ArticleGut2022
Agonist that activates the µ-opioid receptor in acidified microenvironments inhibits colitis pain without side effects.
Article in Gut, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
31 citing papers in PubMed, 45 citations in OpenAlex.
- Development of pH-Sensitive β‑Adrenergic Receptor Antagonists.ACS pharmacology & translational science · 2026Article
- Monoclonal antibody inhibition of PAR2 reduces phenotype severity and pain in murine inflammatory bowel disease.Pain reports · 2026Article
- Mechanisms of chronic abdominal pain in inflammatory bowel disease and implications for treatment.Nature reviews. Gastroenterology & hepatology · 2026Review
- Mechanisms of Location Bias in G Protein-Coupled Receptors.Handbook of experimental pharmacology · 2026Review
- Nanomedicines targeting protease-activated receptor 2 in endosomes provide sustained analgesia.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A Bacteroides fragilis protease activates host PARCell host & microbe · 2025Article
- Emerging therapeutic approaches for treating abdominal pain.Journal of the Canadian Association of Gastroenterology · 2025Review
- Gut sensory neurons as regulators of neuro-immune-microbial interactions: from molecular mechanisms to precision therapy for IBD/IBS.Journal of neuroinflammation · 2025Review
- Pain Signaling by GPCRs and RTKs.Trends in pharmacological sciences · 2025Review
- Discovery of Novel pH-Sensitive μ-Opioid Receptor Agonists as Potent Analgesics with Reduced Side Effects.ACS medicinal chemistry letters · 2025Article
- A pH-sensitive opioid does not exhibit analgesic tolerance in a mouse model of colonic inflammation.British journal of pharmacology · 2025Article
- Effects of pH on opioid receptor activation and implications for drug design.Biophysical journal · 2024Review
- Assessment of the antinociceptive, respiratory-depressant, and reinforcing effects of the low pKNeuropharmacology · 2024Article
- Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments.Gastroenterology · 2024Review
- GPCR kinases differentially modulate biased signaling downstream of CXCR3 depending on their subcellular localization.Science signaling · 2024Article
- Location bias: A "Hidden Variable" in GPCR pharmacology.BioEssays : news and reviews in molecular, cellular and developmental biology · 2023Review
- Article
- Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides sustained pain relief.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- XVIIth Little Brain Big Brain: an extraordinary meeting in extraordinary times.Nature reviews. Gastroenterology & hepatology · 2023Article
- A multi-dimensional view of context-dependent G protein-coupled receptor function.Biochemical Society transactions · 2023Review
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Authors and funding
19 authors at 6 institutions in 4 countries.
Funding
Abstract
objectiveThe 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.
designAntinociceptive 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.
resultsNFEPP 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.
conclusionIn a preclinical IBD model, NFEPP preferentially activates MOPr in acidified microenvironments of inflamed tissues to induce antinociception without causing respiratory depression, constipation and hyperactivity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.