A Fentanyl Analogue That Activates u-Opioid Receptors in Acidified Tissues Inhibits Colitis Pain without Opioid Side Effects

Nestor N. Jimenez-Vargas, Claudius E. Degro, Christoph Stein, Nigel W. Bunnett, Stephen J. Vanner

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Opioid agonists are effective analgesics for treating visceral pain but their use is limited by their on-target side effects, such as constipation, respiratory depression and sedation. The development of a fentanyl analogue, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), which preferentially activates μ opioid receptors (MOPr) in acidified microenvironments of diseased tissues, represents a novel alternative for inhibiting pain in inflamed tissues. Here we review the pharmacokinetic properties of this compound, study the somatic inflammatory and cancer pain models and describe in more detail a series of experiments in a preclinical model of inflammatory bowel disease (IBD) that assess its analgesic efficacy and potential to mitigate on-target side effects in uninflamed tissues. Using a combination of patch-clamp recordings, ex vivo colonic afferent nerve recordings and in vivo visceromotor reflex recordings, as well as monitoring of cardiorespiratory function, colonic motility and locomotion in the DSS colitis mouse model, we showed that NFEPP has similar analgesic efficacy compared to the conventional opioid fentanyl but lacked the common side effects observed with fentanyl. Taken together, these studies show that NFEPP has considerable promise as a highly effective analgesic agent to treat pain in inflamed visceral tissues without opioid side effects, similar to its profile in inflammatory somatic and cancer pain.

Original languageEnglish (US)
Title of host publicationVisceral Pain
PublisherSpringer International Publishing
Pages143-152
Number of pages10
ISBN (Electronic)9783031257025
ISBN (Print)9783031257018
DOIs
StatePublished - Jan 1 2023

Keywords

  • Acidified tissue
  • Fentanyl
  • Inflammation pain related
  • Inflammation selective agonists
  • NFEPP
  • Opioid side effects
  • Opioids
  • PH-sensitive opioid agonists

ASJC Scopus subject areas

  • General Medicine
  • General Neuroscience

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