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Original research
Agonist that activates the µ-opioid receptor in acidified microenvironments inhibits colitis pain without side effects
  1. Nestor Nivardo Jiménez-Vargas1,
  2. Yang Yu1,
  3. Dane D Jensen2,3,
  4. Diana Daeun Bok3,
  5. Matthew Wisdom3,
  6. Rocco Latorre3,
  7. Cintya Lopez1,
  8. Josue O Jaramillo-Polanco1,
  9. Claudius Degro1,
  10. Mabel Guzman-Rodriguez1,
  11. Quentin Tsang1,
  12. Zachary Snow4,
  13. Brian L Schmidt2,
  14. David E Reed1,
  15. Alan Edward Lomax1,
  16. Kara Gross Margolis4,
  17. Christoph Stein5,
  18. Nigel W Bunnett3,6,
  19. Stephen J Vanner1
  1. 1Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queens University, Kingston, Ontario, Canada
  2. 2Bluestone Center for Clinical Research, New York University College of Dentistry, New York, New York, USA
  3. 3Department of Molecular Pathobiology, New York University College of Dentistry, New York, New York, USA
  4. 4Department of Pediatrics, Columbia University in the City of New York, New York, New York, USA
  5. 5Department Experimental Anaesthesiology, Charité Campus Benjamin Franklin, Berlin, Germany
  6. 6Department of Neuroscience and Physiology, Neuroscience Institute, Grossman School of Medicine, New York University, New York, New York, USA
  1. Correspondence to Professor Nigel W Bunnett, Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA; nwb2{at}nyu.edu

Abstract

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.

  • abdominal pain
  • IBD
  • receptor characterisation

Data availability statement

Data are available on reasonable request. Data are available from the corresponding authors on reasonable request.

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Data availability statement

Data are available on reasonable request. Data are available from the corresponding authors on reasonable request.

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Footnotes

  • NNJ-V, YY and DDJ are joint first authors.

  • NWB and SJV are joint senior authors.

  • Funding Supported by grants from National Institutes of Health (NS102722, DE026806, DK118971, DE029951, NWB, BLS; RO1NS01554, KGM), Department of Defence (W81XWH1810431, NWB, BLS; PR160365, KGM), Crohn’s Colitis Canada (SJV, AEL, DER) and Deutsche Forschungsgemeinschaft (STE 477/19-1, EXC 2046 AA1-1, CS).

  • Competing interests NWB is a founding scientist of Endosome Therapeutics Inc.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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