Spinal neuropeptide Y Y1 receptor-expressing neurons are a pharmacotherapeutic target for the alleviation of neuropathic pain

Proc Natl Acad Sci U S A. 2022 Nov 16;119(46):e2204515119. doi: 10.1073/pnas.2204515119. Epub 2022 Nov 7.


Peripheral nerve injury sensitizes a complex network of spinal cord dorsal horn (DH) neurons to produce allodynia and neuropathic pain. The identification of a druggable target within this network has remained elusive, but a promising candidate is the neuropeptide Y (NPY) Y1 receptor-expressing interneuron (Y1-IN) population. We report that spared nerve injury (SNI) enhanced the excitability of Y1-INs and elicited allodynia (mechanical and cold hypersensitivity) and affective pain. Similarly, chemogenetic or optogenetic activation of Y1-INs in uninjured mice elicited behavioral signs of spontaneous, allodynic, and affective pain. SNI-induced allodynia was reduced by chemogenetic inhibition of Y1-INs, or intrathecal administration of a Y1-selective agonist. Conditional deletion of Npy1r in DH neurons, but not peripheral afferent neurons prevented the anti-hyperalgesic effects of the intrathecal Y1 agonist. We conclude that spinal Y1-INs are necessary and sufficient for the behavioral symptoms of neuropathic pain and represent a promising target for future pharmacotherapeutic development of Y1 agonists.

Keywords: allodynia; excitatory interneurons; neuropathic pain; neuropeptide Y; spinal cord dorsal horn.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Hyperalgesia* / drug therapy
  • Mice
  • Neuralgia* / drug therapy
  • Neurons
  • Neuropeptide Y / genetics
  • Neuropeptide Y / pharmacology
  • Spinal Cord


  • neuropeptide Y-Y1 receptor
  • Neuropeptide Y