The Role of the Delta Opioid Receptor in Two Murine Models of Colitis

Open Access
Author:
Bobo, Tia R
Graduate Program:
Laboratory Animal Medicine
Degree:
Master of Science
Document Type:
Master Thesis
Date of Defense:
None
Committee Members:
  • Tiffany Lynn Whitcomb, Thesis Advisor
Keywords:
  • Crohn's disease
  • ulcerative colitis
  • delta opioid receptor
  • 7-Benzylidenenaltrexone (BNTX)
  • disease activity index
  • dextran sodium sulfate (DSS)
  • inflammatory bowel disease (IBD)
  • myeloperoxidase (MPO)
  • naltrexone (NTX)
  • 2
  • 4
  • 6-Trinitrobenzenesulfonic acid (TNBS)
  • naltrindole (NTI)
  • [D-Pen2
  • 5] - Enkephalin hydrate (DPDPE)
  • delta agonist
  • delta antagonist
Abstract:
Crohn’s disease (CD) and ulcerative colitis (UC) are classified as chronic inflammatory disorders of the gastrointestinal tract, and are classically termed inflammatory bowel disease. Currently, there is no known cause or medical cure of this often times debilitating disease and the reported estimated annual cost for medical treatment within the United States is $2 billion. In this study, we investigated the effects of a naltrexone (NTX), a nonselective opioid receptor antagonist, in two murine models of colitis. We compared the anti-inflammatory effects of high dose NTX (1.0 mg/kg) to that of the low dose NTX (0.1 mg/kg) therapy administered subcutaneously (SQ). We also compared the specific opioid delta receptor antagonists, naltrindole (NTI), a delta-1 receptor antagonist, and 7-benzylidenenaltrexone (BNTX), a delta 2-receptor antagonist, in order to study how selective blockade of the delta receptor affects colonic inflammation. A small subset of mice were used to examine whether inflammation was influenced by agonist effects of the delta receptor, and this was achieved by administering [D-Pen2, 5] - Enkephalin hydrate (DPDPE) SQ. For this purpose, male C57BL/6NCrl mice (15 to 20 g; age 6 to 8 wk.; n=110) and female Balb/cAnNCrl mice (15 to 20 g; 6-8 wk.; n=115) were used for the Dextran Sodium Sulfate (DSS) model (that mimics ulcerative colitis) as well as the 2, 4, 6-Trinitrobenzenesulfonic acid (TNBS) model (that mimics Crohn’s disease) respectively. Disease activity indices (DAIs) were used to quantitatively measure colonic symptoms and overall illness. We found that administration with NTX (0.1mg/kg, 1.0 mg/kg) significantly improved overall scores in the DSS model of colitis on days 4 and 5 of therapy. The volume percentage of red blood cells within the blood, also known as hematocrit (HCT), is a good indicator when determining whether anemia or dehydration is present. BNTX and NTX therapy (0.1mg/kg, 1.0 mg/kg) were shown to return HCT values closer to normal values. Therapy with NTX (0.1mg/kg) demonstrated improved colon length, which in active cases of colitis would otherwise be shortened. Microscopic evaluation is a good diagnostic tool to accurately assess active or chronic inflammatory conditions. Treatment with NTX (1.0 mg/kg) significantly reduced histologic indices. In the TNBS model, low dose NTX significantly improved HCT whereas therapy with high dose NTX significantly reduced macroscopic ulcers. Based on the current findings, therapy with NTX exhibited some therapeutic effects in two murine models of colitis, whereas delta agonists and antagonists had limited efficacy.