{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:42:59Z","timestamp":1789054979483,"version":"build-2803163510"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T00:00:00Z","timestamp":1660521600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology, Japan","award":["No.21592002"],"award-info":[{"award-number":["No.21592002"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Adverse effects of morphine on locomotor function after moderate to severe spinal cord injury (SCI) have been reported; however, the effects after mild SCI without damage of lumbar \u03b1-motoneurons have not been investigated. We investigated the effects of lumbar intrathecal morphine on locomotor function after mild thoracic SCI and the involvement of classic opioid receptor activation. A mild thoracic contusive SCI was induced in adult rats at the T9-T10 spine level under sevoflurane anesthesia. We evaluated the effects of single doses of intrathecal morphine and selective \u03bc-, \u03b4-, and \u03ba-opioid receptor agonists, continuous infusion of intrathecal morphine for 72 hours, and administration of physiological saline on locomotor function and muscle tone in the hindlimbs. The numbers of damaged and total \u03b1-motoneurons in the lumbar spinal cord were also investigated. Single doses of morphine aggravated residual locomotor function after SCI but did not affect functional recovery. Single doses of morphine and \u03bc- and \u03b4-opioid receptor agonists significantly aggravated residual locomotor function with increases in muscle tone after SCI, and the effects of the drugs were reversed by naloxone. In contrast, continuous infusion of morphine led to persistent decline in locomotor function with increased muscle tone, which was not reversed by naloxone, but did not increase the number of damaged lumbar \u03b1-motoneurons. These results indicate that a single dose of morphine at an analgesic dose transiently increases muscle tone of the hindlimbs via activation of spinal \u03bc- and \u03b4- opioid receptors, resulting in further deterioration of locomotor function in the acute phase of mild SCI. Our results also suggest that an increased dose of morphine with prolonged administration leads to persistent decline in locomotor function with increased muscle tone via mechanisms other than direct activation of classical opioid receptors. Morphine should be used cautiously even after mild SCI.<\/jats:p>","DOI":"10.1371\/journal.pone.0273095","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T17:35:12Z","timestamp":1660584912000},"page":"e0273095","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Intrathecal morphine exacerbates paresis with increasing muscle tone of hindlimbs in rats with mild thoracic spinal cord injury but without damage of lumbar \u03b1-motoneurons"],"prefix":"10.1371","volume":"17","author":[{"given":"Katsuhiro","family":"Kawakami","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3338-7056","authenticated-orcid":true,"given":"Satoshi","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Sugiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriaki","family":"Mochizuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4483-3026","authenticated-orcid":true,"given":"Mikito","family":"Kawamata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,8,15]]},"reference":[{"issue":"10","key":"pone.0273095.ref001","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1038\/s41393-020-0483-x","article-title":"The first 24 h: opioid administration in people with spinal cord injury and neurologic recovery","volume":"58","author":"A Stampas","year":"2020","journal-title":"Spinal Cord"},{"issue":"4","key":"pone.0273095.ref002","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1097\/00000542-200304000-00012","article-title":"Neuraxial morphine may trigger transient motor dysfunction after a noninjurious interval of spinal cord ischemia: a clinical and experimental study","volume":"98","author":"M Kakinohana","year":"2003","journal-title":"Anesthesiology"},{"issue":"1","key":"pone.0273095.ref003","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1093\/bja\/aei285","article-title":"Mu and delta, but not kappa, opioid agonists induce spastic paraparesis after a short period of spinal cord ischaemia in rats","volume":"96","author":"M Kakinohana","year":"2006","journal-title":"Br J Anaesth"},{"issue":"5","key":"pone.0273095.ref004","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1213\/01.ANE.0000133915.56613.D9","article-title":"Intrathecal morphine, but not buprenorphine or pentazocine, can induce spastic paraparesis after a noninjurious interval of spinal cord ischemia in the rat","volume":"99","author":"S Nakamura","year":"2004","journal-title":"Anesth Analg."},{"key":"pone.0273095.ref005","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.bbi.2019.01.023","article-title":"Morphine increases macrophages at the lesion site following spinal cord injury: Protective effects of minocycline","volume":"79","author":"M Aceves","year":"2019","journal-title":"Brain Behav Immun"},{"issue":"5","key":"pone.0273095.ref006","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1089\/neu.2008.0710","article-title":"Intrathecal morphine attenuates recovery on function after a spinal cord injury","volume":"26","author":"MA Hook","year":"2009","journal-title":"J Neurotrauma"},{"issue":"2","key":"pone.0273095.ref007","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.bbi.2010.10.018","article-title":"An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury","volume":"25","author":"MA Hook","year":"2011","journal-title":"Brain Behav Immun"},{"issue":"10","key":"pone.0273095.ref008","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1161\/01.STR.27.10.1850","article-title":"Effect of proximal arterial perfusion pressure on function, spinal cord blood flow, and histopathologic changes after increasing intervals of aortic occlusion in the rat","volume":"27","author":"Y Taira","year":"1996","journal-title":"Stroke"},{"issue":"24 Suppl","key":"pone.0273095.ref009","first-page":"S68","article-title":"Measurements and recovery patterns in a multicenter study of acute spinal cord injury","volume":"26","author":"Sygen Study Group","year":"2001","journal-title":"Spine (Phila Pa 1976)"},{"key":"pone.0273095.ref010","unstructured":"World Health Organization [Internet]. 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