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Sci.","IJMS"],"abstract":"<jats:p>Full-length ACTH molecule and ACTH-related hexapeptide H-PKKRRP-OH are demonstrated by the patch-clamp method to decrease the NaV1.8 channel activation gating system effective charge in the nociceptive neuron membrane, while ACTH-related tetrapeptide Ac-KKRR-NH2 has no effect. ACTH(1\u201324), a fully functional ACTH mimetic, and H-PKKRRP-OH show analgesic effects in the formalin test in vivo. All peptides contain the cationic KKRR motif, but only H-PKKRRP-OH and ACTH(1\u201324) relieve acute pain, targeting the NaV1.8 channel as a receptor. This seemingly controversial result is explained by application of conformational analysis and blind docking. Though conformational analysis indicates that both H-PKKRRP-OH and Ac-KKRR-NH2 contain the cationic functional groups at the earlier suggested characteristic distance of 9\u201312 \u00c5, Ac-KKRR-NH2 does not interact with the S4I voltage sensor of the NaV1.8 channel activation gating system. The docking demonstrates that an extensive network of ligand\u2013receptor ionic and hydrogen bonds involving D151, E157, R218, and R221 VSDI residues, essential for the analgesic tripeptide Ac-KKK-NH2 binding, is formed upon the H-PKKRRP-OH binding. Particularly important are the ionic bonds between the H-PKKRRP-OH C-terminal carboxylate anion and the S4I R218 and R221 guanidinium groups. The described mechanism of NaV1.8 channel modulation is fundamentally different from the effect of channel blockers.<\/jats:p>","DOI":"10.3390\/ijms27156792","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:13:47Z","timestamp":1785320027000},"page":"6792","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Short Cationic ACTH-Related Peptides Can Modulate the NaV1.8 Channel Functioning, Resulting in an Analgesic Effect"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8336-0604","authenticated-orcid":false,"given":"Ilya V.","family":"Rogachevskii","sequence":"first","affiliation":[{"name":"Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8893-8049","authenticated-orcid":false,"given":"Arina D.","family":"Kalinina","sequence":"additional","affiliation":[{"name":"Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadezhda A.","family":"Boichenko","sequence":"additional","affiliation":[{"name":"Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna V.","family":"Berintseva","sequence":"additional","affiliation":[{"name":"Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iuliia V.","family":"Plakhova","sequence":"additional","affiliation":[{"name":"Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitriy M.","family":"Samosvat","sequence":"additional","affiliation":[{"name":"Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgy G.","family":"Zegrya","sequence":"additional","affiliation":[{"name":"Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina P.","family":"Butkevich","sequence":"additional","affiliation":[{"name":"Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor A.","family":"Mikhailenko","sequence":"additional","affiliation":[{"name":"Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3936-8681","authenticated-orcid":false,"given":"Valentina A.","family":"Penniyaynen","sequence":"additional","affiliation":[{"name":"Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0003-9338","authenticated-orcid":false,"given":"Svetlana A.","family":"Podzorova","sequence":"additional","affiliation":[{"name":"Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6573-6743","authenticated-orcid":false,"given":"Vladimir V.","family":"Kopat","sequence":"additional","affiliation":[{"name":"ATG Service Gene LLC., 199178 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5268-9802","authenticated-orcid":false,"given":"Ilya V.","family":"Dukhovlinov","sequence":"additional","affiliation":[{"name":"ATG Service Gene LLC., 199178 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris V.","family":"Krylov","sequence":"additional","affiliation":[{"name":"Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1152\/physrev.00041.2006","article-title":"Physiology and Neurobiology of Stress and Adaptation: Central Role of the Brain","volume":"87","author":"McEwen","year":"2007","journal-title":"Physiol. 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