{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:44:16Z","timestamp":1760147056802,"version":"build-2065373602"},"reference-count":100,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T00:00:00Z","timestamp":1672790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Development and Innovation (NKFI) Fund","award":["PD-OTKA-101248","OTKA-108518","OTKA-138046","PharmaLab RRF-2.3.1-21-2022-00015","TKP2021-EGA-16A","TKP2021-EGA-25","KTIA_NAP_13-2-2014-0005","2017-1.2.1-NKP-2017-00002","3.6.2-17-2017-00008 N (2017-2019)"],"award-info":[{"award-number":["PD-OTKA-101248","OTKA-108518","OTKA-138046","PharmaLab RRF-2.3.1-21-2022-00015","TKP2021-EGA-16A","TKP2021-EGA-25","KTIA_NAP_13-2-2014-0005","2017-1.2.1-NKP-2017-00002","3.6.2-17-2017-00008 N (2017-2019)"]}]},{"name":"Human Resource Development Operational Programme (EFOP)","award":["PD-OTKA-101248","OTKA-108518","OTKA-138046","PharmaLab RRF-2.3.1-21-2022-00015","TKP2021-EGA-16A","TKP2021-EGA-25","KTIA_NAP_13-2-2014-0005","2017-1.2.1-NKP-2017-00002","3.6.2-17-2017-00008 N (2017-2019)"],"award-info":[{"award-number":["PD-OTKA-101248","OTKA-108518","OTKA-138046","PharmaLab RRF-2.3.1-21-2022-00015","TKP2021-EGA-16A","TKP2021-EGA-25","KTIA_NAP_13-2-2014-0005","2017-1.2.1-NKP-2017-00002","3.6.2-17-2017-00008 N (2017-2019)"]}]},{"name":"E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH)","award":["PD-OTKA-101248","OTKA-108518","OTKA-138046","PharmaLab RRF-2.3.1-21-2022-00015","TKP2021-EGA-16A","TKP2021-EGA-25","KTIA_NAP_13-2-2014-0005","2017-1.2.1-NKP-2017-00002","3.6.2-17-2017-00008 N (2017-2019)"],"award-info":[{"award-number":["PD-OTKA-101248","OTKA-108518","OTKA-138046","PharmaLab RRF-2.3.1-21-2022-00015","TKP2021-EGA-16A","TKP2021-EGA-25","KTIA_NAP_13-2-2014-0005","2017-1.2.1-NKP-2017-00002","3.6.2-17-2017-00008 N (2017-2019)"]}]},{"name":"Brain Research Program 3.0, 2021\u20132025","award":["PD-OTKA-101248","OTKA-108518","OTKA-138046","PharmaLab RRF-2.3.1-21-2022-00015","TKP2021-EGA-16A","TKP2021-EGA-25","KTIA_NAP_13-2-2014-0005","2017-1.2.1-NKP-2017-00002","3.6.2-17-2017-00008 N (2017-2019)"],"award-info":[{"award-number":["PD-OTKA-101248","OTKA-108518","OTKA-138046","PharmaLab RRF-2.3.1-21-2022-00015","TKP2021-EGA-16A","TKP2021-EGA-25","KTIA_NAP_13-2-2014-0005","2017-1.2.1-NKP-2017-00002","3.6.2-17-2017-00008 N (2017-2019)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cocaine- and amphetamine-regulated transcript (CART) peptides are involved in several physiological and pathological processes, but their mechanism of action is unrevealed due to the lack of identified receptor(s). We provided evidence for the antihyperalgesic effect of CART(55-102) by inhibiting dipeptidyl-peptidase 4 (DPP4) in astrocytes and consequently reducing neuroinflammation in the rat spinal dorsal horn in a carrageenan-evoked inflammation model. Both naturally occurring CART(55-102) and CART(62-102) peptides are present in the spinal cord. CART(55-102) is not involved in acute nociception but regulates spinal pain transmission during peripheral inflammation. While the full-length peptide with a globular motif contributes to hyperalgesia, its N-terminal inhibits this process. Although the anti-hyperalgesic effects of CART(55-102), CART(55-76), and CART(62-76) are blocked by opioid receptor antagonists in our inflammatory models, but not in neuropathic Seltzer model, none of them bind to any opioid or G-protein coupled receptors. DPP4 interacts with Toll-like receptor 4 (TLR4) signalling in spinal astrocytes and enhances the TLR4-induced expression of interleukin-6 and tumour necrosis factor alpha contributing to inflammatory pain. Depending on the state of inflammation, CART(55-102) is processed in the spinal cord, resulting in the generation of biologically active isoleucine-proline-isoleucine (IPI) tripeptide, which inhibits DPP4, leading to significantly decreased glia-derived cytokine production and hyperalgesia.<\/jats:p>","DOI":"10.3390\/ijms24020918","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T05:02:30Z","timestamp":1672808550000},"page":"918","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Unique, Specific CART Receptor-Independent Regulatory Mechanism of CART(55-102) Peptide in Spinal Nociceptive Transmission and Its Relation to Dipeptidyl-Peptidase 4 (DDP4)"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5465-2803","authenticated-orcid":false,"given":"M\u00e1rk","family":"Kozsurek","sequence":"first","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, Semmelweis University, H-1094 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7252-0422","authenticated-orcid":false,"given":"Korn\u00e9l","family":"Kir\u00e1ly","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kl\u00e1ra","family":"Gyimesi","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, Semmelweis University, H-1094 Budapest, Hungary"},{"name":"Department of Anaesthesiology, Uzsoki Hospital, H-1145 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika","family":"Luk\u00e1csi","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, Semmelweis University, H-1094 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Csaba","family":"Fekete","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, E\u00f6tv\u00f6s Lor\u00e1nd Research Network, H-1083 Budapest, Hungary"},{"name":"Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bal\u00e1zs","family":"Gereben","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, E\u00f6tv\u00f6s Lor\u00e1nd Research Network, H-1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Moh\u00e1csik","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, E\u00f6tv\u00f6s Lor\u00e1nd Research Network, H-1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zsuzsanna","family":"Helyes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, University of P\u00e9cs, H-7624 P\u00e9cs, Hungary"},{"name":"National Laboratory for Drug Research and Development, H-1117 Budapest, Hungary"},{"name":"Chronic Pain Research Group, E\u00f6tv\u00f6s Lor\u00e1nd Research Network, H-7624 P\u00e9cs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kata","family":"B\u00f6lcskei","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, University of P\u00e9cs, H-7624 P\u00e9cs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Val\u00e9ria","family":"T\u00e9kus","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, University of P\u00e9cs, H-7624 P\u00e9cs, Hungary"},{"name":"National Laboratory for Drug Research and Development, H-1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K\u00e1roly","family":"Pap","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, Uzsoki Hospital, H-1145 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edina","family":"Sz\u0171cs","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Biological Research Centre, E\u00f6tv\u00f6s Lor\u00e1nd Research Network, H-6726 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00e1ndor","family":"Benyhe","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Biological Research Centre, E\u00f6tv\u00f6s Lor\u00e1nd Research Network, H-6726 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T\u00edmea","family":"Imre","sequence":"additional","affiliation":[{"name":"MS Metabolomics Laboratory, Instrumentation Centre, Research Centre for Natural Sciences, E\u00f6tv\u00f6s Lor\u00e1nd Research Network, H-1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2260-4641","authenticated-orcid":false,"given":"P\u00e1l","family":"Szab\u00f3","sequence":"additional","affiliation":[{"name":"MS Metabolomics Laboratory, Instrumentation Centre, Research Centre for Natural Sciences, E\u00f6tv\u00f6s Lor\u00e1nd Research Network, H-1117 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Gajtk\u00f3","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, 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