Arrestin-biased allosteric modulator of neurotensin receptor 1 alleviates acute and chronic pain

  • Cell. 2025 Aug 7;188(16):4332-4349.e21. doi: 10.1016/j.cell.2025.04.038.
Ran Guo  1 ,  Ouyang Chen  2 ,  Yang Zhou  3 ,  Sangsu Bang  1 ,  Sharat Chandra  1 ,  Yize Li  1 ,  Gang Chen  1 ,  Rou-Gang Xie  1 ,  Wei He  1 ,  Jing Xu  1 ,  Richard Zhou  1 ,  Shaoyong Song  1 ,  Kelsey L Person  4 ,  Madelyn N Moore  4 ,  Abigail R Alwin  4 ,  Ivan Spasojevic  5 ,  Michael R Jackson  6 ,  Steven H Olson  6 ,  Marc G Caron  3 ,  Lauren M Slosky  4 ,  William C Wetsel  7 ,  Lawrence S Barak  3 ,  Ru-Rong Ji  8
Affiliations
  • 1. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27705, USA.
  • 2. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27705, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
  • 3. Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
  • 4. Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
  • 5. Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; Pharmacokinetics/Pharmacodynamics Core Laboratory, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA.
  • 6. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 7. Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA; Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
  • 8. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27705, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: [email protected].
PMID: 40393456 DOI: 10.1016/j.cell.2025.04.038
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.

Keywords
NTSR1; acute pain; beta-arrestin-2; biased allosteric modulator; chronic pain; dorsal root ganglion; neurotensin receptor 1; opioid; primary sensory neurons; spinal cord.
Products