{"doi":"10.1172/jci.insight.169554","title":"Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp","abstract":"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.","journal":"JCI Insight","year":2023,"id":336611,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":863583,"name":"Heather N. Allen","orcid":"0000-0003-0771-1959","position":1,"is_corresponding":false},{"id":1067442,"name":"Paramita Basu","orcid":"0000-0001-9263-3160","position":2,"is_corresponding":false},{"id":696212,"name":"Pranav Prasoon","orcid":"0000-0002-5035-3619","position":3,"is_corresponding":false},{"id":449002,"name":"Eileen Nguyen","orcid":"0000-0003-2282-4222","position":4,"is_corresponding":false},{"id":247853,"name":"Cynthia M. Arokiaraj","orcid":"0000-0003-3201-9868","position":5,"is_corresponding":false},{"id":705279,"name":"Diogo Francisco da Silva dos Santos","orcid":"0000-0003-3306-2147","position":6,"is_corresponding":false},{"id":247861,"name":"Rebecca P. Seal","orcid":"0000-0003-4955-703X","position":7,"is_corresponding":false},{"id":236880,"name":"Sarah E. Ross","orcid":"0000-0003-2593-3133","position":8,"is_corresponding":false},{"id":885683,"name":"Andrew J. Todd","orcid":"0000-0002-3007-6749","position":9,"is_corresponding":false},{"id":325507,"name":"Bradley K. Taylor","orcid":"0000-0002-5080-6120","position":10,"is_corresponding":false},{"id":325506,"name":"Tyler S. Nelson","orcid":"0000-0002-6675-4820","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T01:10:21.947540Z","pmid":"37824208","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}