Increased responsiveness of rat colonic splanchnic afferents to 5-HT after inflammation and recovery.
5-Hydroxytryptamine (5-HT) activates colonic splanchnic afferents, a mechanism by which it has been implicated in generating symptoms in postinfectious and postinflammatory states in humans. Here we compared mechanisms of colonic afferent activation by 5-HT and mechanical stimuli in normal and inflamed rat colon, and after recovery from inflammation. Colonic inflammation was induced in rats by dextran sulphate sodium. Single-fibre recordings of colonic lumbar splanchnic afferents revealed that 58% of endings responded to 5-HT (10(-4) m) in controls, 88% in acute inflammation (P<0.05) and 75% after 21 days recovery (P < 0.05 versus control). Maximal responses to 5-HT were also larger, and the estimated EC50 was reduced from 3.2 x 10(-6) to 8 x 10(-7) m in acute inflammation and recovered to 2 x 10(-6) m after recovery. Responsiveness to mechanical stimulation was unaffected. 5-HT3 receptor antagonism with alosetron reduced responses to 5-HT in controls but not during inflammation. Responses to the mast cell degranulator 48/80 mimicked those to 5-HT in inflamed tissue but not in controls, and more 5-HT-containing mast cells were seen close to calcitonin gene-related peptide-containing fibres in inflamed serosa. We conclude that colonic serosal and mesenteric endings exhibit increased sensitivity to 5-HT in inflammation, with both an increase in proportion of responders and an increase in sensitivity, which is maintained after healing of inflammation. This is associated with alterations in the roles of 5-HT3 receptors and mast cells.
Coldwell
Jonathan R
JR
Nerve-Gut Research Laboratory, Department of Gastroenterology, Hepatology and General Medicine, Royal Adelaide Hospital, Adelaide, Australia.
Phillis
Benjamin D
BD
Sutherland
Kate
K
Howarth
Gordon S
GS
Blackshaw
L Ashley
LA
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000818:Animals; D015415:Biomarkers; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D015550:Cell Degranulation / Q000502:physiology; D003092:Colitis / Q000503:physiopathology*; D003106:Colon / Q000276:immunology / Q000294:innervation*; D004195:Disease Models, Animal; D004594:Electrophysiology; D008407:Mast Cells / Q000502:physiology; D009412:Nerve Fibers / Q000378:metabolism; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000502:physiology; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology*; D013153:Splanchnic Nerves / Q000187:drug effects* / Q000502:physiology*
D015415:Biomarkers; D012701:Serotonin; D015740:Calcitonin Gene-Related Peptide