensitivity and depressive state. BPS modified microbiota, thereby inhibition of 1-MNA-CRF pathway, followed by improvement of MS-induced IBS phenotype. These results suggest that the PGI2-IP signaling could be considered to be a therapeutic option for IBS.
Asunto(s)
Síndrome del Colon Irritable , Ratas , Animales , Síndrome del Colon Irritable/metabolismo , Eje Cerebro-Intestino , Epoprostenol , Privación Materna , HecesRESUMEN
Objective Epipericardial fat necrosis (EFN) has been considered to be a rare cause of acute chest pain, and especially important for emergency physicians. Chest computed tomography (CT) is often used for the diagnosis of EFN after excluding life-threatening states, such as acute coronary syndrome and pulmonary embolism. While the proportion of EFN patients who underwent chest CT in emergency departments is being clarified, little is still known about other departments in Japan. To investigate the proportion of EFN patients who underwent chest CT for acute chest pain in various departments. Methods Chest CT performed from January 2015 to July 2020 in Asahikawa Medical University Hospital in Japan was retrospectively analyzed in this study. All images were reviewed by two radiologists. Results There were 373 outpatients identified by a search using the word 'chest pain' who underwent chest CT. Eight patients satisfying the imaging criteria were diagnosed with EFN. The proportions of patients diagnosed with EFN were 10.7%, 4.8%, 2.8%, 0.9% and 0% in the departments of general medicine, cardiovascular surgery, emergency medicine, cardiovascular internal medicine and respiratory medicine, respectively. Only 12.5% of the patients were correctly diagnosed with EFN, and the other patients were treated for musculoskeletal symptoms, acute pericarditis or hypochondriasis. Conclusion EFN is not rare and is often overlooked in various departments. All physicians as well as emergency physicians should consider the possibility of EFN as the cause of pleuritic chest pain.
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Necrosis Grasa , Dolor en el Pecho/diagnóstico por imagen , Dolor en el Pecho/etiología , Diagnóstico Diferencial , Necrosis Grasa/complicaciones , Necrosis Grasa/diagnóstico por imagen , Humanos , Japón , Pericardio/diagnóstico por imagen , Estudios RetrospectivosRESUMEN
Brain oxytocin plays a role in gastrointestinal functions. Among them, oxytocin acts centrally to modulate gastrointestinal motility and visceral sensation. Intestinal barrier function, one of important gut functions, is also regulated by the central nervous system. Little is, however, known about a role of central oxytocin in the regulation of intestinal barrier function. The present study was performed to clarify whether brain oxytocin is also involved in regulation of intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of oxytocin dose-dependently abolished increased colonic permeability in response to lipopolysaccharide while intraperitoneal injection of oxytocin at the same dose failed to block it. Either atropine or surgical vagotomy blocked the central oxytocin-induced improvement of colonic hyperpermeability. Cannabinoid 1 receptor antagonist but not adenosine or opioid receptor antagonist prevented the central oxytocin-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of oxytocin receptor antagonist blocked the ghrelin- or orexin-induced improvement of intestinal barrier function. These results suggest that oxytocin acts centrally in the brain to reduce colonic hyperpermeability. The vagal cholinergic pathway or cannabinoid 1 receptor signaling plays a vital role in the process. The oxytocin-induced improvement of colonic hyperpermeability mediates the central ghrelin- or orexin-induced improvement of intestinal barrier function. We would therefore suggest that activation of central oxytocin signaling may be useful for leaky gut-related diseases such as irritable bowel syndrome and autism.
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Cannabinoides , Oxitocina , Animales , Encéfalo , Cannabinoides/farmacología , Ghrelina/farmacología , Orexinas/farmacología , Oxitocina/farmacología , Ratas , Ratas Sprague-Dawley , Nervio VagoRESUMEN
BACKGROUND: Irritable bowel syndrome is a functional gastrointestinal disease. Visceral hypersensitivity is the most important pathophysiology in irritable bowel syndrome. Currently, diagnosis of irritable bowel syndrome is based on symptoms and exclusion of other organic diseases. Although the diagnosis of irritable bowel syndrome can be made based on the Rome IV criteria, one may speculate that complete exclusion of other organic diseases is not so easy, especially in cases uncontrolled with standard therapies. CASE PRESENTATION: We present herein a case of familial Mediterranean fever in a young Japanese patient who had been suffering from an irritable bowel syndrome-like clinical course. A 25-year-old Japanese male had been diagnosed as having diarrhea-predominant irritable bowel syndrome 5 years earlier. Unfortunately, standard therapies failed to improve irritable bowel syndrome symptoms. After careful medical history-taking, we understood that he had also experienced periodic fever since 10 years ago. Although no mutation was identified in the Mediterranean fever gene, not only periodic fever but abdominal symptoms improved completely after colchicine administration. He was therefore diagnosed as having familial Mediterranean fever and that the abdominal symptoms may be related to the disease. CONCLUSIONS: Familial Mediterranean fever should be considered as a cause of irritable bowel syndrome-like symptoms.
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Amiloidosis , Fiebre Mediterránea Familiar , Síndrome del Colon Irritable , Adulto , Colchicina/uso terapéutico , Diarrea/tratamiento farmacológico , Diarrea/etiología , Fiebre Mediterránea Familiar/complicaciones , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Fiebre/tratamiento farmacológico , Humanos , Síndrome del Colon Irritable/complicaciones , Síndrome del Colon Irritable/diagnóstico , Síndrome del Colon Irritable/tratamiento farmacológico , MasculinoRESUMEN
Short chain fatty acids readily crosses the gut-blood and blood-brain barrier and acts centrally to influence neuronal signaling. We hypothesized that butyrate, a short-chain fatty acid produced by bacterial fermentation, in the central nervous system may play a role in the regulation of intestinal functions. Colonic permeability and visceral sensation was evaluated in rats. Septic lethality was evaluated in a sepsis model induced by subcutaneous administration of both lipopolysaccharide and colchicine. Intracisternal butyrate dose-dependently improved colonic hyperpermeability and visceral nociception. In contrast, subcutaneous injection of butyrate failed to change it. Intracisternal orexin 1 receptor antagonist or surgical vagotomy blocked the central butyrate-induced improvement of colonic hyperpermeability. The improvement of intestinal hyperpermeability by central butyrate or intracisternal orexin-A was blocked by cannabinoid 1 or 2 receptor antagonist. Intracisternal butyrate significantly improved survival period in septic rats. These results suggest that butyrate acts in the central nervous system to improve gut permeability and visceral nociception through cannabinoid signaling. Endogenous orexin in the brain may mediate the reduction of intestinal hyperpermeability by central butyrate through the vagus nerve. We would suggest that improvement of leaky gut by central butyrate may induce visceral antinociception and protection from septic lethality.
Asunto(s)
Butiratos/farmacología , Colon/metabolismo , Ácidos Grasos Volátiles/farmacología , Nocicepción/efectos de los fármacos , Choque Séptico/mortalidad , Vísceras/fisiología , Animales , Encéfalo/metabolismo , Butiratos/administración & dosificación , Colchicina/efectos adversos , Modelos Animales de Enfermedad , Ácidos Grasos Volátiles/administración & dosificación , Lipopolisacáridos/efectos adversos , Masculino , Orexinas/metabolismo , Orexinas/fisiología , Permeabilidad , Ratas Sprague-Dawley , Choque Séptico/inducido químicamente , Choque Séptico/prevención & control , Vísceras/efectos de los fármacosRESUMEN
Leaky gut that is a condition reflecting intestinal barrier dysfunction has been attracting attention for its relations with many diseases such as irritable bowel syndrome or Alzheimer dementia. We have recently demonstrated that ghrelin acts in the brain to improve leaky gut via the vagus nerve. In the present study, we tried to clarify the precise central mechanisms by which ghrelin improves intestinal barrier function through the vagus nerve. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), blocked the intracisternal ghrelin-induced improvement of intestinal hyperpermeability while dopamine, cannabinoid or opioid receptor antagonist failed to prevent it. Since DPCPX can block adenosine A1 and adenosine A2B receptors, we examined which subtype is involved in the mechanism. Intracisternal injection of adenosine A2B agonist but not adenosine A1 agonist improved colonic hyperpermeability, while peripheral injection of adenosine A2B agonist failed to improve it. Intracisternal adenosine A2B agonist-induced improvement of colonic hyperpermeability was blocked by vagotomy. Adenosine A2B specific antagonist, alloxazine blocked the ghrelin- or central vagal stimulation by 2-deoxy-d-glucose-induced improvement of intestinal hyperpermeability. These results suggest that activation of adenosine A2B receptors in the central nervous system is capable of improving intestinal barrier function through the vagal pathway, and the adenosine A2B receptors may mediate the ghrelin-induced improvement of leaky gut in a vagal dependent fashion. These findings may help us understand the pathophysiology in not only gastrointestinal diseases but also non-gastrointestinal diseases associated with the altered intestinal permeability.
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Encéfalo/metabolismo , Ghrelina/metabolismo , Mucosa Intestinal/metabolismo , Receptor de Adenosina A2B/metabolismo , Nervio Vago/metabolismo , Agonistas del Receptor de Adenosina A2/administración & dosificación , Antagonistas del Receptor de Adenosina A2/administración & dosificación , Animales , Encéfalo/efectos de los fármacos , Ghrelina/administración & dosificación , Humanos , Inyecciones Subcutáneas , Mucosa Intestinal/efectos de los fármacos , Masculino , Permeabilidad/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Nervio Vago/efectos de los fármacosRESUMEN
Orexins are neuropeptides implicated in several physiological functions. Accumulating findings suggest a relationship between orexin and sepsis. A recent study demonstrated that orexin acts centrally to improve conditions in sepsis. The present study aims to clarify the precise mechanisms by which central orexin could induce a protective action against septic conditions. We established a new septic model by treating rats with lipopolysaccharide (LPS) and colchicine and used this to examine the effect of brain orexin on survival. Observation of survival was stopped three days after the chemicals injection or at death. We established a lethal model (rats died within 24 h) by injecting subcutaneously a combination of 1 mg/kg LPS and 1 mg/kg colchicine. A Toll-like receptor 4 (TLR4) inhibitor completely blocked lethality, suggesting a vital role of LPS-TLR4 signaling in the process. Intracisternal orexin-A dose-dependently reduced lethality in the sepsis model while neither intracisternal orexin-B nor intraperitoneal orexin-A changed the mortality rate. Vagal stimulation with carbachol or 2-deoxy-D-glucose improved survival and atropine potently blocked the protection by carbachol or 2-deoxy-D-glucose. The orexin-A-induced reduction of lethality was significantly blocked by atropine or surgical vagotomy. Intracisternal injection of an OX1 receptor antagonist blocked the improvement of survival by intracisternal injection of orexin-A, carbachol, or 2-deoxy-D-glucose. These results suggest that orexin acts centrally to reduce the lethality in our septic model treated (LPS and colchicine). Activation of the vagal cholinergic pathway may mediate the action of orexin, and the OX1 receptor in the brain might play a role in the process. Since the efferent vagus nerve mediates anti-inflammatory mechanisms, we speculate that the vagal cholinergic anti-inflammatory pathway is implicated in the mechanisms of septic lethality reduction by brain orexin.
Asunto(s)
Neuronas Colinérgicas/efectos de los fármacos , Colchicina/toxicidad , Lipopolisacáridos/toxicidad , Orexinas/administración & dosificación , Sepsis/prevención & control , Nervio Vago/efectos de los fármacos , Animales , Neuronas Colinérgicas/fisiología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-Dawley , Sepsis/inducido químicamente , Sepsis/mortalidad , Tasa de Supervivencia/tendencias , Nervio Vago/fisiologíaRESUMEN
Brain ghrelin plays a role in gastrointestinal functions. Among them, ghrelin acts centrally to stimulate gastrointestinal motility and induce visceral antinociception. Intestinal barrier function, one of important gastrointestinal functions, is also controlled by the central nervous system. Little is, however, known about a role of central ghrelin in regulation of intestinal permeability. The present study was performed to clarify whether brain ghrelin is also involved in regulation of intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of ghrelin dose-dependently abolished increased colonic permeability in response to LPS while intraperitoneal injection of ghrelin at the same dose or intracisternal injection of des-acyl-ghrelin failed to block it. Carbachol potently attenuated LPS-induced intestinal hyperpermeability, and atropine or bilateral subdiaphragmatic vagotomy prevented the improvement of intestinal hyperpermeability by central ghrelin. Intracisternal (D-Lys3)-GHRP-6, a selective ghrelin receptor antagonist, significantly blocked improvement of intestinal barrier function by intravenously administered 2-deoxy-d-glucose, central vagal stimulant. Intracisternal injection of orexin 1 receptor antagonist, SB-334867 blocked intracisternal ghrelin-induced improvement of colonic hyperpermeability. These results suggest that exogenously administered or endogenously released ghrelin acts centrally to improve a disturbed intestinal barrier function through orexinergic signaling and the vagal cholinergic pathway. Central ghrelin may be involved in the pathophysiology and be a novel therapeutic option in not only gastrointestinal diseases such as irritable bowel syndrome but also non-gastrointestinal diseases associated with the altered intestinal permeability.
Asunto(s)
Colon/efectos de los fármacos , Ghrelina/metabolismo , Ghrelina/farmacología , Permeabilidad/efectos de los fármacos , Nervio Vago/efectos de los fármacos , Nervio Vago/fisiología , Animales , Encéfalo/metabolismo , Carbacol/farmacología , Colon/metabolismo , Desoxiglucosa , Intestinos/fisiología , Lipopolisacáridos/farmacología , Masculino , Antagonistas de los Receptores de Orexina/farmacología , Orexinas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Ghrelina/antagonistas & inhibidores , Receptores de Ghrelina/metabolismoRESUMEN
We have recently demonstrated that levodopa acts centrally to induce antinociceptive action against colonic distension through dopamine D2 receptors in rats. Since serotonin (5-HT) and cannabinoid are involved in the regulation of visceral sensation, we hypothesized that they may contribute to levodopa-induced visceral antinociception. We evaluated visceral sensation by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneously administered levodopa increased the threshold of colonic distension-induced AWR; moreover, an intracisternal injection of methiothepin, an unspecific 5-HT receptor antagonist, blocked the levodopa-induced visceral antinociception. Subsequently, we examined the roles of three 5-HT receptor subtypes: 5-HT1A, 5-HT1B, and 5-HT2A, in levodopa-induced visceral antinociception. Ketanserin is a 5-HT2A receptor antagonist that was intracisternally injected and blocked the levodopa-induced antinociception, but neither WAY100635 (5-HT1A receptor antagonist) nor isomoltane (5-HT1B receptor antagonist) did so. Antagonists AM251 (cannabinoid 1 receptor antagonist) or AM630 (cannabinoid 2 receptor antagonist) did not change the levodopa-induced visceral antinociception, suggesting that cannabinoid signaling may not be implicated in levodopa-induced visceral antinociception. We also examined the relation between dopamine D2 and 5-HT2A receptor signaling in the control of visceral sensation. Ketanserin, but not WAY100635, potently blocked the visceral antinociception by quinpirole, which is a dopamine D2 agonist. These results suggest that 5-HT2A receptors in the central nervous system may play specific roles in levodopa-dopamine D2 receptor-induced antinociceptive action against colonic distension.
Asunto(s)
Analgésicos/farmacología , Encéfalo/efectos de los fármacos , Colon/inervación , Levodopa/farmacología , Dolor Nociceptivo/prevención & control , Umbral del Dolor/efectos de los fármacos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Humanos , Nocicepción/efectos de los fármacos , Dolor Nociceptivo/metabolismo , Dolor Nociceptivo/fisiopatología , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Cannabinoides/metabolismoRESUMEN
We have recently demonstrated that N(6)-cyclopentyladenosine (CPA), an adenosine A1 receptor agonist, acts centrally to induce a visceral antinociception. Since serotonin (5-HT), cannabinoid (CB), dopamine or opioid signaling in the central nervous system is involved in the regulation of visceral sensation, we made a hypothesis that the signaling may play a role in the CPA-induced visceral antinociception. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneously administered CPA significantly increased the threshold of colonic distension-induced AWR. Intracisternal injection of either 5-HT1A or 5-HT2A receptor antagonist blocked the CPA-induced visceral antinociception while 5-HT1B antagonist did not block the CPA-induced visceral antinociception. Subcutaneous injection of dopamine D1 receptor antagonist, CB1 receptor antagonist or naloxone significantly blocked the CPA-induced visceral antinociception while neither subcutaneous injection of dopamine D2 receptor antagonist nor CB2 receptor antagonist blocked the CPA-induced anti-pain action. These results suggest that 5-HT1A, 5-HT2A, dopamine D1, CB1 receptors and the opioid system in the CNS may specifically mediate the CPA-induced visceral antinociception. These findings may help in understanding the physiological relevance of central adenosine with special reference to the pathophysiology of altered visceral sensation especially in irritable bowel syndrome.
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Agonistas del Receptor de Adenosina A1/farmacología , Analgésicos Opioides , Cannabinoides , Analgésicos , Animales , Sistema Nervioso Central , Dopamina , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1 , Receptor Cannabinoide CB2 , Receptor de Serotonina 5-HT1A , Receptor de Serotonina 5-HT2A , Receptores de Dopamina D1 , SerotoninaRESUMEN
Orexins are neuropeptides that are implicated in a number of functions. With regard to the gastrointestinal functions, orexin acts centrally to regulate gastric secretion, gastrointestinal motility and visceral sensation. Little is however known about a role of central orexin in the control of intestinal barrier function. The present study was performed to clarify whether brain orexin plays a role in the control of intestinal permeability. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternally administered orexin-A but not orexin-B dose-dependently blocked the increased intestinal permeability by lipopolysaccharide (LPS) or corticotropin-releasing factor while intraperitoneally injected orexin-A failed to block it. Atropine or vagotomy abolished the action by central orexin-A. Intravenous injection of 2-deoxy-D-glucose (2-DG), a central vagal stimulant, significantly blocked the LPS-induced increase in intestinal permeability and atropine prevented the action of 2-DG. Intracisternal injection of SB-334687, a selective orexin 1 receptor antagonist, significantly blocked the action of 2-DG-induced improvement of intestinal hyperpermeability. These results suggest that exogenously administered or endogenously released orexin acts centrally to improve the intestinal hyperpermeability by LPS via the vagal cholinergic pathway. The findings also suggest for the first time that the brain could control intestinal permeability. The neuronal rapid protective advantage to the host by improving the intestinal barrier function by the neuropeptide may help us understand the brain-gut interaction in stress sensitive gastrointestinal disorders like irritable bowel syndrome associated with the altered intestinal permeability.
Asunto(s)
Colon/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Antagonistas Muscarínicos/farmacología , Antagonistas de los Receptores de Orexina/farmacología , Orexinas/farmacología , Permeabilidad/efectos de los fármacos , Nervio Vago/efectos de los fármacos , Animales , Antimetabolitos/farmacología , Atropina/farmacología , Benzoxazoles/farmacología , Colon/metabolismo , Desoxiglucosa/farmacología , Vías Eferentes , Mucosa Intestinal/metabolismo , Lipopolisacáridos/farmacología , Naftiridinas/farmacología , Orexinas/metabolismo , Ratas , Espacio Subaracnoideo , Urea/análogos & derivados , Urea/farmacología , Vagotomía , Nervio Vago/fisiologíaRESUMEN
Platelets play an important role in both physiological hemostasis and pathological thrombosis. Thromboxane (TX) A2 and prostaglandin (PG) I2 are well known as a potent stimulator and an inhibitor of platelet function, respectively. Recently, PGE2 has also been reported to regulate platelet function via PGE2 receptor subtypes. However, the effect of PGF2α on platelet function remains to be determined. The aim of the present study was to clarify the effect of PGF2α on murine platelet function both in vitro and in vivo. Platelets prepared from wild-type mice (WT platelets) expressed several types of prostanoid receptors, including the PGE2 receptor subtype EP3 and the TXA2 receptor TP, while expression of the PGF2α receptor FP was not detected. In WT platelets, PGF2α potentiated adenosine diphosphate-induced aggregation in a concentration-dependent manner, while PGF2α alone did not induce aggregation. In platelets prepared from mice lacking FP, however, PGF2α-induced potentiation was not significantly different from that in WT platelets. Interestingly, the potentiation was significantly blunted in platelets lacking EP3 or TP and disappeared completely in platelets lacking both EP3 and TP. Accordingly, PGF2α decreased the cyclic adenosine monophosphate level via EP3 and increased the inositol triphosphate level via TP in WT platelets. Intravenously administered PGF2α significantly shortened the bleeding time and aggravated arachidonic acid-induced acute thromboembolism in WT mice, suggesting that PGF2α works as a platelet stimulator also in vivo. In conclusion, PGF2α potentiates platelet aggregation in vitro via EP3 and TP but not FP. Accordingly, PGF2α facilitates hemostasis and thromboembolism in vivo.
Asunto(s)
Activación Plaquetaria , Subtipo EP3 de Receptores de Prostaglandina E/metabolismo , Receptores de Tromboxano A2 y Prostaglandina H2/metabolismo , Animales , Tiempo de Sangría , Plaquetas/metabolismo , AMP Cíclico/metabolismo , Dinoprost , Femenino , Hemostasis , Humanos , Fosfatos de Inositol/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Adhesividad Plaquetaria , Agregación Plaquetaria , Tromboembolia/sangreRESUMEN
BACKGROUND AND AIM: Metformin has been shown to have anti-cytokine property. Lipopolysaccharide (LPS)-induced or repeated water avoidance stress (WAS)-induced visceral allodynia and increased gut permeability were pro-inflammatory cytokine-dependent responses, which were considered to be animal models of irritable bowel syndrome (IBS). We hypothesized that metformin improves symptoms in the patients with IBS by attenuating these visceral changes and tested the hypothesis in rats. METHODS: The threshold of the visceromotor response induced by colonic balloon distention was measured. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue for 15 min spectrophotometrically. RESULTS: Subcutaneously injected LPS (1 mg/kg) reduced the threshold of visceromotor response, and metformin (5-50 mg/kg for 3 days) intraperitoneally attenuated this response in a dose-dependent manner. Repeated WAS (1 h daily for 3 days) induced visceral allodynia, which was also blocked by metformin. The antinociceptive effect of metformin on the LPS-induced allodynia was reversed by compound C, an adenosine monophosphate-activated protein kinase inhibitor or NG -nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor but not modified by naloxone. Additionally, it was blocked by sulpiride, a dopamine D2 receptor antagonist, but domperidone, a peripheral dopamine D2 receptor antagonist, did not alter it. Metformin also blocked the LPS-induced or repeated WAS-induced increased colonic permeability. CONCLUSIONS: Metformin attenuated the visceral allodynia and increased gut permeability in animal IBS models. These actions may be evoked via activation of adenosine monophosphate-activated protein kinase, nitric oxide, and central dopamine D2 pathways. These results indicate the possibility that metformin can be useful for treating IBS.
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Azul de Evans/metabolismo , Hiperalgesia/prevención & control , Hipoglucemiantes/uso terapéutico , Mucosa Intestinal/metabolismo , Síndrome del Colon Irritable/fisiopatología , Metformina/uso terapéutico , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Animales , Colon/metabolismo , Modelos Animales de Enfermedad , Domperidona/farmacología , Antagonistas de Dopamina/farmacología , Hiperalgesia/etiología , Hipoglucemiantes/farmacología , Síndrome del Colon Irritable/inducido químicamente , Lipopolisacáridos , Masculino , Metformina/farmacología , NG-Nitroarginina Metil Éster/farmacología , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Nocicepción/efectos de los fármacos , Permeabilidad/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Estrés Fisiológico , Sulpirida/farmacologíaRESUMEN
Central oxytocin is implicated in a wide variety of physiological functions. With regard to gastrointestinal functions, oxytocin acts centrally to regulate gastrointestinal motility. Visceral sensation is also known as one of key gastrointestinal functions which are controlled by the central nervous system (CNS). Little is, however, known about a role of central oxytocin in visceral sensation. The present study was therefore performed to clarify whether oxytocin in the CNS may be involved in visceral sensation. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternally administered oxytocin increased the threshold volume of colonic distension-induced AWR while intraperitoneal injection of oxytocin did not alter the threshold volume. Pretreatment with subcutaneous injection of naloxone hydrochloride, a peripheral and central opioid antagonist, blocked the oxytocin-induced visceral antinociception while neither subcutaneous injection of naloxone methiodide, a peripheral selective opioid antagonist, sulpiride, a dopamine D2 receptor antagonist, DPCPX, an adenosine A1 receptor antagonist, AM251, a cannabinoid 1 receptor antagonist nor AM630, a cannabinoid 2 receptor antagonist blocked the antinociception. Intracisternally administered oxytocin antagonist, L368,899 significantly blocked the intracisternal orexin-A-induced visceral antinociception. These results suggest that oxytocin specifically acts in the CNS to enhance antinociceptive response to colonic distension through the central opioid system. The oxytocin signaling may mediate the central orexin-induced visceral antinociception.
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Analgésicos/farmacología , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Nocicepción/efectos de los fármacos , Oxitocina/farmacología , Reflejo/efectos de los fármacos , Antagonistas del Receptor de Adenosina A1/farmacología , Animales , Canfanos/farmacología , Agonistas de Receptores de Cannabinoides/farmacología , Antagonistas de los Receptores de Dopamina D2/farmacología , Antagonistas de Hormonas/farmacología , Indoles/farmacología , Masculino , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Oxitocina/antagonistas & inhibidores , Sulpirida/farmacología , Xantinas/farmacologíaRESUMEN
We hypothesized that the cannabinoid (CB) system may mediate the brain orexin- or ghrelin-induced visceral antinociception. Intraperitoneal injection of either CB1/2 agonist, WIN 55212 or O-Arachidonoyl ethanolamine increased the threshold volume of colonic distension-induced abdominal withdrawal reflex in rats, suggesting CB could induce visceral antinociception. Pretreatment with either the CB1 or CB2 antagonist potently blocked the centrally injected orexin-A-induced antinociceptive action against colonic distension while CB2 but not CB1 antagonist blocked the brain ghrelin-induced visceral antinociception. These results suggest that the cannabinoid signaling may be involved in the central orexin- or ghrelin-induced antinociceptive action in a different mechanistic manner.
Asunto(s)
Analgésicos/farmacología , Analgésicos/uso terapéutico , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Estado de Conciencia/fisiología , Ghrelina/fisiología , Orexinas/fisiología , Dolor Visceral/tratamiento farmacológico , Animales , Benzoxazinas/farmacología , Ghrelina/farmacología , Masculino , Morfolinas/farmacología , Naftalenos/farmacología , Orexinas/farmacología , Ratas Sprague-Dawley , Transducción de Señal/fisiologíaRESUMEN
Increasing evidence implicates brain ghrelin in a wide variety of physiological functions. Among its gastrointestinal functions, ghrelin is known to act centrally to regulate gastrointestinal motility. Visceral sensation is one of the key gastrointestinal functions controlled by the central nervous system. Little is, however, known about the role of central ghrelin in visceral sensation. The present study thus aimed to clarify whether brain ghrelin is involved in visceral sensation. Visceral sensation was evaluated by the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternally administered ghrelin increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner. By contrast, neither intraperitoneal injection of ghrelin nor intracisternal des-acyl-ghrelin altered the threshold volume. Pretreatment with subcutaneous injection of either naloxone hydrochloride or sulpiride, a dopamine D2 receptor antagonist, significantly blocked ghrelin-induced visceral antinociception; furthermore, neither subcutaneous injection of naloxone methiodide, a peripheral selective opioid antagonist, SCH23390, a dopamine D1 receptor antagonist, nor DPCPX, an adenosine A1 receptor antagonist, blocked antinociception. Although intracisternal SB334867, an orexin 1 receptor antagonist, alone failed to change the threshold volume, centrally injected SB334867 potently blocked ghrelin-induced antinociceptive action during colonic distension. These results provide the first evidence that ghrelin acts centrally in the brain to enhance antinociceptive response to colonic distension through the central opioid system, dopamine D2 signaling, and the orexinergic pathway.
Asunto(s)
Analgésicos Opioides/farmacología , Dopamina/metabolismo , Ghrelina/farmacología , Dolor Visceral/tratamiento farmacológico , Analgésicos/farmacología , Animales , Benzoxazoles/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Estado de Conciencia/efectos de los fármacos , Estado de Conciencia/fisiología , Masculino , Naftiridinas , Orexinas/metabolismo , Ratas Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Urea/análogos & derivados , Urea/farmacologíaRESUMEN
BACKGROUND AND AIM: A glucagon-like peptide-1 analog, liraglutide, has been reported to block inflammatory somatic pain. We hypothesized that liraglutide attenuates lipopolysaccharide (LPS)-induced and repeated water avoidance stress (WAS)-induced visceral hypersensitivity and tested the hypothesis in rats. METHODS: The threshold of the visceromotor response induced by colonic balloon distention was measured to assess visceral sensation. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue spectrophotometrically, which was instilled in the proximal colon for 15 min. The interleukin-6 level in colonic mucosa was also quantified using ELISA. RESULTS: Subcutaneously injected LPS (1 mg/kg) reduced the visceromotor response threshold after 3 h. Liraglutide (300 µg/kg subcutaneously) at 15 h and 30 min before injecting LPS eliminated LPS-induced allodynia. It also blocked the allodynia induced by repeated water avoidance stress for 1 h for three consecutive days. Neither vagotomy nor naloxone altered the antinociceptive effect of liraglutide, but NG -nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor, blocked it. LPS increased colonic permeability and the interleukin-6 level, and the analog significantly inhibited these responses. CONCLUSIONS: This study suggests that liraglutide blocked LPS-induced visceral allodynia, which may be a nitric oxide-dependent response, and was probably mediated by inhibiting pro-inflammatory cytokine production and attenuating the increased gut permeability. Because the LPS-cytokine system is considered to contribute to altered visceral sensation in irritable bowel syndrome, these results indicate the possibility that liraglutide can be useful for treating this disease.
Asunto(s)
Colon/metabolismo , Péptido 1 Similar al Glucagón/farmacología , Liraglutida/farmacología , Dolor Visceral/prevención & control , Animales , Citocinas/metabolismo , Péptido 1 Similar al Glucagón/uso terapéutico , Técnicas In Vitro , Mediadores de Inflamación/metabolismo , Síndrome del Colon Irritable/tratamiento farmacológico , Síndrome del Colon Irritable/fisiopatología , Lipopolisacáridos , Liraglutida/uso terapéutico , Masculino , Óxido Nítrico/metabolismo , Permeabilidad , Ratas Sprague-Dawley , Dolor Visceral/etiologíaRESUMEN
Nonalcoholic steatohepatitis (NASH) is a hepatic manifestation of metabolic syndrome. Although the prostaglandin (PG)I2 receptor IP is expressed broadly in the liver, the role of PGI2-IP signaling in the development of NASH remains to be determined. Here, we investigated the role of the PGI2-IP system in the development of steatohepatitis using mice lacking the PGI2 receptor IP [IP-knockout (IP-KO) mice] and beraprost (BPS), a specific IP agonist. IP-KO and wild-type (WT) mice were fed a methionine- and choline-deficient diet (MCDD) for 2, 5, or 10 wk. BPS was administered orally to mice every day during the experimental periods. The effect of BPS on the expression of chemokine and inflammatory cytokines was examined also in cultured Kupffer cells. WT mice fed MCDD developed steatohepatitis at 10 wk. IP-KO mice developed steatohepatitis at 5 wk with augmented histologic derangements accompanied by increased hepatic monocyte chemoattractant protein-1 (MCP-1) and TNF-α concentrations. After 10 wk of MCDD, IP-KO mice had greater hepatic iron deposition with prominent oxidative stress, resulting in hepatocyte damage. In WT mice, BPS improved histologic and biochemical parameters of steatohepatitis, accompanied by reduced hepatic concentration of MCP-1 and TNF-α. Accordingly, BPS suppressed the LPS-stimulated Mcp-1 and Tnf-α mRNA expression in cultured Kupffer cells prepared from WT mice. PGI2-IP signaling plays a crucial role in the development and progression of steatohepatitis by modulating the inflammatory response, leading to augmented oxidative stress. We suggest that the PGI2-IP system is an attractive therapeutic target for treating patients with NASH.-Kumei, S., Yuhki, K.-I., Kojima, F., Kashiwagi, H., Imamichi, Y., Okumura, T., Narumiya, S., Ushikubi, F. Prostaglandin I2 suppresses the development of diet-induced nonalcoholic steatohepatitis in mice.
Asunto(s)
Epoprostenol/farmacología , Alimentos Formulados/efectos adversos , Hepatocitos/metabolismo , Macrófagos del Hígado/metabolismo , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Animales , Quimiocina CCL2/biosíntesis , Quimiocina CCL2/genética , Epoprostenol/análogos & derivados , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/patología , Macrófagos del Hígado/patología , Hígado/patología , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Receptores de Epoprostenol/agonistas , Receptores de Epoprostenol/genética , Receptores de Epoprostenol/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Statins have been reported to block inflammatory somatic pain and have an anti-cytokine property. Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral hypersensitivity and increases gut permeability in rats, which are mediated through proinflammatory cytokine-dependent pathways. Since visceral hypersensitivity with increased gut permeability plays a crucial role in the pathophysiology of irritable bowel syndrome (IBS), these above animal models are considered to simulate IBS. We hypothesized that lovastatin improves symptoms in the patients with IBS by attenuating these visceral changes. The threshold of visceromotor response (VMR) induced by colonic balloon distention was measured for the assessment of visceral sensation in rats. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15min using a spectrophotometer. Subcutaneously (s.c.) injected LPS (1mg/kg) reduced the threshold of VMR after 3h. Pretreatment with lovastatin (20mg/kg s.c. daily for 3 days) abolished this response by LPS. Repeated WAS (1h daily for 3 days) induced visceral allodynia, which was also blocked by repeated injection of lovastatin before each stress session. The antinociceptive effect of lovastatin on the LPS-induced allodynia was reversed by mevalonolactone, NG-nitro-L-arginine methyl ester or naloxone. Lovastatin also blocked the LPS- or repeated WAS-induced increased gut permeability. These results indicate the possibility that lovastatin can be useful for treating IBS.
Asunto(s)
Reacción de Prevención , Colon/efectos de los fármacos , Colon/metabolismo , Hiperalgesia/tratamiento farmacológico , Lipopolisacáridos/farmacología , Lovastatina/farmacología , Estrés Psicológico , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Hiperalgesia/metabolismo , Hiperalgesia/psicología , Lovastatina/uso terapéutico , Masculino , NG-Nitroarginina Metil Éster/farmacología , Permeabilidad/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , AguaRESUMEN
Familial Mediterranean fever (FMF) is a genetic autoinflammatory disease characterized by recurrent fever with serosal inflammation. We experienced a 53-year-old male who had been suffering from periodic attacks with slight fever and myalgia which were mainly triggered by cold exposure in winter. Although his clinical course did not satisfy the criteria for familial Mediterranean fever, heterozygous E148Q/M694I mutation in the Mediterranean fever (MEFV) gene was detected. Further attacks were prevented by treatment with colchicine. Attention should therefore be paid to the possibility of atypical FMF symptoms, which should be accurately diagnosed by genetic analyses to prevent the development of amyloidosis.