{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T10:07:06Z","timestamp":1790158026476,"version":"4.1.0"},"reference-count":62,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>This hypothesis originated from the first author\u2019s personal experience in adult neurology, in which selected refractory cranial or postherpetic neuralgias occasionally appeared to improve rapidly after off-label misoprostol. The original records are unavailable; these physician recollections are not efficacy data and serve only as the hypothesis generator. Independent published precedents are limited to small uncontrolled reports in multiple-sclerosis-associated trigeminal neuralgia. A further recollection was that perceived benefit often waned after several weeks at conventional daily exposure, whereas lower or intermittent exposure sometimes appeared to remain useful for longer; this observation is likewise unverifiable and does not define a therapeutic dose. Misoprostol is rapidly converted to misoprostol acid (plasma half-life of 20\u201340 min). We ask whether a brief, reversible exposure could produce pharmacodynamic persistence, defined here as a reproducible pain-relevant effect that outlasts measurable drug exposure, through EP-receptor trafficking, compartmentalized GPCR signaling, or downstream cellular changes. The model also predicts that the concentration\u2013response relationship may be non-monotonic: increasing or repeated exposure could attenuate or reverse a favorable effect by recruiting opposing EP pathways or adaptive receptor\/cellular responses. No direct evidence shows that misoprostol produces such persistence in neural tissue, and PGE2\/EP signaling can also be pronociceptive. Receptor-resolved concentration\u2013response and pulse-washout experiments must therefore separately demonstrate receptor signaling, persistent cellular change, altered neuronal excitability, and ultimately blinded analgesic benefit. Neuropathic corneal pain is considered only a secondary mechanistic model. No evidence-based dose can currently be recommended.<\/jats:p>","DOI":"10.3390\/ijms27198455","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:28:43Z","timestamp":1790090923000},"page":"8455","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Misoprostol in Refractory Neuralgic Pain: From Clinical Neurology to an EP-Receptor Hypothesis of Pharmacodynamic Persistence"],"prefix":"10.3390","volume":"27","author":[{"given":"Ronald B.","family":"Bukowy","sequence":"first","affiliation":[{"name":"Independent Researcher, Geneva, IL 60134, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9577-2585","authenticated-orcid":false,"given":"Dario","family":"Rusciano","sequence":"additional","affiliation":[{"name":"Neurovisual Science Technology, Via Tomaselli 43, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8424-0068","authenticated-orcid":false,"given":"Caterina","family":"Gagliano","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Surgery, University of Enna \u201cKore\u201d, 94100 Enna, Italy"},{"name":"Mediterranean Foundation G.B. Morgagni, Ophthalmology Clinic, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7152-2613","authenticated-orcid":false,"given":"Mario D.","family":"Toro","sequence":"additional","affiliation":[{"name":"Eye Clinic, Department of Public Health, University of Naples Federico II, 80131 Naples, Italy"},{"name":"Department of General and Paediatric Ophthalmology, Medical University of Lublin, 20-079 Lublin, Poland"},{"name":"Department of Special Surgery, University of Jordan, Queen Rania St., Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1111\/ene.13950","article-title":"European Academy of Neurology guideline on trigeminal neuralgia","volume":"26","author":"Bendtsen","year":"2019","journal-title":"Eur. J. 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