Pregabalin inhibits accelerated defecation and decreased colonic nociceptive threshold in sensitized rats.
Pregabalin, a ligand of alpha(2)delta subunits of voltage-gated calcium channels, reduces visceral hypersensitivity associated with irritable bowel syndrome. However, effects of pregabalin on bowel function are not well described. We investigated the effects of pregabalin on bowel dysfunction and colonic nociceptive threshold in sensitized rats. Increased fecal pellet output was evoked by non-ulcerogenic stress. Decreased colonic nociceptive threshold was induced in separate rats by administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the lumen of the proximal colon. Fecal pellet output was significantly increased during 2h restraint stress. Oral pregabalin (10-100mg/kg, p.o.) inhibited this increased fecal output dose-dependently, but did not change fecal output in naïve rats. The response threshold to distension of the non-inflamed distal colon was significantly decreased seven days after TNBS administration. An anti-hyperalgesic effect of pregabalin (30-100mg/kg, p.o.) that opposed the decreased colonic nociceptive threshold in TNBS-sensitized rats was observed, but nociceptive thresholds were not changed in naïve rats. Moreover, pregabalin was more potent in reducing disturbed defecation compared with reduction in nociceptive threshold to distension in TNBS-sensitized rats. This is the first report that pregabalin modulates stress-induced defecation in rats. These data indicate that pregabalin can ameliorate both altered defecation and decreases in colonic nociceptive threshold, suggesting that pregabalin might warrant investigation for the treatment of irritable bowel syndrome.
Ohashi-Doi
Katsuyo
K
Discovery Research, Pfizer Global Research and Development, Nagoya laboratories, Aichi, Japan. k.ohashidoi@gmail.com
Gale
Jeremy D
JD
Kurebayashi
Yoichi
Y
D015746:Abdominal Pain / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003672:Defecation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000503:physiopathology*; D008297:Male; D017288:Pain Threshold / Q000187:drug effects*; D000069583:Pregabalin; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000503:physiopathology; D014302:Trinitrobenzenesulfonic Acid; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
D000700:Analgesics; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D014302:Trinitrobenzenesulfonic Acid