The opioid antagonist naltrexone improves murine inflammatory bowel disease.
Inflammatory bowel disease (IBD) is a condition of the intestine with significant morbidity. Although hereditary, environmental, immunologic, and bacterial factors have been implicated, the etiology of IBD remains unknown. Since opioid peptides modulate inflammatory cytokine production and opioid antagonists promote tissue growth and repair, we hypothesized the opioid antagonist naltrexone could reduce inflammation of the bowel. Using a chemically-induced mouse model of IBD, C57BL/6J mice received either untreated drinking water or water containing 2% dextran sulfate sodium (DSS) in two parallel regimens modeling moderate and severe colitis. After colitis was established, animals in the moderate colitis study were administered either saline (control) or naltrexone (NTX; 8 or 400 microg/kg) daily, while those in the severe colitis study received 0.1 or 10 mg/kg NTX. DSS-treated animals had significant weight loss (p = 0.006) and higher disease activity index (DAI) scores (p < 0.001) compared to water controls. However, NTX treatment of mice with moderate colitis resulted in less weight loss, lower DAI scores, and less histologic evidence of inflammation compared to controls. Significantly, elevated levels of colonic RNA for pro-inflammatory cytokines interleukin (IL)-6 and IL-12 were also decreased toward normal with NTX. Similar to patients with severe and unresponsive disease, animals in the severe colitis study did not significantly respond to treatment. Thus, NTX therapy reverses physical symptoms, histologic evidence, and molecular markers of inflammation in moderate colitis. The mechanism by which NTX acts to reverse colitis is related in part to the decreased expression of pro-inflammatory cytokines.
Matters
Gail L
GL
Departments of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Harms
John F
JF
McGovern
Christopher
C
Fitzpatrick
Leo
L
Parikh
Anuj
A
Nilo
Nicholas
N
Smith
Jill P
JP
D000818:Animals; D015415:Biomarkers; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018664:Interleukin-12 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D051379:Mice; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D015431:Weight Loss / Q000187:drug effects
D015415:Biomarkers; D018836:Inflammation Mediators; D015850:Interleukin-6; D009292:Narcotic Antagonists; D018664:Interleukin-12; D009271:Naltrexone; D016264:Dextran Sulfate