Pușcașu Ciprian, Andrei Corina, Olaru Octavian Tudorel, Zanfirescu Anca
Faculty of Pharmacy, "Carol Davila" University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania.
Curr Issues Mol Biol. 2025 Jan 17;47(1):63. doi: 10.3390/cimb47010063.
Chronic pain is a debilitating condition affecting millions worldwide, often resulting from complex interactions between the nervous and immune systems. Recent advances highlight the critical role of metabolite-sensing G protein-coupled receptors (GPCRs) in various chronic pain types. These receptors link metabolic changes with cellular responses, influencing inflammatory and degenerative processes. Receptors such as free fatty acid receptor 1 (FFAR1/GPR40), free fatty acid receptor 4 (FFAR4/GPR120), free fatty acid receptor 2 (FFAR2/GPR43), and Takeda G protein-coupled receptor 5 (TGR5/GPR131/GPBAR1) are key modulators of nociceptive signaling. GPR40, activated by long-chain fatty acids, exhibits strong anti-inflammatory effects by reducing cytokine expression. Butyrate-activated GPR43 inhibits inflammatory mediators like nitric oxide synthase-2 and cyclooxygenase-2, mitigating inflammation. TGR5, activated by bile acids, regulates inflammation and cellular senescence through pathways like NF-κB and p38. These receptors are promising therapeutic targets in chronic pain, addressing the metabolic and inflammatory factors underlying nociceptive sensitization and tissue degeneration. This review explores the molecular mechanisms of metabolite-sensing receptors in chronic pain, their therapeutic potential, and challenges in clinical application. By uncovering these mechanisms, metabolite-sensing receptors could lead to safer, more effective pain management strategies.
慢性疼痛是一种使人衰弱的病症，影响着全球数百万人，通常由神经系统和免疫系统之间的复杂相互作用引起。最近的进展突出了代谢物感知G蛋白偶联受体（GPCRs）在各种慢性疼痛类型中的关键作用。这些受体将代谢变化与细胞反应联系起来，影响炎症和退行性过程。诸如游离脂肪酸受体1（FFAR1/GPR40）、游离脂肪酸受体4（FFAR4/GPR120）、游离脂肪酸受体2（FFAR2/GPR43）和武田G蛋白偶联受体5（TGR5/GPR131/GPBAR1）等受体是伤害性信号传导的关键调节因子。由长链脂肪酸激活的GPR40通过降低细胞因子表达表现出强大的抗炎作用。丁酸盐激活的GPR43抑制一氧化氮合酶-2和环氧化酶-2等炎症介质，减轻炎症。由胆汁酸激活的TGR5通过NF-κB和p38等途径调节炎症和细胞衰老。这些受体是慢性疼痛中有前景的治疗靶点，可解决伤害性致敏和组织退化背后的代谢和炎症因素。本综述探讨了代谢物感知受体在慢性疼痛中的分子机制、它们的治疗潜力以及临床应用中的挑战。通过揭示这些机制，代谢物感知受体可能会带来更安全、更有效的疼痛管理策略。
