Degro Claudius E, Jiménez-Vargas Nestor Nivardo, Guzman-Rodriguez Mabel, Schincariol Hailey, Tsang Quentin, Reed David E, Lomax Alan E, Bunnett Nigel W, Stein Christoph, Vanner Stephen J
Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, Ontario, Canada.
Department of General and Visceral Surgery, Charité - Universitätsmedizin Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany.
Br J Pharmacol. 2025 Feb;182(3):581-595. doi: 10.1111/bph.17363. Epub 2024 Oct 13.
Tolerance to the analgesic effects of opioids and resultant dose escalation is associated with worsening of side effects and greater addiction risk. Here, we compare the development of tolerance to the conventional opioid fentanyl with a novel pH-sensitive μ-opioid receptor (MOR) agonist, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP) that is active only in acidic inflammatory microenvironments.
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 days. 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-clamp 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.
VMRs and tail immersion tests demonstrated tolerance to fentanyl, but not to NFEPP in colitis mice. Cross-tolerance 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-treated mice. Similarly, in patch-clamp recordings from isolated dorsal root ganglia neurons, DAMGO inhibited neurons from NFEPP-, but not fentanyl-treated mice.
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.
对阿片类药物镇痛作用的耐受性以及由此导致的剂量增加与副作用加重和更高的成瘾风险相关。在此，我们比较了对传统阿片类药物芬太尼与新型pH敏感的μ-阿片受体（MOR）激动剂（±）-N-（3-氟-1-苯乙基哌啶-4-基）-N-苯基丙酰胺（NFEPP）耐受性的发展情况，后者仅在酸性炎症微环境中具有活性。
利用雄性C57BL/6小鼠，无论有无葡聚糖硫酸钠诱导的结肠炎，通过在5天内递增芬太尼或NFEPP的剂量建立阿片类药物耐受性模型。通过测量对有害结肠扩张的内脏运动反应（VMR）在体内评估内脏痛觉，通过测量肠系膜神经的结肠传入神经活动并对分离的背根神经节神经元进行膜片钳记录在体外评估内脏痛觉。使用尾部浸入试验测试躯体热痛觉。通过脉搏血氧仪实验分析心肺效应。
VMR和尾部浸入试验表明结肠炎小鼠对芬太尼产生耐受性，但对NFEPP未产生耐受性。对芬太尼也出现交叉耐受性，但对NFEPP未出现。MOR激动剂DAMGO抑制了暴露于慢性NFEPP的结肠炎小鼠的结肠传入神经活动，但未抑制芬太尼处理小鼠的结肠传入神经活动。同样，在分离的背根神经节神经元的膜片钳记录中，DAMGO抑制了NFEPP处理小鼠的神经元，但未抑制芬太尼处理小鼠 的神经元。
与芬太尼不同，NFEPP在炎症性疼痛模型中未表现出耐受性。因此，可以避免在炎症进展过程中为维持镇痛而增加剂量，从而降低副作用的潜在风险。
