{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T04:24:49Z","timestamp":1787977489516,"version":"build-2784847793"},"reference-count":26,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002803","name":"Fondazione Cariplo","doi-asserted-by":"publisher","award":["2018\u20100231"],"award-info":[{"award-number":["2018\u20100231"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GJC21084"],"award-info":[{"award-number":["GJC21084"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012352","name":"Universit\u00e0 degli Studi di Milano","doi-asserted-by":"publisher","award":["SPR2023_ASAPO"],"award-info":[{"award-number":["SPR2023_ASAPO"]}],"id":[{"id":"10.13039\/100012352","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012352","name":"Universit\u00e0 degli Studi di Milano","doi-asserted-by":"publisher","award":["SPR2025_ASAPO"],"award-info":[{"award-number":["SPR2025_ASAPO"]}],"id":[{"id":"10.13039\/100012352","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"abstract":"\n Abstract<\/jats:title>\n \n Hyperpolarization\u2010activated cyclic nucleotide\u2010gated 2 (HCN2) channels regulate action potential firing in nociceptors and are critical mediators of neuronal hyperexcitability in response to inflammation and nerve injury. These channels are activated by membrane hyperpolarization and potentiated by direct cAMP binding to their C\u2010terminal cyclic nucleotide\u2010binding domain (CNBD). Although a role for cAMP in modulating HCN2 activity and contributing to neuropathic pain has been hypothesized, direct evidence has been lacking. To test this causal link, here we employ TRIP8b\n nano<\/jats:sub>\n , comprising a minimal peptide derivative from the brain protein TRIP8b that selectively antagonizes cAMP binding to HCN channels. TRIP8b\n nano<\/jats:sub>\n effectively abolished cAMP\u2010mediated potentiation of HCN2 currents in small\u2010diameter dorsal root ganglion (DRG) neurons, validating its utility as a functional inhibitor. In a rat model of neuropathic pain, DRG\u2010targeted expression of TRIP8b\n nano<\/jats:sub>\n significantly reduced mechanical and thermal hypersensitivity. These findings provide the first direct evidence that cAMP binding to HCN2 channels drives nociceptor hyperexcitability and neuropathic pain and establishes disruption of this interaction as a promising therapeutic strategy.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Activation of HCN2 channels is potentiated by cAMP binding to their cyclic nucleotide binding domain (CNBD).<\/jats:p>\n <\/jats:list-item>\n \n \n TRIP8b\n nano<\/jats:sub>\n abolishes cAMP binding to CNBD, thus inhibiting potentiation of HCN2 currents in both HEK 293T cells and rat DRG neurons.\n <\/jats:p>\n <\/jats:list-item>\n \n \n TRIP8b\n nano<\/jats:sub>\n reduces mechanical and thermal hypersensitivity in a rat model of neuropathic pain.\n <\/jats:p>\n <\/jats:list-item>\n \n Our findings confirm a direct role of cAMP\u2013HCN2 signalling in neuropathic pain and suggest a new therapeutic target.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp290260","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T04:54:20Z","timestamp":1776747260000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["TRIP8b\n nano<\/sub>\n peptide prevents cAMP binding to HCN2 channels alleviating pain\u2010like behaviors in rats with neuropathic pain"],"prefix":"10.1113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6207-8370","authenticated-orcid":false,"given":"Santiago I.","family":"Loya\u2010Lopez","sequence":"first","affiliation":[{"name":"Department of Pharmacology & Therapeutics and Center for Advanced Pain Therapeutics and Research (CAPToR) University of Florida Gainesville FL USA"},{"name":"McKnight Brain Institute University of Florida College of Medicine Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Gomez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics and Center for Advanced Pain Therapeutics and Research (CAPToR) University of Florida Gainesville FL USA"},{"name":"McKnight Brain Institute University of Florida College of Medicine Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-6165","authenticated-orcid":false,"given":"Alessandro","family":"Porro","sequence":"additional","affiliation":[{"name":"Department of Biosciences University of Milano Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Thiel","sequence":"additional","affiliation":[{"name":"Department of Biosciences University of Milano Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Moroni","sequence":"additional","affiliation":[{"name":"Department of Biosciences University of Milano Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0771-1959","authenticated-orcid":false,"given":"Heather N.","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics and Center for Advanced Pain Therapeutics and Research (CAPToR) University of Florida Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9066-2969","authenticated-orcid":false,"given":"Rajesh","family":"Khanna","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics and Center for Advanced Pain Therapeutics and Research (CAPToR) University of Florida Gainesville FL USA"},{"name":"McKnight Brain Institute University of Florida College of Medicine Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5035-5174","authenticated-orcid":false,"given":"Andrea","family":"Saponaro","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences University of Milano Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"issue":"43","key":"e_1_2_2_2_1","doi-asserted-by":"crossref","first-page":"17794","DOI":"10.1074\/jbc.M117.800722","article-title":"Mechanism for the inhibition of the cAMP dependence of HCN ion channels by the auxiliary subunit TRIP8b","volume":"292","author":"Bankston J. 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