{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T22:29:53Z","timestamp":1790375393347,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2017,1,20]],"date-time":"2017-01-20T00:00:00Z","timestamp":1484870400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003803","name":"University of Hong Kong","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003803","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Spinal cord stimulation (<jats:styled-content style=\"fixed-case\">SCS<\/jats:styled-content>) has been shown to be effective in the management of certain neuropathic pain conditions, however, the underlying mechanisms are incompletely understood. In this study, we investigated repetitive <jats:styled-content style=\"fixed-case\">SCS<\/jats:styled-content> in a rodent neuropathic pain model, revealing long\u2010lasting and incremental attenuation of hyperalgesia and a mechanism of action involving endocannabinoids.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>Animals were implanted with monopolar electrodes at the time of partial sciatic nerve injury. Dorsal columns at spinal segments T12\/13 were stimulated 3\u00a0days later (early <jats:styled-content style=\"fixed-case\">SCS<\/jats:styled-content>), and again at day 7 (late <jats:styled-content style=\"fixed-case\">SCS<\/jats:styled-content>) using low\u2010frequency parameters. Hypersensitivity to cutaneous mechanical stimuli was assessed using von Frey filaments. Pharmacological agents, selected to identify endocannabinoid and opioid involvement, were administered intraperitoneally, 10\u00a0min before <jats:styled-content style=\"fixed-case\">SCS<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Early <jats:styled-content style=\"fixed-case\">SCS<\/jats:styled-content> caused partial reversal of mechanical hypersensitivity with corresponding changes in the biomarker of central sensitization, [phospho\u2010Tyr<jats:sup>1472<\/jats:sup>]\u2010GluN2B. The partial reversal of hyperalgesia by early <jats:styled-content style=\"fixed-case\">SCS<\/jats:styled-content> was amplified by co\u2010administration of <jats:styled-content style=\"fixed-case\">LY<\/jats:styled-content> 2183240, an inhibitor of endocannabinoid reuptake\/breakdown. This amplification was inhibited by a <jats:styled-content style=\"fixed-case\">CB<\/jats:styled-content><jats:sub>1<\/jats:sub>R antagonist, <jats:styled-content style=\"fixed-case\">AM<\/jats:styled-content>251, but not by a <jats:styled-content style=\"fixed-case\">CB<\/jats:styled-content><jats:sub>2<\/jats:sub>R antagonist, <jats:styled-content style=\"fixed-case\">AM<\/jats:styled-content>630. Early <jats:styled-content style=\"fixed-case\">SCS<\/jats:styled-content>\u2010induced reversal of hyperalgesia was attenuated by naloxone, indicating a role for opioids. Late <jats:styled-content style=\"fixed-case\">SCS<\/jats:styled-content> resulted in an incremental level of reversal of hyperalgesia, which was inhibited by <jats:styled-content style=\"fixed-case\">AM<\/jats:styled-content>251, but not by <jats:styled-content style=\"fixed-case\">CB<\/jats:styled-content><jats:sub>2<\/jats:sub> or opioid receptor antagonists.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The endocannabinoid system, and in particular the <jats:styled-content style=\"fixed-case\">CB<\/jats:styled-content><jats:sub>1<\/jats:sub>R, plays a pivotal role in the long\u2010lasting and incremental reversal of hyperalgesia induced by repetitive <jats:styled-content style=\"fixed-case\">SCS<\/jats:styled-content> in a neuropathic pain model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Alternative parameters for repetitive spinal cord stimulation (<jats:styled-content style=\"fixed-case\">SCS<\/jats:styled-content>) at 25\/10\u00a0Hz elicit particularly long\u2010lasting and incremental reversal of hyperalgesia in a neuropathic pain model through a mechanism involving endocannabinoids.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ejp.983","type":"journal-article","created":{"date-parts":[[2017,1,20]],"date-time":"2017-01-20T21:53:20Z","timestamp":1484949200000},"page":"804-814","source":"Crossref","is-referenced-by-count":40,"title":["Endocannabinoid activation of CB<sub>1<\/sub> receptors contributes to long\u2010lasting reversal of neuropathic pain by repetitive spinal cord stimulation"],"prefix":"10.1002","volume":"21","author":[{"given":"L.","family":"Sun","sequence":"first","affiliation":[{"name":"Laboratory and Clinical Research Institute for Pain Department of Anaesthesiology The University of Hong Kong HKSAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Tai","sequence":"additional","affiliation":[{"name":"Laboratory and Clinical Research Institute for Pain 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