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Updated: Nov 25, 2025

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Morphine Antinociception Restored by Use of Methadone in the Morphine-Resistant Inflammatory Pain State
Chizuko Watanabe1, Asami Komiyama1, Masaru Yoshizumi1
1Department of Physiology and Anatomy, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
Abstract:
The antinociceptive effect of methadone in the morphine-resistant inflammatory pain state was described in the paw-withdrawal test using the complete Freund's 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 min prior to or 3 days after CFA pretreatment. The suppressed morphine antinociception was also bilaterally restored by intraperitoneal treatment with MK-801 30 min prior to CFA pretreatment; however, the s.c. injection of morphine 30 min prior to CFA pretreatment failed to restore the suppressed morphine antinociception in the CFA model mice. The expression level of mRNA for µ-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 µ-opioid receptors.
Insights
Methadone effectively treats inflammatory pain resistant to morphine. It restores morphine
Area of Science:
- Pharmacology
- Pain Management
- Neuroscience
Background:
- Inflammatory pain states can lead to reduced efficacy of common analgesics like morphine.
- Understanding mechanisms of opioid resistance is crucial for developing effective pain therapies.
Purpose of the Study:
- To investigate the antinociceptive effect of methadone in a morphine-resistant inflammatory pain model.
- To determine if methadone can restore morphine's efficacy in this resistant state.
Main Methods:
- Utilized the complete Freund's adjuvant (CFA)-induced mouse inflammatory pain model.
- Assessed thermal hyperalgesia using the paw-withdrawal test.
- Administered methadone, morphine, fentanyl, and oxycodone via subcutaneous (s.c.) injection.
Main Results:
- Methadone maintained its antinociceptive effect in CFA-treated mice, unlike morphine, fentanyl, and oxycodone.
- Methadone treatment restored suppressed morphine antinociception in the CFA model.
- MK-801 also restored morphine antinociception, but pre-CFA morphine administration did not.
Conclusions:
- Methadone is highly effective against thermal hyperalgesia in morphine-resistant inflammatory pain.
- Methadone restores suppressed morphine antinociception without altering µ-opioid receptor mRNA expression.
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