Combined administration of secretin and oxytocin inhibits chronic colitis and associated activation of forebrain neurons.
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.


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
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.
Welch
Martha G
MG
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. mgw13@columbia.edu
Anwar
Muhammad
M
Chang
Christine Y
CY
Gross
Kara J
KJ
Ruggiero
David A
DA
Tamir
Hadassah
H
Gershon
Michael D
MD
D000679:Amygdala / Q000187:drug effects; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016762:Genes, fos / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007371:Interferon-gamma / Q000378:metabolism; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D009474:Neurons / Q000187:drug effects*; D010121:Oxytocin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects; D016548:Prosencephalon / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012633:Secretin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014628:Vagotomy
D014409:Tumor Necrosis Factor-alpha; D012633:Secretin; D010121:Oxytocin; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid