Agonist that activates the µ-opioid receptor in acidified microenvironments inhibits colitis pain without side effects.
IBD
abdominal pain
receptor characterisation
Journal
Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
08
01
2021
revised:
15
02
2021
accepted:
09
03
2021
pubmed:
1
4
2021
medline:
10
5
2022
entrez:
31
3
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 33785555
pii: gutjnl-2021-324070
doi: 10.1136/gutjnl-2021-324070
pmc: PMC8608554
mid: NIHMS1756490
doi:
Substances chimiques
Receptors, Opioid
0
Fentanyl
UF599785JZ
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
695-704Subventions
Organisme : NINDS NIH HHS
ID : R01 NS015547
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK126644
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK118971
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102722
Pays : United States
Organisme : NIA NIH HHS
ID : T35 AG044303
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE026806
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK130517
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE029951
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: NWB is a founding scientist of Endosome Therapeutics Inc.
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