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This study provides a novel approach to develop painkillers for chronic pain treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The rat formalin pain test and spinal nerve ligation model of neuropathic pain were used to evaluate antinociception of protopanaxadiol. Primary cell cultures, immunofluorescence staining, and gene and protein expression were also performed for mechanism studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Gavage protopanaxadiol remarkably produces pain antihypersensitive effects in neuropathic pain, bone cancer pain and inflammatory pain, with efficacy comparable with gabapentin. Long\u2010term PPD administration does not induce antihypersensitive tolerance, but prevents and reverses the development and expression of morphine analgesic tolerance. Oral protopanaxadiol specifically stimulates spinal expression of dynorphin A in microglia but not in astrocytes or neurons. Protopanaxadiol gavage\u2010related pain antihypersensitivity is abolished by the intrathecal pretreatment with the microglial metabolic inhibitor minocycline, dynorphin antiserum or specific \u03ba\u2010opioid receptor antagonist GNTI. Intrathecal pretreatment with glucocorticoid receptor)antagonists RU486 and dexamethasone\u201021\u2010mesylate, but not GPR\u201030 antagonist G15 or mineralocorticoid receptor antagonist eplerenone, completely attenuates protopanaxadiol\u2010induced spinal dynorphin A expression and pain antihypersensitivity in neuropathic pain. Treatment with protopanaxadiol, the glucocorticoid receptor agonist dexamethasone and membrane\u2010impermeable glucocorticoid receptor agonist dexamethasone\u2010BSA in cultured microglia induces remarkable dynorphin A expression, which is totally blocked by pretreatment with dexamthasone\u201021\u2010mesylate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>All the results, for the first time, indicate that protopanaxadiol produces pain antihypersensitivity in neuropathic pain probably through spinal microglial dynorphin A expression after glucocorticoid receptor activation and hypothesize that microglial membrane glucocorticoid receptor\/dynorphin A pathway is a potential target to discover and develop novel painkillers in chronic pain.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15471","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T05:37:35Z","timestamp":1617169055000},"page":"2976-2997","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Protopanaxadiol alleviates neuropathic pain by spinal microglial dynorphin A expression following glucocorticoid receptor activation"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7797-4589","authenticated-orcid":false,"given":"Rana Muhammad","family":"Shoaib","sequence":"first","affiliation":[{"name":"King's Lab Shanghai Jiao Tong University School of Pharmacy  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalil Ali","family":"Ahmad","sequence":"additional","affiliation":[{"name":"King's Lab Shanghai Jiao Tong University School of Pharmacy  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5557-0076","authenticated-orcid":false,"given":"Yong\u2010Xiang","family":"Wang","sequence":"additional","affiliation":[{"name":"King's Lab Shanghai Jiao Tong University School of Pharmacy  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2021.04.007"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14747"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.4103\/1658-354X.87267"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2019.01.016"},{"issue":"3","key":"e_1_2_11_7_1","first-page":"1243","article-title":"Selective N\u2010type neuronal voltage\u2010sensitive calcium channel blocker, SNX\u2010111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain","volume":"279","author":"Bowersox S. 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