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Neuroscience. 2004;125(3):541-3.

[d-Ala2,N-MePhe4,Gly-ol5]enkephalin-induced internalization of the micro opioid receptor in the spinal cord of morphine tolerant rats.

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Departments of Anatomy and Physiology and W. M. Keck Foundation for Integrative Neuroscience, University of California at San Francisco, San Francisco, CA 94143, USA.


Several theories of opioid tolerance predict that the magnitude of micro opioid receptor (MOR) internalization in response to ligand changes in the setting of morphine tolerance. Here we show that in rats rendered tolerant to the analgesic action of morphine, cross-tolerance to the analgesic action of intrathecally administered [d-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO) can be produced without changes in the magnitude of DAMGO-induced internalization of the MOR in lamina II neurons of the rat spinal cord. These results suggest that opioid tolerance-related changes in signaling are located downstream from or in parallel with receptor activation and internalization and support the idea that key features of opioid signaling are maintained, rather than reduced, in the setting of morphine tolerance.

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