Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp

JCI Insight, 2023 · DOI: https://doi.org/10.1172/jci.insight.169554 · Published: October 12, 2023

Simple Explanation

This study investigates how neuropeptide Y (NPY) reduces neuropathic pain by targeting specific interneurons in the spinal cord. It identifies a subpopulation of Npy1r-expressing interneurons (Y1-INs) that coexpress gastrin-releasing peptide (Grp) as crucial for the analgesic effects of NPY. The research demonstrates that these Grp/Npy1r-INs are conserved across mice, nonhuman primates, and humans. The researchers used fluorescence in situ hybridization (FISH) to characterize the coexpression of various markers with the Npy1r gene, finding that Y1-INs largely segregated into three subpopulations based on coexpression with Cck, Grp, and Npff. Functional studies in mice revealed that inhibiting Npff/Npy1r-INs did not alleviate neuropathic pain, while pharmacological inhibition of Y1-INs with a Y1 agonist reduced pain only when Npy1r was present in GRP-INs. The findings suggest that Grp/Npy1r-INs are a promising and precise target for treating neuropathic pain. The study supports the idea that targeting these specific interneurons could offer a more effective and evolutionarily conserved approach to pain management.

Study Duration

Not specified

Participants

Mice, rhesus macaque, and human organ donors

Evidence Level

Not specified

Key Findings

1
Y1-INs in the spinal dorsal horn are excitatory neurons that segregate into three distinct subpopulations based on coexpression of Npy1r with Grp, Npff, or Cck.
2
The Grp/Npy1r-IN subpopulation is conserved across higher-order mammalian species, including mice, rhesus macaques, and humans.
3
Inhibition of Npff/Npy1r-INs does not change neuropathic hypersensitivity, while the Y1 agonist [Leu31, Pro34]-NPY eliminates nerve injury-induced mechanical and cold hypersensitivity in mice with conditional deletion of Cck but not Grp from Npy1r-INs.

Research Summary

This study demonstrates that spinal Npy1r-expressing DH interneurons that coexpress Grp are evolutionarily conserved across rodent, nonhuman primate, and human and are necessary for the efficacy of spinally directed Y1 agonists to inhibit neuropathic pain. The Grp subpopulation of Npy1r-expressing DH INs represent an optimal and precise future pharmacotherapeutic target for the treatment of neuropathic pain. Our results establish GRP-INs (specifically those that coexpress Npy1r) as a mediator of neuropathic allodynia.

Practical Implications

Therapeutic Target Refinement

GRP/NPY1R-INs are identified as a more specific therapeutic target for neuropathic pain compared to broader NPY1R targeting.

Drug Development

Future drug development should focus on spinally directed NPY Y1 agonists, especially those targeting GRP/NPY1R-INs, for clinical neuropathic pain management.

Gene Therapy Potential

Promoter-specific gene therapy targeting GRP/NPY1R-INs could offer a highly specific approach to modulate pain signaling with minimized side effects.

Study Limitations

1
The study evaluated human cervical spinal cord tissue, and variance in RNA expression between cervical and lumbar spinal cord cannot be ruled out.
2
The lack of NPFF expression result further supports the integrity of our cervical FISH results and reveals the sparse to nondetectable expression of NPFF in the adult human spinal cord DH.
3
The human RNA-sequencing data suggest that NPY1R expression is rather nonspecific across excitatory interneurons in humans, and a GRP/NPY1R-selective approach may therefore be optimal.

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