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To treat localized itch or pain with minimal burning, low capsaicin concentrations can be repeatedly applied. We hypothesized that alternatively controlled release of capsaicin from poly(lactic-co-glycolic acid) (PLGA) nanoparticles desensitizes superficially terminating nociceptors, reducing burning. Methods: Capsaicin-loaded PLGA nanoparticles were prepared (single-emulsion solvent evaporation) and characterized (size, morphology, capsaicin loading, encapsulation efficiency, in vitro release profile). Capsaicin-PLGA nanoparticles were applied to murine skin and evaluated in healthy human participants (n = 21) for 4 days under blinded conditions, and itch and nociceptive sensations evoked by mechanical, heat stimuli and pruritogens cowhage, \u03b2-alanine, BAM8-22 and histamine were evaluated. Results: Nanoparticles (loading: 58 \u00b5g capsaicin\/mg) released in vitro 23% capsaicin within the first hour and had complete release at 72 h. In mice, 24 h post-application Capsaicin-PLGA nanoparticles penetrated the dermis and led to decreased nociceptive behavioral responses to heat and mechanical stimulation (desensitization). Application in humans produced a weak to moderate burning, dissipating after 3 h. A loss of heat pain up to 2 weeks was observed. After capsaicin nanoparticles, itch and nociceptive sensations were reduced in response to pruritogens cowhage, \u03b2-alanine or BAM8-22, but were normal to histamine. Conclusions: Capsaicin nanoparticles could be useful in reducing pain and itch associated with pruritic diseases that are histamine-independent.<\/jats:p>","DOI":"10.3390\/ijms23095275","type":"journal-article","created":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T21:23:27Z","timestamp":1652131407000},"page":"5275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Topical Capsaicin in Poly(lactic-co-glycolic)acid (PLGA) Nanoparticles Decreases Acute Itch and Heat Pain"],"prefix":"10.3390","volume":"23","author":[{"given":"Nathalie M.","family":"Malewicz","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Yale University School of Medicine, 330 Cedar St, New Haven, CT 06510, USA"},{"name":"Clinics for Anesthesiology, Intensive Care and Pain Medicine, Medical Faculty of Ruhr-University Bochum, BG University Hospital Bergmannsheil, 44789 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8371-8549","authenticated-orcid":false,"given":"Zahra","family":"Rattray","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9695-8771","authenticated-orcid":false,"given":"Sebastian","family":"Oeck","sequence":"additional","affiliation":[{"name":"Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510, USA"},{"name":"Department of Medical Oncology, West German Cancer Center, University Hospital Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0365-5710","authenticated-orcid":false,"given":"Sebastian","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Yale University School of Medicine, 330 Cedar St, New Haven, CT 06510, USA"},{"name":"ZEMOS Center for Solvation Science, Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0973-9728","authenticated-orcid":false,"given":"Vicente","family":"Escamilla-Rivera","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Yale University School of Medicine, 330 Cedar St, New Haven, CT 06510, USA"},{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeming","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangjun","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1201-5360","authenticated-orcid":false,"given":"Jiangbing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"LaMotte","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Yale University School of Medicine, 330 Cedar St, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"532","DOI":"10.2340\/00015555-1572","article-title":"Incidence and determinants of chronic pruritus: A population-based cohort study","volume":"93","author":"Matterne","year":"2013","journal-title":"Acta Derm.-Venereol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7659","DOI":"10.1523\/JNEUROSCI.1760-08.2008","article-title":"A role for polymodal C-fiber afferents in nonhistaminergic itch","volume":"28","author":"Johanek","year":"2008","journal-title":"J. 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