Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp
Neuropeptide Y targets the Y1 receptor (Y1) in the spinal dorsal horn (DH) to produce endogenous and exogenous analgesia. DH interneurons that express Y1 (Y1-INs; encoded by Npy1r) are necessary and sufficient for neuropathic hypersensitivity after peripheral nerve injury. However, as Y1-INs are het...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-11-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.169554 |
| _version_ | 1797634194444124160 |
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| author | Tyler S. Nelson Heather N. Allen Paramita Basu Pranav Prasoon Eileen Nguyen Cynthia M. Arokiaraj Diogo F.S. Santos Rebecca P. Seal Sarah E. Ross Andrew J. Todd Bradley K. Taylor |
| author_facet | Tyler S. Nelson Heather N. Allen Paramita Basu Pranav Prasoon Eileen Nguyen Cynthia M. Arokiaraj Diogo F.S. Santos Rebecca P. Seal Sarah E. Ross Andrew J. Todd Bradley K. Taylor |
| author_sort | Tyler S. Nelson |
| collection | DOAJ |
| description | Neuropeptide Y targets the Y1 receptor (Y1) in the spinal dorsal horn (DH) to produce endogenous and exogenous analgesia. DH interneurons that express Y1 (Y1-INs; encoded by Npy1r) are necessary and sufficient for neuropathic hypersensitivity after peripheral nerve injury. However, as Y1-INs are heterogenous in composition in terms of morphology, neurophysiological characteristics, and gene expression, we hypothesized that a more precisely defined subpopulation mediates neuropathic hypersensitivity. Using fluorescence in situ hybridization, we found that Y1-INs segregate into 3 largely nonoverlapping subpopulations defined by the coexpression of Npy1r with gastrin-releasing peptide (Grp/Npy1r), neuropeptide FF (Npff/Npy1r), and cholecystokinin (Cck/Npy1r) in the superficial DH of mice, nonhuman primates, and humans. Next, we analyzed the functional significance of Grp/Npy1r, Npff/Npy1r, and Cck/Npy1r INs to neuropathic pain using a mouse model of peripheral nerve injury. We found that chemogenetic inhibition of Npff/Npy1r-INs did not change the behavioral signs of neuropathic pain. Further, inhibition of Y1-INs with an intrathecal Y1 agonist, [Leu31, Pro34]-NPY, reduced neuropathic hypersensitivity in mice with conditional deletion of Npy1r from CCK-INs and NPFF-INs but not from GRP-INs. We conclude that Grp/Npy1r-INs are conserved in higher order mammalian species and represent a promising and precise pharmacotherapeutic target for the treatment of neuropathic pain. |
| first_indexed | 2024-03-11T12:05:19Z |
| format | Article |
| id | doaj.art-12aac04266fb4e319cbf254fd2f81a36 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:19Z |
| publishDate | 2023-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-12aac04266fb4e319cbf254fd2f81a362023-11-07T16:26:27ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-11-01822Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress GrpTyler S. NelsonHeather N. AllenParamita BasuPranav PrasoonEileen NguyenCynthia M. ArokiarajDiogo F.S. SantosRebecca P. SealSarah E. RossAndrew J. ToddBradley K. TaylorNeuropeptide Y targets the Y1 receptor (Y1) in the spinal dorsal horn (DH) to produce endogenous and exogenous analgesia. DH interneurons that express Y1 (Y1-INs; encoded by Npy1r) are necessary and sufficient for neuropathic hypersensitivity after peripheral nerve injury. However, as Y1-INs are heterogenous in composition in terms of morphology, neurophysiological characteristics, and gene expression, we hypothesized that a more precisely defined subpopulation mediates neuropathic hypersensitivity. Using fluorescence in situ hybridization, we found that Y1-INs segregate into 3 largely nonoverlapping subpopulations defined by the coexpression of Npy1r with gastrin-releasing peptide (Grp/Npy1r), neuropeptide FF (Npff/Npy1r), and cholecystokinin (Cck/Npy1r) in the superficial DH of mice, nonhuman primates, and humans. Next, we analyzed the functional significance of Grp/Npy1r, Npff/Npy1r, and Cck/Npy1r INs to neuropathic pain using a mouse model of peripheral nerve injury. We found that chemogenetic inhibition of Npff/Npy1r-INs did not change the behavioral signs of neuropathic pain. Further, inhibition of Y1-INs with an intrathecal Y1 agonist, [Leu31, Pro34]-NPY, reduced neuropathic hypersensitivity in mice with conditional deletion of Npy1r from CCK-INs and NPFF-INs but not from GRP-INs. We conclude that Grp/Npy1r-INs are conserved in higher order mammalian species and represent a promising and precise pharmacotherapeutic target for the treatment of neuropathic pain.https://doi.org/10.1172/jci.insight.169554Neuroscience |
| spellingShingle | Tyler S. Nelson Heather N. Allen Paramita Basu Pranav Prasoon Eileen Nguyen Cynthia M. Arokiaraj Diogo F.S. Santos Rebecca P. Seal Sarah E. Ross Andrew J. Todd Bradley K. Taylor Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp JCI Insight Neuroscience |
| title | Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp |
| title_full | Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp |
| title_fullStr | Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp |
| title_full_unstemmed | Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp |
| title_short | Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp |
| title_sort | alleviation of neuropathic pain with neuropeptide y requires spinal npy1r interneurons that coexpress grp |
| topic | Neuroscience |
| url | https://doi.org/10.1172/jci.insight.169554 |
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