{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T02:27:55Z","timestamp":1777948075502,"version":"3.51.4"},"reference-count":29,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec id=\"j_sjpain-2026-0009_abs_001\">\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Repetitive noxious stimulation can increase perceived pain intensity, a phenomenon known as Temporal Summation of Pain (TSP), thought to reflect central sensitization via neuronal \u201cwind-up\u201d in the spinal cord. As neuronal wind-up occurs only at stimulation frequencies above 0.2\u202fHz, we have tested whether TSP also appears at two different frequencies using our recently developed TSP protocol in healthy volunteers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_sjpain-2026-0009_abs_002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In a randomized crossover design, 30 healthy male participants (27\u00b14 years) underwent two experimental sessions involving 90 repetitive heat stimuli applied to the forearm at individually determined pain tolerance temperatures. Stimuli were delivered using a thermode at either 0.4 or 0.15\u202fHz. Pain intensity was rated using a computerized visual analog scale (0\u2013100). TSP was assessed via linear mixed-effects model (LMM), with pain intensity as the dependent variable.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_sjpain-2026-0009_abs_003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All participants finished the study. LMM revealed a significant main effect of stimulation frequency (\n                      <jats:italic>F<\/jats:italic>\n                      <jats:sub>1, 540<\/jats:sub>\n                      =14.20, p&lt;0.001), indicating TSP. Pain intensity was higher at 0.4\u202fHz compared with 0.15\u202fHz (\u03b2=14.77, 95\u202f% confidence intervals (CI) 6.87\u201322.68, p&lt;0.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_sjpain-2026-0009_abs_004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The presence of TSP at 0.4\u202fHz but not at 0.15\u202fHz aligns with previous findings on neuronal wind-up, supporting its reliance to central sensitization. These findings enhance our understanding of the physiological basis of TSP and offer a robust platform for future investigations into pain modulation and therapeutic intervention strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1515\/sjpain-2026-0009","type":"journal-article","created":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T03:59:16Z","timestamp":1777780756000},"source":"Crossref","is-referenced-by-count":0,"title":["Evidence for frequency-dependent neuronal \u201cwind-up\u201d origin of temporal summation of pain - an experimental crossover investigation"],"prefix":"10.1515","volume":"26","author":[{"given":"Maximilian","family":"Bremer","sequence":"first","affiliation":[{"name":"Department of Anesthesiology , University Medicine of Greifswald , Greifswald , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henriette","family":"Janner","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology , University Medicine of Greifswald , Greifswald , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vasyl","family":"Hizhko","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology , University Medicine of Greifswald , Greifswald , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Nowak","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Intensive Medicine, Emergency Medicine and Pain Therapy , Hospital Dresden-Friedrichstadt , Dresden , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Busemann","sequence":"additional","affiliation":[{"name":"Department of Surgery , University Medicine of Greifswald , Greifswald , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus","family":"Hahnenkamp","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology , University Medicine of Greifswald , Greifswald , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taras I.","family":"Usichenko","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology , University Medicine of Greifswald , Greifswald , Germany"},{"name":"Department of Anesthesia , McMaster University , Hamilton , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"374","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"2026050305265100799_j_sjpain-2026-0009_ref_001","doi-asserted-by":"crossref","unstructured":"Arendt-Nielsen, L. Central sensitization in humans: assessment and pharmacology. Handb Exp Pharmacol 2015;227:79\u2013102.","DOI":"10.1007\/978-3-662-46450-2_5"},{"key":"2026050305265100799_j_sjpain-2026-0009_ref_002","doi-asserted-by":"crossref","unstructured":"Staahl, C, Drewes, AM. Experimental human pain models: a review of standardised methods for preclinical testing of analgesics. Basic Clin Pharmacol Toxicol 2004;95:97\u2013111. https:\/\/doi.org\/10.1111\/j.1742-7843.2004.950301.x.","DOI":"10.1111\/j.1742-7843.2004.950301.x"},{"key":"2026050305265100799_j_sjpain-2026-0009_ref_003","doi-asserted-by":"crossref","unstructured":"Woolf, CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011;152:S2\u201315. https:\/\/doi.org\/10.1016\/j.pain.2010.09.030.","DOI":"10.1016\/j.pain.2010.09.030"},{"key":"2026050305265100799_j_sjpain-2026-0009_ref_004","doi-asserted-by":"crossref","unstructured":"Lautenbacher, S, Kunz, M, Strate, P, Nielsen, J, Arendt-Nielsen, L. Age effects on pain thresholds, temporal summation and spatial summation of heat and pressure pain. Pain 2005;115:410\u201318. https:\/\/doi.org\/10.1016\/j.pain.2005.03.025.","DOI":"10.1016\/j.pain.2005.03.025"},{"key":"2026050305265100799_j_sjpain-2026-0009_ref_005","doi-asserted-by":"crossref","unstructured":"Mendell, LM, Wall, PD. Responses of single dorsal cells to peripheral cutaneous unmyelinated fibers. Nature 1965;206:97\u20139. https:\/\/doi.org\/10.1038\/206097a0.","DOI":"10.1038\/206097a0"},{"key":"2026050305265100799_j_sjpain-2026-0009_ref_006","doi-asserted-by":"crossref","unstructured":"Price, DD. Characteristics of second pain and flexion reflexes indicative of prolonged central summation. Exp Neurol 1972;37:371\u201387. https:\/\/doi.org\/10.1016\/0014-4886(72)90081-7.","DOI":"10.1016\/0014-4886(72)90081-7"},{"key":"2026050305265100799_j_sjpain-2026-0009_ref_007","doi-asserted-by":"crossref","unstructured":"Staud, R, Price, DD, Fillingim, RB. Advanced continuous-contact heat pulse design for efficient temporal summation of second pain (windup). J\u00a0Pain 2006;7:575\u201382. https:\/\/doi.org\/10.1016\/j.jpain.2006.02.005.","DOI":"10.1016\/j.jpain.2006.02.005"},{"key":"2026050305265100799_j_sjpain-2026-0009_ref_008","doi-asserted-by":"crossref","unstructured":"Vierck, CJ, Cannon, RL, Fry, G, Maixner, W, Whitsel, BL. Characteristics of temporal summation of second pain sensations elicited by brief contact of glabrous skin by a preheated thermode. J\u00a0Neurophysiol 1997;78:992\u20131002. https:\/\/doi.org\/10.1152\/jn.1997.78.2.992.","DOI":"10.1152\/jn.1997.78.2.992"},{"key":"2026050305265100799_j_sjpain-2026-0009_ref_009","doi-asserted-by":"crossref","unstructured":"Schouenborg, J. Functional and topographical properties of field potentials evoked in rat dorsal horn by cutaneous C-fibre stimulation. 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