TY - JOUR
T1 - Agonist that activates the μ-opioid receptor in acidified microenvironments inhibits colitis pain without side effects
AU - Jiménez-Vargas, Nestor Nivardo
AU - Yu, Yang
AU - Jensen, Dane D.
AU - Bok, Diana Daeun
AU - Wisdom, Matthew
AU - Latorre, Rocco
AU - Lopez, Cintya
AU - Jaramillo-Polanco, Josue O.
AU - Degro, Claudius
AU - Guzman-Rodriguez, Mabel
AU - Tsang, Quentin
AU - Snow, Zachary
AU - Schmidt, Brian L.
AU - Reed, David E.
AU - Lomax, Alan Edward
AU - Margolis, Kara Gross
AU - Stein, Christoph
AU - Bunnett, Nigel W.
AU - Vanner, Stephen J.
N1 - Funding Information:
1Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queens University, Kingston, Ontario, Canada 2Bluestone Center for Clinical Research, New York University College of Dentistry, New York, New York, USA 3Department of Molecular Pathobiology, New York University College of Dentistry, New York, New York, USA 4Department of Pediatrics, Columbia University in the City of New York, New York, New York, USA 5Department Experimental Anaesthesiology, Charité Campus Benjamin Franklin, Berlin, Germany 6Department of Neuroscience and Physiology, Neuroscience Institute, Grossman School of Medicine, New York University, New York, New York, USA 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).
Publisher Copyright:
©
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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.
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.
KW - IBD
KW - abdominal pain
KW - receptor characterisation
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U2 - 10.1136/gutjnl-2021-324070
DO - 10.1136/gutjnl-2021-324070
M3 - Article
C2 - 33785555
AN - SCOPUS:85103506983
SN - 0017-5749
VL - 71
SP - 695
EP - 704
JO - Gut
JF - Gut
IS - 4
ER -