Antinociceptive and antidiarrheal effects of pioglitazone in a rat model of diarrhoea-predominant irritable bowel syndrome: role of nitric oxide.
Irritable bowel syndrome (IBS) is a prevalent disease characterized by abdominal pain and abnormal bowel habits. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) γ agonist and, although it is mostly used as an antidiabetic agent, it has been reported to have analgesic effects. Nitric oxide (NO), a gaseous molecule that mediates many of the effects of pioglitazone, has been implicated in the pathophysiology of IBS. The aim of the present study was to investigate the effects of pioglitazone on symptoms in a rat model of diarrhoea-predominant IBS (D-IBS).and to determine the role of NO in these effects. Diarrhoea-predominant IBS was induced by intracolonic instillation of acetic acid. Pioglitazone (2 mg/kg, i.p.) was administered on Days 7, 9 and 11 after acetic acid instillation. To investigate the mechanism involved in pioglitazone action, rats were also administered either the PPARγ antagonist GW9662 (3 mg/kg, i.p.), the NO synthase (NOS) inhibitor N(G) -nitro-l-arginine methyl ester (l-NAME; 10 mg/kg, i.p.) or the NO precursor l-arginine (250 mg/kg, i.p.) along with pioglitazone. Visceral hypersensitivity, nociceptive thresholds, defecation frequency, stool form, serum and colon NO production and inducible (i) NOS activity were assessed 1 h after the final injection of pioglitazone or dimethylsulphoxide (used as the vehicle). Pioglitazone reduced visceral hypersensitivity and defecation frequency, increased nociceptive thresholds, NO production and iNOS activity and shifted stool form towards hard stools in D-IBS rats. These effects of pioglitazone were significantly reversed by l-NAME, but not GW9662. l-Arginine augmented the effects of pioglitazone. In conclusion, pioglitazone alleviates symptoms in a rat model of D-IBS through an NO-dependent mechanism.
Rheumatology Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran.
Pedram
P
Paragomi
Reza
R
Rahimian
Mohammad Hossein
MH
Kazemi
Mohammad Hadi
MH
Gharedaghi
Amin
A
Khalifeh-Soltani
Saeedeh
S
Azary
Abbas Norouzi
AN
Javidan
Kamran
K
Moradi
Stephen
S
Sakuma
Ahmad Reza
AR
Dehpour
D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000930:Antidiarrheals / Q000008:administration & dosage / Q000627:therapeutic use*; D003967:Diarrhea / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D000700:Analgesics; D000930:Antidiarrheals; D045162:Thiazolidinediones; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000077205:Pioglitazone
antinociception; irritable bowel syndrome; nitric oxide; pioglitazone; rats