{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T09:59:32Z","timestamp":1790589572476,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Central post\u2010stroke pain (CPSP) is a refractory complication that occurs after stroke and is classified as central neuropathic pain. Its pathophysiological mechanisms remain unclear and effective pharmacological treatments are limited. Previously, we demonstrated that hypothalamic orexin expression is reduced in a bilateral carotid artery occlusion (BCAO) mouse model of CPSP. Here, we investigated whether impairment of orexinergic signalling contributes to the pathophysiology of CPSP and whether chemogenetic activation of lateral hypothalamic (LH) orexin neurons alleviates mechanical hypersensitivity after cerebral ischaemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Mice were subjected to BCAO for 30\u2009min. The von Frey test assessed mechanical hypersensitivity. To specifically activate orexin\u2010expressing LH neurons, we bilaterally injected Flp\u2010dependent adeno\u2010associated viruses expressing excitatory DREADD hM3Dq into the LH of orexin\u2010Flp mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      BCAO mice showed significantly increased withdrawal responses to mechanical stimulation on Day 3 after a stroke. Hypothalamic\n                      <jats:italic>prepro\u2010orexin<\/jats:italic>\n                      mRNA expression was significantly decreased in BCAO mice. Cleaved caspase\u20103\u2010positive cells and glial activation were observed in the hypothalamus, including the LH. Chemogenetic activation of orexin neurons significantly attenuated BCAO\u2010induced mechanical hypersensitivity in heterozygous Orexin\u2010Flp mice but not in homozygous Orexin\u2010Flp mice. The antinociceptive effect was inhibited by pretreatment with SB334867, an orexin receptor 1 antagonist.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings suggest that impaired hypothalamic orexinergic signalling may contribute to the pathophysiology of CPSP and that modulation of orexinergic signalling may represent a potential therapeutic strategy for post\u2010stroke pain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>Central post\u2010stroke pain (CPSP) lacks effective therapies, and its underlying mechanisms remain poorly understood. Using a mouse model of BCAO, we found reduced hypothalamic prepro\u2010orexin expression together with neuroinflammatory and apoptotic changes in the hypothalamus. Chemogenetic activation of lateral hypothalamic orexin neurons attenuated mechanical hypersensitivity, at least in part through orexin receptor 1 signalling. These findings suggest that impaired hypothalamic orexinergic signalling contributes to the pathophysiology of CPSP and identify the orexinergic system as a potential therapeutic target for post\u2010stroke pain.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejp.70400","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T09:43:58Z","timestamp":1790588638000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Direct Activation of Orexin Neurons Attenuates Central Post\u2010Stroke Pain in Mice"],"prefix":"10.1002","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7536-4576","authenticated-orcid":false,"given":"Kazuo","family":"Nakamoto","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences Kobe Gakuin University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruki","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences Kobe Gakuin University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4984-6045","authenticated-orcid":false,"given":"Shogo","family":"Tokuyama","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences Kobe Gakuin University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s11538-025-01412-6","article-title":"A Data\u2010Informed Mathematical Model of Microglial Cell Dynamics During Ischemic Stroke in the Middle Cerebral Artery","volume":"87","author":"Amato S.","year":"2025","journal-title":"Bulletin of Mathematical Biology"},{"key":"e_1_2_12_3_1","doi-asserted-by":"crossref","DOI":"10.3389\/fneur.2021.678198","article-title":"Central Post\u2010Stroke Pain: An Integrative Review of Somatotopic Damage, Clinical Symptoms, and Neurophysiological Measures","volume":"12","author":"Betancur D. 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