Related Experiment Video
Updated: Nov 11, 2025
Intracranial Pharmacotherapy and Pain Assays in Rodents
Published on: April 9, 2019
Agonist that activates the µ-opioid receptor in acidified microenvironments inhibits colitis pain without side
Nestor Nivardo Jiménez-Vargas1, Yang Yu1, Dane D Jensen2,3
1Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queens University, Kingston, Ontario, Canada.
Objective:
The effectiveness of µ-opioid receptor (MOPr) agonists for treatment of visceral pain is compromised by constipation, respiratory depression, sedation and addiction. We investigated whether a fentanyl analogue, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), which preferentially activates MOPr in acidified diseased tissues, would inhibit pain in a preclinical model of inflammatory bowel disease (IBD) without side effects in healthy tissues.
Design:
Antinociceptive actions of NFEPP and fentanyl were compared in control mice and mice with dextran sodium sulfate colitis by measuring visceromotor responses to colorectal distension. Patch clamp and extracellular recordings were used to assess nociceptor activation. Defecation, respiration and locomotion were assessed. Colonic migrating motor complexes were assessed by spatiotemporal mapping of isolated tissue. NFEPP-induced MOPr signalling and trafficking were studied in human embryonic kidney 293 cells.
Results:
NFEPP inhibited visceromotor responses to colorectal distension in mice with colitis but not in control mice, consistent with acidification of the inflamed colon. Fentanyl inhibited responses in both groups. NFEPP inhibited the excitability of dorsal root ganglion neurons and suppressed mechanical sensitivity of colonic afferent fibres in acidified but not physiological conditions. Whereas fentanyl decreased defecation and caused respiratory depression and hyperactivity in mice with colitis, NFEPP was devoid of these effects. NFEPP did not affect colonic migrating motor complexes at physiological pH. NFEPP preferentially activated MOPr in acidified extracellular conditions to inhibit cAMP formation, recruit β-arrestins and evoke MOPr endocytosis.
Conclusion:
In a preclinical IBD model, NFEPP preferentially activates MOPr in acidified microenvironments of inflamed tissues to induce antinociception without causing respiratory depression, constipation and hyperactivity.
Insights
A novel fentanyl analogue, NFEPP, effectively treats visceral pain in inflammatory bowel disease models by targeting acidified tissues. It provides pain relief without common opioid side effects like respiratory depression or constipation.
Area of Science:
- Pharmacology
- Gastroenterology
- Pain Medicine
Background:
- Mu-opioid receptor (MOPr) agonists effectively treat visceral pain but cause significant side effects.
- Constipation, respiratory depression, sedation, and addiction limit MOPr agonist utility.
- Developing targeted MOPr agonists for visceral pain is crucial.
Purpose of the Study:
- To investigate the efficacy of a fentanyl analogue, NFEPP, in a preclinical inflammatory bowel disease (IBD) model.
- To determine if NFEPP, which targets acidified tissues, can inhibit pain without side effects.
- To compare NFEPP's antinociceptive and side effect profile to fentanyl.
Main Methods:
- Compared NFEPP and fentanyl antinociception in control and colitis-induced mice using visceromotor responses.
- Assessed nociceptor activation via patch clamp and extracellular recordings.
- Evaluated defecation, respiration, locomotion, and colonic motor function; studied MOPr signaling in vitro.
Main Results:
- NFEPP inhibited pain in colitis mice but not controls, correlating with colonic acidification.
- Fentanyl inhibited pain in both groups.
- NFEPP showed no respiratory depression, constipation, or hyperactivity, unlike fentanyl, and did not affect colonic motor function at physiological pH.
Conclusions:
- NFEPP demonstrates targeted antinociception in a preclinical IBD model by activating MOPr in acidified inflamed tissues.
- NFEPP offers potential for visceral pain management without the adverse effects associated with traditional MOPr agonists.
- This targeted approach represents a promising strategy for treating inflammatory pain conditions.
Related Concept Videos
01:25Analgesia and Pain Management
01:17Drugs Affecting GI Tract Motility: Opioids as Antidiarrheal Agents
Opioids, widely used antidiarrheal agents, mitigate diarrhea by slowing down...
01:22Opioid Receptors: Overview
01:28Acid Suppressive Drugs for Peptic Ulcer Disease: Histamine H2-Receptor Antagonists
01:20Drugs for Peptic Ulcer Disease: Prostaglandin Analogs as Mucosal Protective Agents
Non-steroidal anti-inflammatory drugs (NSAIDs) can induce peptic ulcers by inhibiting cyclooxygenase, decreasing...
01:20Opioid Analgesics: Morphine and Other Natural Cogeners