2. Academic Validation
  3. Arrestin-biased allosteric modulator of neurotensin receptor 1 alleviates acute and chronic pain

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

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.

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