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Here, we compare the development of tolerance to the conventional opioid fentanyl with a novel pH\u2010sensitive <jats:italic>\u03bc<\/jats:italic>\u2010opioid receptor (MOR) agonist, (\u00b1)\u2010N\u2010(3\u2010fluoro\u20101\u2010phenethylpiperidine\u20104\u2010yl)\u2010N\u2010phenyl propionamide (NFEPP) that is active only in acidic inflammatory microenvironments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>An opioid tolerance model was developed in male C57BL\/6 mice, with and without dextran sulphate sodium colitis, using increasing doses of either fentanyl or NFEPP over 5\u2009days. Visceral nociception was assessed in vivo by measuring visceromotor responses (VMRs) to noxious colorectal distensions and in vitro measuring colonic afferent nerve activity of mesenteric nerves and performing patch\u2010clamp recordings from isolated dorsal root ganglia neurons. Somatic thermal nociception was tested using a tail immersion assay. Cardiorespiratory effects were analysed by pulse oximeter experiments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>VMRs and tail immersion tests demonstrated tolerance to fentanyl, but not to NFEPP in colitis mice. Cross\u2010tolerance also occurred to fentanyl, but not to NFEPP. The MOR agonist DAMGO inhibited colonic afferent nerve activity in colitis mice exposed to chronic NFEPP, but not those from fentanyl\u2010treated mice. Similarly, in patch\u2010clamp recordings from isolated dorsal root ganglia neurons, DAMGO inhibited neurons from NFEPP\u2010, but not fentanyl\u2010treated mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>NFEPP did not exhibit tolerance in an inflammatory pain model, unlike fentanyl. Consequently, dose escalation to maintain analgesia during an evolving inflammation could be avoided, mitigating the potential risk of side effects.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17363","type":"journal-article","created":{"date-parts":[[2024,10,13]],"date-time":"2024-10-13T22:36:56Z","timestamp":1728859016000},"page":"581-595","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A pH\u2010sensitive opioid does not exhibit analgesic tolerance in a mouse model of colonic inflammation"],"prefix":"10.1111","volume":"182","author":[{"given":"Claudius E.","family":"Degro","sequence":"first","affiliation":[{"name":"Gastrointestinal Diseases Research Unit, Kingston General Hospital Queen's University  Kingston Ontario Canada"},{"name":"Department of General and Visceral Surgery Charit\u00e9 \u2013 Universit\u00e4tsmedizin Corporate Member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu 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