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1.
Neurogastroenterol Motil ; 22(6): 654-e202, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20210978

ABSTRACT

BACKGROUND: The pathogenesis of inflammatory bowel disease is unknown; however, the disorder is aggravated by psychological stress and is itself psychologically stressful. Chronic intestinal inflammation, moreover, has been reported to activate forebrain neurons. We tested the hypotheses that the chronically inflamed bowel signals to the brain through the vagi and that administration of a combination of secretin (S) and oxytocin (OT) inhibits this signaling. METHODS: Three daily enemas containing 2,4,6-trinitrobenzene sulfonic acid (TNBS), which were given to rats produced chronic colitis and ongoing activation of Fos in brain neurons. KEY RESULTS: Fos was induced in neurons in the paraventricular nucleus of the hypothalamus, basolateral amygdala, central amygdala, and piriform cortex. Subdiaphragmatic vagotomy failed to inhibit this activation of Fos, suggesting that colitis activates forebrain neurons independently of the vagi. When administered intravenously, but not when given intracerebroventricularly, in doses that were individually ineffective, combined S/OT prevented colitis-associated activation of central neurons. Strikingly, S/OT decreased inflammatory infiltrates into the colon and colonic expression of tumor necrosis factor-alpha and interferon-gamma. CONCLUSIONS & INFERENCES: These observations suggest that chronic colonic inflammation is ameliorated by the systemic administration of S/OT, which probably explains the parallel ability of systemic S/OT to inhibit the colitis-associated activation of forebrain neurons. It is possible that S and OT, which are endogenous to the colon, might normally combine to restrict the severity of colonic inflammatory responses and that advantage might be taken of this system to develop novel means of treating inflammation-associated intestinal disorders.


Subject(s)
Colitis/drug therapy , Neurons/drug effects , Oxytocin/pharmacology , Prosencephalon/drug effects , Secretin/pharmacology , Amygdala/drug effects , Animals , Cerebral Cortex/drug effects , Chronic Disease , Colitis/chemically induced , Colitis/pathology , Genes, fos/drug effects , Injections, Intraperitoneal , Injections, Intraventricular , Interferon-gamma/metabolism , Intestinal Mucosa/pathology , Male , Oxytocin/administration & dosage , Oxytocin/therapeutic use , Paraventricular Hypothalamic Nucleus/drug effects , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Secretin/administration & dosage , Secretin/therapeutic use , Signal Transduction/drug effects , Trinitrobenzenesulfonic Acid , Tumor Necrosis Factor-alpha/metabolism , Vagotomy
2.
J Comp Neurol ; 512(2): 256-70, 2009 Jan 10.
Article in English | MEDLINE | ID: mdl-19003903

ABSTRACT

Although oxytocin (OT) and oxytocin receptor (OTR) are known for roles in parturition and milk let-down, they are not hypothalamus-restricted. OT is important in nurturing and opposition to stress. Transcripts encoding OT and OTR have been reported in adult human gut, and OT affects intestinal motility. We tested the hypotheses that OT is endogenous to the enteric nervous system (ENS) and that OTR signaling may participate in enteric neurophysiology. Reverse transcriptase polymerase chain reaction confirmed OT and OTR transcripts in adult mouse and rat gut and in precursors of enteric neurons immunoselected from fetal rats. Enteric OT and OTR expression continued through adulthood but was developmentally regulated, peaking at postnatal day 7. Coincidence of the immunoreactivities of OTR and the neural marker Hu was 100% in the P3 and 71% in the adult myenteric plexus, when submucosal neurons were also OTR-immunoreactive. Co-localization with NeuN established that intrinsic primary afferent neurons are OTR-expressing. Because OTR transcripts and protein were detected in the nodose ganglia, OT signaling might also affect extrinsic primary afferent neurons. Although OT immunoreactivity was found only in approximately 1% of myenteric neurons, extensive OT-immunoreactive varicosities surrounded many others. Villus enterocytes were OTR-immunoreactive through postnatal day 17; however, by postnatal day 19, immunoreactivity waned to become restricted to crypts and concentrated at crypt-villus junctions. Immunoelectron microscopy revealed plasmalemmal OTR at enterocyte adherens junctions. We suggest that OT and OTR signaling might be important in ENS development and function and might play roles in visceral sensory perception and neural modulation of epithelial biology.


Subject(s)
Enteric Nervous System/physiology , Intestinal Mucosa/physiology , Oxytocin/metabolism , Receptors, Oxytocin/metabolism , Animals , Enteric Nervous System/anatomy & histology , Female , Humans , Immunohistochemistry , Intestinal Mucosa/anatomy & histology , Mice , Neurons/cytology , Neurons/metabolism , Oxytocin/genetics , Pregnancy , Rats , Rats, Sprague-Dawley , Receptors, Oxytocin/genetics
3.
Inflamm Bowel Dis ; 13(7): 918-32, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17343284

ABSTRACT

Inflammatory bowel disease (IBD) is a chronic, relapsing condition involving complex interactions between genes and the environment. The mechanisms triggering the initial attack and relapses, however, are not well understood. In the past several years the enteric nervous system (ENS) has been implicated in the pathophysiology of IBD. Both the ENS and the central nervous system (CNS) can amplify or modulate aspects of intestinal inflammation through secretion of neuropeptides that serve as a link between the ENS and CNS. Neuropeptides are defined as any peptide released from the nervous system that serves as an intercellular signaling molecule. Neuropeptides thought to play a potentially key role in IBD include substance P, corticotropin-releasing hormone, neurotensin, vasoactive intestinal peptide, mu-opioid receptor agonists, and galanin. This review focuses on the role of these neuropeptides in the pathophysiology of IBD and discusses the cell types and mechanisms involved in this process. The available evidence that neuropeptide blockade may be considered a therapeutic approach in both Crohn's disease and ulcerative colitis will also be discussed.


Subject(s)
Inflammatory Bowel Diseases/physiopathology , Intestinal Mucosa/physiopathology , Neuropeptides/physiology , Receptors, Neuropeptide/physiology , Central Nervous System/physiopathology , Colon/physiopathology , Enteric Nervous System/physiopathology , Humans , Neuropeptides/immunology
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