PT  - JOURNAL ARTICLE
AU  - Nestor Nivardo Jiménez-Vargas
AU  - Yang Yu
AU  - Dane D Jensen
AU  - Diana Daeun Bok
AU  - Matthew Wisdom
AU  - Rocco Latorre
AU  - Cintya Lopez
AU  - Josue O Jaramillo-Polanco
AU  - Claudius Degro
AU  - Mabel Guzman-Rodriguez
AU  - Quentin Tsang
AU  - Zachary Snow
AU  - Brian L Schmidt
AU  - David E Reed
AU  - Alan Edward Lomax
AU  - Kara Gross Margolis
AU  - Christoph Stein
AU  - Nigel W Bunnett
AU  - Stephen J Vanner
TI  - Agonist that activates the µ-opioid receptor in acidified microenvironments inhibits colitis pain without side effects
AID  - 10.1136/gutjnl-2021-324070
DP  - 2022 Apr 01
TA  - Gut
PG  - 695--704
VI  - 71
IP  - 4
4099  - http://gut.bmj.com/content/71/4/695.short
4100  - http://gut.bmj.com/content/71/4/695.full
SO  - Gut2022 Apr 01; 71
AB  - 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.Data are available on reasonable request. Data are available from the corresponding authors on reasonable request.