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Promoting Receptor Endocytosis to Reduce Tolerance and Dependence

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Science's STKE  14 Jun 2005:
Vol. 2005, Issue 288, pp. tw220
DOI: 10.1126/stke.2882005tw220

Although morphine is highly effective against pain, its effective long-term use is limited by its ability to induce tolerance and dependence--both likely associated with up-regulation of cyclic adenosine monophosphate (cAMP) signaling and adaptive changes in the expression of target genes. Morphine analgesia and tolerance are mediated through the μ opioid peptide receptor (MOP), which is also activated by endogenous opiates and methadone; however, unlike these other opiates, morphine does not stimulate endocytosis of the MOP receptor. He and Whistler found that concentrations of methadone that alone would not stimulate endocytosis, when administered with saturating concentrations of morphine, promoted MOP receptor endocytosis in both rat brain and human embryonic kidney (HEK) 293 cells stably transfected with the MOP receptor. The authors interpreted this as due to the dimeric or oligomeric nature of the MOP receptor and proposed that, when the other protomers are occupied by morphine, occupation by methadone of a single protomer could engage the endocytotic machinery. When administered with morphine, such low concentrations of methadone reduced morphine-induced up-regulation of the cAMP pathway in HEK293 cells. In rats, methadone inhibited the development of morphine tolerance (assessed by tail-flick) and dependence (assessed by the behavioral response to pharmacologically induced opiate withdrawal) at concentrations that did not affect acute morphine analgesia. Methadone also prevented an increase in the striatal abundance of the NR2A subunit of the N-methyl-D-aspartate receptor that occurred with chronic morphine treatment. Thus, the authors suggest that promotion of receptor endocytosis by coadministered methadone inhibits adaptive changes associated with chronic exposure to morphine and may thereby enhance the effectiveness of morphine in treating chronic pain.

L. He, J. L. Whistler, An opiate cocktail that reduces morphine tolerance and dependence. Current Biology 15, 1028-1033 (2005). [PubMed]

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