{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T14:10:08Z","timestamp":1778595008907,"version":"3.51.4"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T00:00:00Z","timestamp":1607040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15K08678"],"award-info":[{"award-number":["15K08678"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The antinociceptive effect of methadone in the morphine-resistant inflammatory pain state was described in the paw-withdrawal test using the complete Freund\u2019s adjuvant (CFA)-induced mouse inflammatory pain model. After intraplantar (i.pl.) injection of CFA, thermal hyperalgesia was observed in the ipsilateral paw. The antinociceptive effects of subcutaneous (s.c.) injection of morphine, fentanyl, and oxycodone against thermal hyperalgesia in the inflammatory pain state were reduced in the ipsilateral paw 7 days after CFA pretreatment. On the contrary, the antinociceptive effect of s.c. injection of methadone was maintained in the ipsilateral paw 7 days after CFA pretreatment. The suppressed morphine antinociception in the CFA model mice was bilaterally restored following s.c. treatment with methadone 20\u00a0min prior to or 3 days after CFA pretreatment. The suppressed morphine antinociception was also bilaterally restored by intraperitoneal treatment with MK-801 30\u00a0min prior to CFA pretreatment; however, the s.c. injection of morphine 30\u00a0min prior to CFA pretreatment failed to restore the suppressed morphine antinociception in the CFA model mice. The expression level of mRNA for \u00b5-opioid receptors 7 days after i.pl. pretreatment was not significantly changed by i.pl. pretreatment with CFA or s.c. pretreatment with methadone. In conclusion, methadone is extremely effective against thermal hyperalgesia in the morphine-resistant inflammatory pain state, and restores suppressed morphine antinociception in the inflammatory pain state without altering the expression level of mRNA for \u00b5-opioid receptors.<\/jats:p>","DOI":"10.3389\/fphar.2020.593647","type":"journal-article","created":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T06:33:05Z","timestamp":1607063585000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Morphine Antinociception Restored by Use of Methadone in the Morphine-Resistant Inflammatory Pain State"],"prefix":"10.3389","volume":"11","author":[{"given":"Chizuko","family":"Watanabe","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asami","family":"Komiyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaru","family":"Yoshizumi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinobu","family":"Sakurada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirokazu","family":"Mizoguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.neulet.2013.12.020","article-title":"Differential alternation of the antinociceptive effect of narcotic analgesics on the inflammatory pain state","volume":"560","author":"Aoki","year":"","journal-title":"Neurosci. 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