The Opioid Antagonist Naltrexone Improves Murine Inflammatory Bowel Disease

Abstract

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 µg/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 Abbreviations: Dextran sulfate sodium, DSS; Disease activity index, DAI; Inflammatory bowel disease, IBD; Naltrexone, NTX.Address correspondence to Jill P. Smith, M.D., H-045 GI and Hepatology, Pennsylvania State University, 500 University Drive, Hershey, PA 17033, USA; e-mail: jsmith2@psu.edu 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.

Mu Opioid Signaling Protects Against Acute Murine Intestinal Injury in a Manner Involving Stat3 Signaling

“…Interestingly, previous reports have shown that low-dose therapy of the nonspecific opioid antagonist naltrexone protects against both DSS-induced injury in mice and ameliorates Crohn's disease in a small, open-label patient study. 41,42 In these studies, naltrexone was deliberately administered at levels below the dose needed to pharmacologically block receptor function. Because the MOR-specific antagonist cyprodime exacerbates DSS-induced colitis, it is probable that low-dose naltrexone therapy acts to potentiate endogenous opiate signaling.…”

“…Because the MOR-specific antagonist cyprodime exacerbates DSS-induced colitis, it is probable that low-dose naltrexone therapy acts to potentiate endogenous opiate signaling. [41][42][43] However, such a mechanism remains controversial and has never been truly established.…”

Duration of opioid receptor blockade determines biotherapeutic response

“…Although few basic science reports have been published, patient studies are provocative. In a murine model of inflammatory bowel disease, low dosages of naltrexone were shown to reduce the weight loss and lessen the disease activity, normally associated with progression of the disorder [85]. The short term opioid receptor blockade reversed the physical symptoms, pathology, and molecular markers of inflammation associated with colitis.…”

“…Other autoimmune diseases that respond to partial opioid receptor blockade include the family of inflammatory bowel disorders (Crohn"s and colitis) [82][83][84][85]. Although few basic science reports have been published, patient studies are provocative.…”

Evaluation of therapeutic effect of low dose naltrexone in experimentally-induced Crohn's disease in rats

“…Matters et al [57] reported that naltrexone reduced intestinal inflammation and pro-inflammatory cytokines in dextran sulfate sodium (DSS) model in mice.…”