A pH-sensitive mu-opioid receptor agonist: Studies for a role in the treatment of pain in models of Inflammatory Bowel Disease

Abstract

Introduction: Targeting acidified tissues with pH-sensitive opioids has recently been introduced as a novel approach to managing pain in inflammatory bowel disease (IBD). The fluorinated analogue of fentanyl, ±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP) selectively activates opioid receptors in acidic tissues but has no effect at physiological pH, providing analgesia without side effects. This thesis aimed to (1) investigate NFEPP in a model of transmural inflammation. Methods: (1) 2,4,6-trinitrobenzene sulfonic acid (TNBS) and dinitrobenzene sulfonic acid (DNBS) were used to induce a model of transmural inflammation in C57BL/6 mice. Weight and disease activity index (DAI) were used to measure the development of colitis. (2) Dextran sulphate sodium (DSS) was used to induce a model of colitis only involving mucosa/submucosa in C57BL/6 mice. Mice received injections of fentanyl, NFEPP or vehicle, three times a day over four days, or DAMGO administered once per day. Weight, DAI, myeloperoxidase (MPO) activity, and colon length/thickness were used to evaluate the effects of each opioid on the development of colitis. (3) A paw pulse oximeter was used to measure heart rate and oxygen saturation levels following the subcutaneous administration of NFEPP, fentanyl, naloxone, naloxone methiodide or vehicle. Results: (1) TNBS and DNBS models did not produce consistent inflammation to further investigate the effects of opioids on transmural inflammation. (2) NFEPP and fentanyl reduced MPO but did not improve or exacerbate other measures of DSS-induced colitis compared to vehicle. Fentanyl caused 25% more weight loss compared to NFEPP and vehicle, which did not differ. (3) NFEPP-induced bradycardia at higher doses which was blocked by naloxone but not naloxone methiodide. Conclusion: (1) TNBS and DNBS models were not ideal models to study an analgesic dependent on the tissue's pH. (2) The anti-inflammatory effects of DAMGO, NFEPP and fentanyl were inconclusive but suggested a potential anti-inflammatory action based on MPO levels. (3) NFEPP-mediated bradycardia in mice is mediated by MOR. Together, these findings provide new insights into the potential role of pH-sensitive opioids as a novel therapy for the treatment of pain in IBD.