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

Summary

This preclinical study identifies SBI-810, a β-arrestin–biased NTSR1 positive allosteric modulator, as a potent analgesic across postoperative, inflammatory, and neuropathic pain models. Analgesia required NTSR1/β-arrestin-2, reduced excitatory signaling (NMDA/ERK), decreased Nav1.7 surface expression and neuronal firing, and attenuated C-fiber responses, while reducing opioid reward, constipation, and withdrawal behaviors.

Key Findings

• SBI-810 produced robust analgesia in postoperative, inflammatory, and neuropathic pain models via systemic and local routes.
• Analgesia required NTSR1 and β-arrestin-2, but not NTSR2 or β-arrestin-1, indicating mechanism specificity.
• SBI-810 suppressed NMDA/ERK signaling, reduced Nav1.7 surface expression and neuronal firing, and dampened C-fiber responses.
• Behaviorally, SBI-810 reduced opioid-induced conditioned place preference, constipation, and chronic opioid withdrawal symptoms.

Clinical Implications

While preclinical, these findings support the development of biased NTSR1 modulators as non-addictive analgesics that could reduce reliance on opioids and mitigate opioid-related adverse effects.

Limitations

• Preclinical rodent data without human pharmacokinetics, safety, or efficacy.
• Long-term safety, tolerance, and off-target effects remain uncharacterized.

Future Directions

Advance to IND-enabling studies including GLP toxicology and PK/PD, followed by phase 1 trials; explore indications beyond pain (e.g., pruritus) and combination with reduced-dose opioids.