IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-12-09 DOI:10.1016/j.jpet.2024.100056
Jyoti N Sengupta, Maia Terashvili, Bidyut K Medda
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引用次数: 0

摘要

全球有 10%-15% 的人患有膀胱疼痛综合征和肠易激综合征。目前针对这些综合征的治疗方案对严重的疾病进展无效,而且充满不良反应。长期使用传统阿片类药物会导致便秘、呼吸抑制、耐受和成瘾。在两种阿片受体(ORs)上具有激动剂/拮抗剂混合特性的双功能阿片配体具有治疗优势。治疗以腹泻为主的肠易激综合征的药物 Eluxadoline(ELX,Viberzi)对μ-阿片受体(MOR)具有激动作用,对δ-阿片受体(DOR)具有拮抗作用。ELX 可通过激活 MOR 缓解疼痛并使肠蠕动正常化,但不会导致便秘,这是一种 DOR 拮抗作用。然而,其镇痛作用机制尚不清楚。我们通过记录器官胀痛时的粘液运动反应(VMRs),研究了ELX对结肠和膀胱疼痛的镇痛机制,并确定了该药物在疼痛信号通路中的作用部位。ELX通过激活脊髓MOR抑制VMRs。外周受限的MOR拮抗剂纳洛酮-甲碘化物(meth-NLX)不能逆转ELX对VMR的抑制,而中枢作用的NLX则能逆转这种抑制。ELX 不能抑制支配膀胱或结肠的腰 6(L6)和骶 1(S1)背根机械敏感传入纤维的兴奋。相反,ELX 可抑制膀胱膨胀反应性 L6 和 S1 脊髓神经元的兴奋。NLX 可以逆转这种抑制作用,而甲基-NLX 则不能。电生理学结果加强了行为实验,表明 ELX 可通过减弱脊髓神经元的反应产生镇痛效果,但不能减弱内脏感觉传入。意义声明:双功能阿片配体艾洛沙多林是美国食品与药物管理局(FDA)批准用于治疗以腹泻为主的肠易激综合征的药物,可使肠蠕动正常化并缓解腹痛。据我们所知,这项研究首次证明,与使腹泻恢复正常的外周作用不同,该药物通过调节骶尾部(L6-S1)脊髓神经元的反应,从中枢缓解结肠和膀胱疼痛。
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Visceral analgesic effect of eluxadoline (Viberzi): A central action.

Painful bladder syndrome and irritable bowel syndrome affect 10%-15% of the global population. Current treatment options for these syndromes are ineffective in severe disease progression and are fraught with adverse effects. Prolonged use of conventional opioids causes constipation, respiratory depression, tolerance, and addiction. Bifunctional opioid ligands with mixed agonist/antagonist profiles at 2 types of opioid receptors (ORs) possess therapeutic advantages. Eluxadoline (ELX, Viberzi), a drug for diarrhea-predominant irritable bowel syndrome, has an agonistic effect on μ-opioid receptor (MOR) and an antagonistic effect on δ-opioid receptor (DOR). ELX alleviates pain and normalizes peristalsis by activating MOR without causing constipation, a DOR antagonistic effect. However, its mechanism of analgesic action is not known. We investigated the analgesic mechanism of ELX in colon and bladder pain by recording the visceromotor responses (VMRs) to painful distension of the organ and identified the site of action of the drug in pain signaling pathways. ELX inhibited VMRs via the activation of spinal MOR. The peripherally restricted MOR antagonist naloxone-methiodide (meth-NLX) did not reverse the VMR inhibition by ELX, whereas centrally acting NLX reversed it. ELX did not inhibit the excitation of mechanosensitive afferent fibers in lumbar 6 (L6) and sacral 1 (S1) dorsal root innervating the bladder or colon. In contrast, ELX inhibited excitation of bladder distension-responsive L6 and S1 spinal neurons. The inhibition was reversed by NLX, but not by meth-NLX. Electrophysiology results reinforce behavioral experiments suggesting that ELX produces analgesia by attenuating responses of spinal neurons, but not visceral sensory afferents. SIGNIFICANCE STATEMENT: The bifunctional opioid ligand eluxadoline is an FDA-approved drug for the treatment of diarrhea-predominant irritable bowel syndrome to normalize bowel movement and to relieve abdominal pain. This study documents for the first time to our knowledge that unlike its peripheral action to normalize diarrhea, the drug alleviates colon and bladder pain centrally by modulating responses of lumbo-sacral (L6-S1) spinal neurons.

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来源期刊
CiteScore
6.90
自引率
0.00%
发文量
115
审稿时长
1 months
期刊介绍: A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.
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