杜克大学Ru-Rong Ji课题组近日取得一项新成果。经过不懈努力，他们提出了神经紧张素受体1的抑制因子偏置变构调节剂减轻急性和慢性疼痛。相关论文于2025年5月19日发表在《细胞》杂志上。
研究团队之前报道了SBI-553，一种神经紧张素受体1 （NTSR1）阳性的变构调节剂偏向于βarr2信号，可以减弱小鼠的精神兴奋作用。研究小组证明其类似物SBI-810通过全身和局部给药，在啮齿动物术后疼痛、炎症性疼痛和神经性疼痛模型中表现出有效的抗伤害性特性。SBI-810的镇痛作用需要NTSR1和βarr1，而不需要NTSR2和βarr1。在机制上，SBI-810抑制兴奋性突触传递，抑制脊髓伤害性神经元中的NMDA受体和细胞外调节信号激酶（ERK）信号，降低初级感觉神经元中Nav1.7表面表达和动作电位放电，并抑制C-纤维反应。在行为上，它减少阿片类药物诱导的条件位置偏好，缓解便秘，减轻慢性阿片类药物戒断症状。这些发现强调了NTSR1偏倚的变张力调节剂作为一种有希望的、非成瘾性的治疗策略，通过外周和中枢机制作用于急性和慢性疼痛管理。
据了解，G蛋白偏向性激动剂已被证明通过绕过β-抑制素-2 （βarr2）信号传导来增强阿片镇痛。
附：英文原文
Title: Arrestin-biased allosteric modulator of neurotensin receptor 1 alleviates acute and chronic pain
Author: Ran Guo, Ouyang Chen, Yang Zhou, Sangsu Bang, Sharat Chandra, Yize Li, Gang Chen, Rou-Gang Xie, Wei He, Jing Xu, Richard Zhou, Shaoyong Song, Kelsey L. Person, Madelyn N. Moore, Abigail R. Alwin, Ivan Spasojevic, Michael R. Jackson, Steven H. Olson, Marc G. Caron, Lauren M. Slosky, William C. Wetsel, Lawrence S. Barak, Ru-Rong Ji
Issue&Volume: 2025-05-19
Abstract: G-protein-biased agonists have been shown to enhance opioid analgesia by circumventing β-arrestin-2 (βarr2) signaling. We previously reported that SBI-553, a neurotensin receptor 1 (NTSR1)-positive allosteric modulator biased toward βarr2 signaling, attenuates psychostimulant effects in mice. Here, we demonstrate that its analog, SBI-810, exhibits potent antinociceptive properties in rodent models of postoperative pain, inflammatory pain, and neuropathic pain via systemic and local administration. SBI-810’s analgesic effects require NTSR1 and βarr2 but not NTSR2 or βarr1. Mechanistically, SBI-810 suppresses excitatory synaptic transmission, inhibits NMDA receptor and extracellular-regulated signal kinase (ERK) signaling in spinal cord nociceptive neurons, reduces Nav1.7 surface expression and action potential firing in primary sensory neurons, and dampens C-fiber responses. Behaviorally, it reduces opioid-induced conditioned place preference, alleviates constipation, and mitigates chronic opioid withdrawal symptoms. These findings highlight NTSR1-biased allosteric modulators as a promising, non-addictive therapeutic strategy for acute and chronic pain management, acting through both peripheral and central mechanisms.
DOI: 10.1016/j.cell.2025.04.038
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00508-2