Abstract
Chronic treatment of pain with opiate drugs can lead to analgesic tolerance and drug dependence. Although all opiate drugs can promote tolerance and dependence in practice, the severity of those unwanted side effects differs depending on the drug used. Although each opiate drug has its own unique set of pharmacological profiles, methadone is the only clinically used opioid drug that produces substantial receptor endocytosis at analgesic doses. Here, we examined whether moderate doses of methadone carry any benefits over chronic use of equianalgesic morphine, the prototypical opioid. Our data show that chronic administration of methadone produces significantly less analgesic tolerance than morphine. Furthermore, we found significantly reduced precipitated withdrawal symptoms after chronic methadone treatment than after chronic morphine treatment. Finally, using a novel animal model with a degrading μ-opioid receptor we showed that, although endocytosis seems to protect against tolerance development, endocytosis followed by receptor degradation produces a rapid onset of analgesic tolerance to methadone. Together, these data indicated that opioid drugs that promote receptor endocytosis and recycling, such as methadone, may be a better choice for chronic pain treatment than morphine and its derivatives that do not.
Footnotes
This study was supported in part by a long-term fellowship from Svenska Stiftelsen för Medicinsk Forskning (to J.E.); a Shrödinger fellowship from the Austrian Science Fund [J2967-B09] (to L.M.L.); the National Institutes of Health National Institute on Drug Abuse [Grant DA019958] (to J.L.W.); and funds provided by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco (to J.L.W.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- MOR
- μ-opiate receptor
- DMOR
- degrading MOR
- DOR
- δ-opiate receptor
- WT
- wild type
- ANOVA
- analysis of variance
- NMDA
- N-methyl-d-aspartate
- WDS
- wet dog shakes
- PT
- paw tremor
- ED50
- effective dose at 50%.
- Received September 1, 2011.
- Accepted November 4, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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