{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T14:29:49Z","timestamp":1787581789485,"version":"build-2736575974"},"reference-count":55,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2023,4]]},"abstract":"\n Abstract<\/jats:title>\n \n Morphine diminishes pain, but its long\u2010term use is compromised by tolerance and hyperalgesia. Studies implicate \u03b4 receptors, \u03b2\u2010arrestin2 and Src kinase in tolerance. We examined whether these proteins are also involved in morphine\u2010induced hypersensitivity (MIH). A common pathway for tolerance and hypersensitivity may provide a single target to guide improved analgesic approaches. We examined mechanical sensitivity using automated von Frey in wild\u2010type (WT) and transgenic male and female C57Bl\/6\u00a0mice before and after hind paw inflammation by complete Freund's adjuvant (CFA). CFA\u2010evoked hypersensitivity ceased on day 7 in WT but persisted for the 15\u2010day testing period in \u03bc\n \u2212\/\u2212<\/jats:sup>\n . Recovery was delayed until day 13 in \u03b4\n \u2212\/\u2212<\/jats:sup>\n . We explored the expression of opioid genes in the spinal cord using quantitative RT\u2010PCR. Restoration to basal sensitivity in WT occurred with increased \u03b4 expression. By contrast, \u03ba expression was reduced, while \u03bc remained unchanged. Daily morphine reduced hypersensitivity in WT on day 3 compared to controls; however, hypersensitivity recurred on day 9 and beyond. By contrast, WT had no recurrence of hypersensitivity in the absence of daily morphine. We used \u03b2\u2010arrestin2\n \u2212\/\u2212<\/jats:sup>\n , \u03b4\n \u2212\/\u2212<\/jats:sup>\n and Src inhibition by dasatinib in WT to establish whether these approaches, which diminish tolerance, also attenuate MIH. While none of these approaches affected CFA\u2010evoked inflammation or acute hypersensitivity, all caused sustained morphine anti\u2010hypersensitivity, abolishing MIH. Like morphine tolerance, MIH in this model requires \u03b4 receptors, \u03b2\u2010arrestin2 and Src activity. Our findings suggest that MIH is caused by a tolerance\u2010induced reduction in endogenous opioid signalling.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Morphine is effective for treating severe acute pain, but tolerance and hypersensitivity often develop during its use in treating chronic pain.<\/jats:p>\n <\/jats:list-item>\n \n It is unclear whether these detrimental effects share similar mechanisms; if so, it might be possible to develop a single approach to minimise both phenomena.<\/jats:p>\n <\/jats:list-item>\n \n Mice deficient in \u03bc receptors, \u03b4 receptors or \u03b2\u2010arrestin2 and wild type mice treated with the Src inhibitor dasatinib exhibit negligible morphine tolerance.<\/jats:p>\n <\/jats:list-item>\n \n We show that these same approaches also prevent the development of morphine\u2010induced hypersensitivity during persistent inflammation.<\/jats:p>\n <\/jats:list-item>\n \n This knowledge identifies strategies, such as the use of Src inhibitors, which may mitigate tolerance and morphine induced hyperalgesia.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp284003","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T00:38:58Z","timestamp":1677717538000},"page":"1483-1500","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Morphine\u2010induced mechanical hypersensitivity in mice requires \u03b4 receptors, \u03b2\u2010arrestin2, and c\u2010Src activity"],"prefix":"10.1113","volume":"601","author":[{"given":"Samuel","family":"Singleton","sequence":"first","affiliation":[{"name":"The Institute of Academic Anaesthesia, Division of Systems Medicine, School of Medicine, Ninewells Hospital University of Dundee Dundee 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