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07 Jun 2005

Although morphine is well known as a highly effective analgesic, its clinical utility is severely limited by the development of drug tolerance,  the requirement for increasing doses to maintain analgesic effect, and the development of physical dependence. In the June 7 issue of Current Biology, researchers report a new study showing that the administration of a drug cocktail containing morphine along with small doses of two versions of methadone, a related opioid drug, significantly reduced both tolerance and dependence in test animals.

The work is reported by Li He and Jennifer Whistler of the Ernest Gallo Clinic and Research Center and the University of California, San Francisco.

The analgesic effects of morphine arise through the interaction of the drug with a specialized protein on the surface of cells, the mu opioid peptide receptor, or "MOP" receptor.  MOP receptors are also activated by other opioid drugs and by endogenous opioids, such as endorphins.    However, morphine is unique in that unlike other opioids,  it does not cause the MOP receptor to be internalized into the cell's interior after activation.  »»  It is thought that the activated receptor's persistence at the cell surface leads to a compensatory overactivation of a particular signaling pathway in the cell--a signaling imbalance that is a hallmark  of opiate tolerance and dependence.  This suggests that the promotion of MOP-receptor internalization might prevent such cellular signaling imbalances, and indeed past work from Whistler indicated that mutant versions of the receptor that are more readily internalized were associated with reduced levels of morphine tolerance in mice.

In the new work, the researchers sought a more clinically practical approach to facilitating MOP-receptor internalization in the presence of morphine. Reasoning that because other opioid drugs promote internalization of MOP receptors, and that their presence in combination with morphine may prevent the persistence of activated MOP receptors at the cell surface, the authors developed a drug cocktail containing morphine along with two chemical versions of the opioid methadone, which is tolerated, with limited side effects, at low doses.

The authors indeed found that the combination of morphine with the methadone mixture prevented the activation of cellular signaling pathways associated with morphine tolerance and dependence.  They also showed, perhaps most importantly, that whereas rats receiving only morphine develop tolerance to the drug, those rats receiving the morphine/methadone cocktail did not show tolerance. 

Moreover, past work has not indicated whether the promotion of MOP-receptor internalization could prevent the development of morphine dependence, but in  the new study, the authors discovered that rats receiving the morphine/methadone cocktail also experienced reduced morphine dependence.

In light of their findings, the authors propose that an opiate cocktail that combines morphine with small doses of methadone would increase the effectiveness of morphine for the treatment of chronic pain.

The researchers include Li He and Jennifer L. Whistler of the Ernest Gallo Clinic and Research Center and University of California, San Francisco. This work was supported by National Institute on Drug Abuse (NIDA) grant and funds provided by the state of California for medical research on alcohol and substance abuse through the University of California, San Francisco (UCSF) to J.L.W.

He, L., and Whistler, J.L. (2005). An Opiate Cocktail that Reduces Morphine Tolerance and Dependence. DOI 10.1016/j.cub.2005.04.052 Publishing in Current Biology, Vol. 15, June 7, 2005, pages 1028-1033. www.current-biology.com

Contact: Heidi Hardman
hhardman@cell.com
1-617-397-2879
Cell Press

The page was updated on 27 August 2005

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