RESUMO
Intestinal barrier dysfunction, leaky gut, is implicated in various diseases, including irritable bowel syndrome (IBS) and neurodegenerative conditions like Alzheimer's disease. Our recent investigation revealed that basal forebrain cholinergic neurons (BFCNs), critical for cognitive function, receive signals from butyrate and orexin, playing a role in regulating intestinal barrier function through adenosine A2B signaling and the vagus. This study explores the involvement and function of brain histamine, linked to BFCNs, in the regulation of intestinal barrier function. Colonic permeability, assessed by quantifying absorbed Evans blue in rat colonic tissue, showed that histamine did not affect increased colonic permeability induced by LPS when administered subcutaneously. However, intracisternal histamine administration improved colonic hyperpermeability. Elevating endogenous histamine levels in the brain with SKF91488, a histamine N-methyltransferase inhibitor, also improved colonic hyperpermeability. This effect was abolished by intracisternal chlorpheniramine, an histamine H1 receptor antagonist, not ranitidine, an H2 receptor antagonist. The SKF91488-induced improvement in colonic hyperpermeability was blocked by vagotomy, intracisternal pirenzepine (suppressing BFCNs activity), or alloxazine (an adenosine A2B receptor antagonist). Additionally, intracisternal chlorpheniramine injection eliminated butyrate-induced improvement in colonic hyperpermeability. These findings suggest that brain histamine, acting via the histamine H1 receptor, regulates intestinal barrier function involving BFCNs, adenosine A2B signaling, and the vagus. Brain histamine appears to centrally regulate intestinal barrier function influenced by butyrate, differentiating its actions from peripheral histamine in conditions like IBS, where mast cell-derived histamine induces leaky gut. Brain histamine emerges as a potential pharmacological target for diseases associated with leaky gut, such as dementia and IBS.
Assuntos
Neurônios Colinérgicos , Colo , Histamina , Permeabilidade , Ratos Sprague-Dawley , Receptor A2B de Adenosina , Nervo Vago , Animais , Histamina/metabolismo , Histamina/farmacologia , Ratos , Masculino , Receptor A2B de Adenosina/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/fisiologia , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologia , Nervo Vago/metabolismo , Colo/metabolismo , Colo/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/metabolismoRESUMO
BACKGROUND: Postoperative ileus (POI) is a major complication of abdominal surgery (AS). Impaired gut barrier mediated via Toll-like receptor 4 (TLR4) and interleukin-1 (IL-1) receptor is involved in the development of POI. Phlorizin is a nonselective inhibitor of sodium-linked glucose transporters (SGLTs) and is known to improve lipopolysaccharide (LPS)-induced impaired gut barrier. This study aimed to clarify our hypothesis that AS-induced gastric ileus is mediated via TLR4 and IL-1 signaling, and phlorizin improves the ileus. METHODS: AS consisted of a celiotomy and manipulation of the cecum for 1 min. Gastric emptying (GE) in 20 min with liquid meal was determined 3 h after the surgery in rats. The effect of subcutaneous (s.c.) injection of LPS (1 mg kg-1 ) was also determined 3 h postinjection. KEY RESULTS: AS delayed GE, which was blocked by TAK-242, an inhibitor of TLR4 signaling and anakinra, an IL-1 receptor antagonist. LPS delayed GE, which was also mediated via TLR4 and IL-1 receptor. Phlorizin (80 mg kg-1 , s.c.) significantly improved delayed GE induced by both AS and LPS. However, intragastrical (i.g.) administration of phlorizin did not alter it. As gut mainly expresses SGLT1, SGLT2 may not be inhibited by i.g. phlorizin. The effect of phlorizin was blocked by ghrelin receptor antagonist in the LPS model. CONCLUSIONS & INFERENCES: AS-induced gastric ileus is mediated via TLR4 and IL-1 signaling, which is simulated by LPS. Phlorizin improves the gastric ileus via activation of ghrelin signaling, possibly by inhibition of SGLT2. Phlorizin may be useful for the treatment of POI.
Assuntos
Íleus , Obstrução Intestinal , Ratos , Animais , Receptor 4 Toll-Like , Florizina/farmacologia , Transportador 2 de Glucose-Sódio , Lipopolissacarídeos/toxicidade , Íleus/tratamento farmacológico , Íleus/etiologia , Complicações Pós-Operatórias/tratamento farmacológico , Obstrução Intestinal/complicações , Interleucina-1 , Receptores de Interleucina-1RESUMO
Accumulating evidence suggest that ghrelin plays a role as an antiseptic peptide. The present study aimed to clarify whether the brain may be implicated ghrelin's antiseptic action. We examined the effect of brain ghrelin on survival in a novel endotoxemic model achieved by treating rats with lipopolysaccharide (LPS) and colchicine. The observation of survival stopped three days after chemicals' injection or at death. Intracisternal ghrelin dose-dependently reduced lethality in the endotoxemic model; meanwhile, neither intraperitoneal injection of ghrelin nor intracisternal des-acyl-ghrelin injection affected the mortality rate. The brain ghrelin-induced lethality reduction was significantly blocked by surgical vagotomy. Moreover, intracisternal injection of a ghrelin receptor antagonist blocked the improved survival achieved by intracisternal ghrelin injection or intravenous 2-deoxy-d-glucose administration. Intracisternal injection of an adenosine A2B receptor agonist reduced the lethality and the ghrelin-induced improvement of survival was blocked by adenosine A2B receptor antagonist. I addition, intracisternal ghrelin significantly blocked the colonic hyperpermeability produced by LPS and colchicine. These results suggest that ghrelin acts centrally to reduce endotoxemic lethality. Accordingly, activation of the vagal pathway and adenosine A2B receptors in the brain may be implicated in the ghrelin-induced increased survival. Since the efferent vagus nerve mediates anti-inflammatory mechanisms, we speculate that the vagal cholinergic anti-inflammatory pathway is implicated in the decreased septic lethality caused by brain ghrelin.
Assuntos
Anti-Infecciosos Locais , Grelina , Ratos , Animais , Grelina/farmacologia , Grelina/uso terapêutico , Adenosina/farmacologia , Lipopolissacarídeos/toxicidade , Nervo Vago/fisiologia , Encéfalo , Colchicina/farmacologia , Anti-Infecciosos Locais/farmacologiaRESUMO
We herein report a rare case of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome that occurred in an 18-year-old man. He visited our hospital with recurrent episodes of a fever, pharyngitis and adenitis without suggestive findings of infection. These episodes resolved within 5 days and recurred quite regularly, with an interval of about 30 days. As the febrile episodes significantly impaired his quality of life, he was treated with colchicine (0.5 mg) as prophylaxis. This completely prevented the episodes during six months of follow-up. Colchicine may therefore be effective in cases of adult-onset PFAPA syndrome.
Assuntos
Amiloidose , Linfadenite , Linfadenopatia , Faringite , Estomatite Aftosa , Masculino , Humanos , Adulto , Adolescente , Colchicina/uso terapêutico , Estomatite Aftosa/diagnóstico , Estomatite Aftosa/tratamento farmacológico , Estomatite Aftosa/prevenção & controle , Qualidade de Vida , Febre/tratamento farmacológico , Febre/etiologia , Linfadenite/diagnóstico , Linfadenite/tratamento farmacológico , Linfadenite/prevenção & controle , Faringite/complicações , Faringite/tratamento farmacológico , Linfadenopatia/tratamento farmacológico , Amiloidose/tratamento farmacológico , SíndromeRESUMO
Intestinal barrier dysfunction, a leaky gut, contributes to the pathophysiology of various diseases such as dementia and irritable bowel syndrome (IBS). We recently clarified that orexin, ghrelin, or adenosine A2B signaling in the brain improved leaky gut through the vagus nerve. The present study was performed to clarify whether basal forebrain cholinergic neurons (BFCNs) are implicated in the central regulation of intestinal barrier function. We activated BFCNs using benzyl quinolone carboxylic acid (BQCA), a positive muscarinic M1 allosteric modulator, and evaluated colonic permeability by quantifying the absorbed Evans blue in rat colonic tissue. Intracisternal (not intraperitoneal) injection of BQCA blocked the increased colonic permeability in response to lipopolysaccharide. Vagotomy blocked BQCA-induced improvement of colonic hyperpermeability. Intracisternally administered pirenzepine, a muscarinic M1 selective antagonist, prevented intestinal barrier function improvement by intravenously administered 2-deoxy-d-glucose, central vagal stimulant. Adenosine A2B receptor antagonist but not dopamine or opioid receptor antagonist prevented BQCA-induced blockade of colonic hyperpermeability. Additionally, intracisternal injection of pirenzepine blocked orexin- or butyrate-induced intestinal barrier function improvement. These results suggest that BFCNs improve leaky gut through adenosine A2B signaling and the vagal pathway. Furthermore, BFCNs mediate orexin- or butyrate-induced intestinal barrier function improvement. Since BFCNs play a role in cognitive function and a leaky gut is associated with dementia, the present finding may lead us to speculate that BFCNs are involved in the development of dementia by regulating intestinal barrier function.
Assuntos
Prosencéfalo Basal , Demência , Animais , Ratos , Adenosina/farmacologia , Butiratos , Colinérgicos , Neurônios Colinérgicos , Orexinas , Pirenzepina , Receptor A2B de Adenosina , Nervo VagoRESUMO
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.
Assuntos
Canabinoides , Ocitocina , Animais , Encéfalo , Canabinoides/farmacologia , Grelina/farmacologia , Orexinas/farmacologia , Ocitocina/farmacologia , Ratos , Ratos Sprague-Dawley , Nervo VagoRESUMO
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.
Assuntos
Amiloidose , Febre Familiar do Mediterrâneo , Síndrome do Intestino Irritável , Adulto , Colchicina/uso terapêutico , Diarreia/tratamento farmacológico , Diarreia/etiologia , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre/tratamento farmacológico , Humanos , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/diagnóstico , Síndrome do Intestino Irritável/tratamento farmacológico , MasculinoRESUMO
Visceral hypersensitivity and impaired gut barrier are crucial contributors to the pathophysiology of irritable bowel syndrome (IBS), and those are mediated via corticotropin-releasing factor (CRF)-Toll like receptor 4-pro-inflammatory cytokine signaling. Phlorizin is an inhibitor of sodium-linked glucose transporters (SGLTs), and known to have anti-cytokine properties. Thus, we hypothesized that phlorizin may improve these gastrointestinal changes in IBS, and tested this hypothesis in rat IBS models, i.e., lipopolysaccharide (LPS) or CRF-induced visceral hypersensitivity and colonic hyperpermeability. The visceral pain threshold in response to colonic balloon distention was estimated by abdominal muscle contractions by electromyogram, and colonic permeability was measured by quantifying the absorbed Evans blue in colonic tissue. Subcutaneous (s.c.) injection of phlorizin inhibited visceral hypersensitivity and colonic hyperpermeability induced by LPS in a dose-dependent manner. Phlorizin also blocked CRF-induced these gastrointestinal changes. Phlorizin is known to inhibit both SGLT1 and SGLT2, but intragastric administration of phlorizin may only inhibit SGLT1 because gut mainly expresses SGLT1. We found that intragastric phlorizin did not display any effects, but ipragliflozin, an orally active and selective SGLT2 inhibitor improved the gastrointestinal changes in the LPS model. Compound C, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor and naloxone, an opioid receptor antagonist reversed the effects of phlorizin. In conclusions, phlorizin improved visceral hypersensitivity and colonic hyperpermeability in IBS models. These effects may result from inhibition of SGLT2, and were mediated via AMPK, NO and opioid pathways. Phlorizin may be effective for the treatment of IBS.
Assuntos
Colo/metabolismo , Hiperalgesia/tratamento farmacológico , Síndrome do Intestino Irritável/tratamento farmacológico , Florizina/uso terapêutico , Músculos Abdominais/efeitos dos fármacos , Animais , Colo/efeitos dos fármacos , Hormônio Liberador da Corticotropina/farmacologia , Relação Dose-Resposta a Droga , Eletromiografia , Injeções Subcutâneas , Lipopolissacarídeos/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Naloxona/farmacologia , Permeabilidade , Florizina/antagonistas & inibidores , Florizina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
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.
Assuntos
Encéfalo/metabolismo , Grelina/metabolismo , Mucosa Intestinal/metabolismo , Receptor A2B de Adenosina/metabolismo , Nervo Vago/metabolismo , Agonistas do Receptor A2 de Adenosina/administração & dosagem , Antagonistas do Receptor A2 de Adenosina/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Grelina/administração & dosagem , Humanos , Injeções Subcutâneas , Mucosa Intestinal/efeitos dos fármacos , Masculino , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Nervo Vago/efeitos dos fármacosRESUMO
Visceral hypersensitivity is a major pathophysiology in irritable bowel syndrome (IBS). Although brain-gut interaction is considered to be involved in the regulation of visceral sensation, little had been known how brain controls visceral sensation. To improve therapeutic strategy in IBS, we should develop a novel approach to control visceral hypersensitivity. Here, we summarized recent data on central control of visceral sensation by neuropeptides in rats. Orexin, ghrelin or oxytocin in the brain is capable of inducing visceral antinociception. Dopamine, cannabinoid, adenosine, serotonin or opioid in the central nervous system (CNS) plays a role in the visceral hyposensitivity. Central ghrelin, levodopa or morphine could induce visceral antinociception via the orexinergic signaling. Orexin induces visceral antinociception through dopamine, cannabinoid, adenosine or oxytocin. Orexin nerve fibers are identified widely throughout the CNS and orexins are implicated in a number of functions. With regard to gastrointestinal functions, in addition to its visceral antinociception, orexin acts centrally to stimulate gastrointestinal motility and improve intestinal barrier function. Brain orexin is also involved in regulation of sleep/awake cycle and anti-depressive action. From these evidence, we would like to make a hypothesis that decreased orexin signaling in the brain may play a role in the pathophysiology in a part of patients with IBS who are frequently accompanied with sleep disturbance, depressive state and disturbed gut functions such as gut motility disturbance, leaky gut and visceral hypersensitivity.
Assuntos
Colo , Orexinas/fisiologia , Sensação/fisiologia , Animais , Humanos , Síndrome do Intestino Irritável/fisiopatologia , Orexinas/metabolismo , Estimulação FísicaRESUMO
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.
Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Analgésicos Opioides , Canabinoides , Analgésicos , Animais , Sistema Nervoso Central , Dopamina , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide , Receptor 5-HT1A de Serotonina , Receptor 5-HT2A de Serotonina , Receptores de Dopamina D1 , SerotoninaRESUMO
Grape seed extract (GSE) is rich in polyphenols composed mainly of proanthocyanidins, which are known to attenuate proinflammatory cytokine production. Repeated water avoidance stress (WAS) induces visceral allodynia and colonic hyperpermeability via toll-like receptor 4 (TLR4) and proinflammatory cytokine pathways, which is a rat irritable bowel syndrome (IBS) model. Thus, we explored the effects of GSE on repeated WAS (1 h for 3 days)-induced visceral allodynia and colonic hyperpermeability in Sprague-Dawley rats. Paracellular permeability, as evaluated by transepithelial electrical resistance and flux of carboxyfluorescein, was analyzed in Caco-2 cell monolayers treated with interleukin-6 (IL-6) and IL-1ß. WAS caused visceral allodynia and colonic hyperpermeability, and intragastric administration of GSE (100 mg/kg, once daily for 11 days) inhibited these changes. Furthermore, GSE also suppressed the elevated colonic levels of IL-6, TLR4, and claudin-2 caused by WAS. Paracellular permeability was increased in Caco-2 cell monolayers in the presence of IL-6 and IL-1ß, which was inhibited by GSE. Additionally, GSE suppressed the claudin-2 expression elevated by cytokine stimulation. The effects of GSE on visceral changes appear to be evoked by suppressing colonic TLR4-cytokine signaling and maintaining tight junction integrity. GSE may be useful for treating IBS.
Assuntos
Colo/efeitos dos fármacos , Extrato de Sementes de Uva/farmacologia , Hiperalgesia/tratamento farmacológico , Síndrome do Intestino Irritável/tratamento farmacológico , Animais , Células CACO-2 , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mucosa Intestinal/efeitos dos fármacos , Masculino , Permeabilidade , Ratos , Ratos Sprague-Dawley , Estresse Fisiológico , ÁguaRESUMO
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.
Assuntos
Azul Evans/metabolismo , Hiperalgesia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Mucosa Intestinal/metabolismo , Síndrome do Intestino Irritável/fisiopatologia , Metformina/uso terapêutico , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Colo/metabolismo , Modelos Animais de Doenças , Domperidona/farmacologia , Antagonistas de Dopamina/farmacologia , Hiperalgesia/etiologia , Hipoglicemiantes/farmacologia , Síndrome do Intestino Irritável/induzido quimicamente , Lipopolissacarídeos , Masculino , Metformina/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Nociceptividade/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Estresse Fisiológico , Sulpirida/farmacologiaRESUMO
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.
Assuntos
Analgésicos/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Nociceptividade/efeitos dos fármacos , Ocitocina/farmacologia , Reflexo/efeitos dos fármacos , Antagonistas do Receptor A1 de Adenosina/farmacologia , Animais , Canfanos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Antagonistas de Hormônios/farmacologia , Indóis/farmacologia , Masculino , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Ocitocina/antagonistas & inibidores , Sulpirida/farmacologia , Xantinas/farmacologiaRESUMO
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.
Assuntos
Analgésicos Opioides/farmacologia , Dopamina/metabolismo , Grelina/farmacologia , Dor Visceral/tratamento farmacológico , Analgésicos/farmacologia , Animais , Benzoxazóis/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Estado de Consciência/efeitos dos fármacos , Estado de Consciência/fisiologia , Masculino , Naftiridinas , Orexinas/metabolismo , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Ureia/análogos & derivados , Ureia/farmacologiaRESUMO
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.
Assuntos
Temperatura Baixa/efeitos adversos , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/etiologia , Mutação , Pirina/genética , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Moduladores de Tubulina/uso terapêuticoRESUMO
BACKGROUND AND AIM: Repeated water avoidance stress (WAS) induces visceral hypersensitivity. Additionally, it is also known to activate corticotropin-releasing factor (CRF), mast cells, and pro-inflammatory cytokines systems, but their precise roles on visceral sensation have not been determined definitely. The aim of the study was to explore this issue. METHODS: Abdominal muscle contractions induced by colonic balloon distention, that is, visceromotor response (VMR) was detected electrophysiologically in conscious rats. WAS or sham stress as control for 1 h daily was loaded, and the threshold of VMR was determined before and at 24 h after the stress. RESULTS: Repeated WAS for three consecutive days reduced the threshold of VMR, but sham stress did not induce any change. Astressin, a CRF receptor antagonist (50 µg/kg) intraperitoneally (ip) at 10 min before each WAS session, prevented the visceral allodynia, but the antagonist (200 µg/kg) ip at 30 min and 15 h before measurement of the threshold after completing 3-day stress session did not modify the response. Ketotifen, a mast cell stabilizer (3 mg/kg), anakinra, an interleukin (IL)-1 receptor antagonist (20 mg/kg) or IL-6 antibody (16.6 µg/kg) ip for two times before the measurement abolished the response. CONCLUSIONS: Repeated WAS for three consecutive days induced visceral allodynia, which was mediated through mast cells, IL-1, and IL-6 pathways. Inhibition of peripheral CRF signaling prevented but did not reverse this response, suggesting that peripheral CRF may be an essential trigger but may not contribute to the maintenance of repeated WAS-induced visceral allodynia.
Assuntos
Hormônio Liberador da Corticotropina/fisiologia , Hiperalgesia/etiologia , Interleucina-1/fisiologia , Interleucina-6/fisiologia , Transdução de Sinais/fisiologia , Estresse Psicológico/complicações , Vísceras , Músculos Abdominais/fisiopatologia , Animais , Modelos Animais de Doenças , Hiperalgesia/fisiopatologia , Masculino , Mastócitos , Contração Muscular , Ratos Sprague-DawleyRESUMO
BACKGROUND: Lipopolysaccharide (LPS) induces visceral hypersensitivity, and corticotropin-releasing factor (CRF) also modulates visceral sensation. Besides, LPS increases CRF immunoreactivity in rat colon, which raises the possibility of the existence of a link between LPS and the CRF system in modulating visceral sensation. The present study tried to clarify this possibility. METHODS: Visceral sensation was assessed by abdominal muscle contractions induced by colonic balloon distention, i.e., visceromotor response, electrophysiologically in conscious rats. The threshold of visceromotor response was measured before and after administration of drugs. RESULTS: LPS at a dose of 1 mg/kg subcutaneously (sc) decreased the threshold at 3 h after the administration. Intraperitoneal (ip) administration of anakinra (20 mg/kg), an interleukin-1 (IL-1) receptor antagonist, or interleukin-6 (IL-6) antibody (16.6 µg/kg) blocked this effect. Additionally, IL-1ß (10 µg/kg, sc) or IL-6 (10 µg/kg, sc) induced visceral allodynia. Astressin (200 µg/kg, ip), a non-selective CRF receptor antagonist, abolished the effect of LPS, but astressin2-B (200 µg/kg, ip), a CRF receptor type 2 (CRF2) antagonist, did not alter it. Peripheral CRF receptor type 1 (CRF1) stimulation by cortagine (60 µg/kg, ip) exaggerated the effect of LPS, but activation of CRF2 by urocortin 2 (60 µg/kg, ip) abolished it. CONCLUSIONS: LPS induced visceral allodynia possibly through stimulating IL-1 and IL-6 release. In addition, this effect was mediated through peripheral CRF signaling. Since the LPS-cytokine system is thought to contribute to altered visceral sensation in the patients with irritable bowel syndrome, these results may further suggest that CRF plays a crucial role in the pathophysiology of this disease.
Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Lipopolissacarídeos/toxicidade , Estresse Fisiológico , Dor Visceral/fisiopatologia , Animais , Modelos Animais de Doenças , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Transdução de SinaisAssuntos
Endoscopia do Sistema Digestório/efeitos adversos , Gastrostomia/efeitos adversos , Penfigoide Bolhoso/etiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Endoscopia do Sistema Digestório/métodos , Nutrição Enteral/efeitos adversos , Nutrição Enteral/métodos , Feminino , Gastrostomia/métodos , Humanos , Incidência , Masculino , Penfigoide Bolhoso/epidemiologia , Penfigoide Bolhoso/fisiopatologia , Prognóstico , Doenças Raras , Medição de Risco , Estudos de Amostragem , Taxa de SobrevidaRESUMO
We have recently demonstrated that orexin acts centrally through the brain orexin 1 receptors to induce an antinociceptive action against colonic distension in conscious rats. Adenosine signaling is capable of inducing an antinociceptive action against somatic pain; however, the association between changes in the adenosinergic system and visceral pain perception has not been investigated. In the present study, we hypothesized that the adenosinergic system may be involved in visceral nociception, and thus, adenosine signaling may mediate orexin-induced visceral antinociception. Visceral sensation was evaluated based on the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneous (0.04-0.2mg/rat) or intracisternal (0.8-4µg/rat) injection of N(6)-cyclopentyladenosine (CPA), an adenosine A1 receptor (A1R) agonist, increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner, thereby suggesting that CPA acts centrally in the brain to induce an antinociceptive action against colonic distension. Pretreatment with theophylline, an adenosine antagonist, or 1,3-dipropyl-8-cyclopentylxanthine, an A1R antagonist, subcutaneously injected potently blocked the centrally injected CPA- or orexin-A-induced antinociceptive action against colonic distension. These results suggest that adenosinergic signaling via A1Rs in the brain induces visceral antinociception and that adenosinergic signaling is involved in the central orexin-induced antinociceptive action against colonic distension.