{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T13:10:36Z","timestamp":1753881036248,"version":"3.41.2"},"reference-count":80,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"889","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2025,6,3]]},"abstract":"<jats:p>\n            Natriuretic peptide receptor 2 (Npr2; also termed guanylyl cyclase B) is a transmembrane guanylyl cyclase that is highly abundant in nociceptors. Here, we investigated the role of production of cyclic GMP (cGMP) by Npr2 in pain processing. Adult mice with a deletion of Npr2 specifically in nociceptive sensory neurons exhibited deficits in noxious heat sensing, which can activate the nonselective cation channels TRPV1 and TRPA1. In parallel, Npr2-deficient mice showed a reduction in TRPV1-mediated nocifensive behavior and Ca\n            <jats:sup>2+<\/jats:sup>\n            influx into sensory neurons. Furthermore, Npr2-deficient mice had considerably reduced hypersensitivity after hindpaw injection of TRPA1 and TRPV1 activators or after hindpaw injection of complete Freund adjuvant, a model of persistent inflammatory pain. These results indicate that Npr2 contributes to the pain sensitization that can lead to chronic pain. Patch-clamp recordings revealed that the endogenous Npr2 ligand, C-type natriuretic peptide (CNP), enhanced the excitability of nociceptive sensory neurons through Npr2. CNP\/Npr2 signaling led to the phosphorylation of cysteine-rich LIM-only protein 4 (CRP4), a substrate of cGMP-dependent protein kinase I. Behavioral and electrophysiological analyses using CRP4-deficient mice revealed that CRP4 limited CNP\/Npr2-mediated pain sensitization. Our findings reveal a role for CNP\/Npr2 signaling in sensory neurons in acute nociceptive and chronic pain and suggest that CRP4 is a downstream target that attenuates pain sensitization.\n          <\/jats:p>","DOI":"10.1126\/scisignal.adq4238","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T17:58:44Z","timestamp":1748973524000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Nociceptor-specific signaling of the receptor guanylyl cyclase Npr2 contributes to acute and persistent pain"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9849-4094","authenticated-orcid":true,"given":"Hannah","family":"Gerninghaus","sequence":"first","affiliation":[{"name":"Institute of Pharmacology and Clinical Pharmacy, Goethe University Frankfurt, 60438 Frankfurt am Main, 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