Abstract
μ-Opioid receptors are the pharmacological targets of endogenous opioid peptides and morphine-like alkaloid drugs. Previous studies of transfected cells and peripheral neurons indicate that opioid receptors are rapidly internalized after activation by the alkaloid agonist etorphine but not after activation by morphine. To determine whether opioid receptors in the central nervous system are regulated by a similar process of agonist-selective internalization, μ-opioid receptors were examined in rat brain neurons after treatment of animals with opioid drugs. Internalized μ receptors were observed within 30 min after intraperitoneal injection of the alkaloid agonist etorphine, and this process was blocked by the antagonist naloxone. Colocalization of internalized opioid receptors with transferrin receptors in confocal optical sections indicated that receptor internalization observedin vivo is mediated by a membrane trafficking pathway similar to that observed previously in vitro using transfected human embryonic kidney 293 cells. Morphine failed to induce detectable rapid internalization of receptors, even when administered to animals at doses far in excess of those required to induce analgesia. To quantify these agonist-selective differences and to analyze an array of opioid ligands for their ability to trigger internalization, we used flow cytometry on stably transfected 293 cells. These studies indicated that the different effects of individual agonists are not correlated with their potencies for receptor activation and that a variety of clinically important agonists differ significantly in their relative abilities to stimulate the rapid internalization of opioid receptors.
Footnotes
- Received August 18, 1997.
- Accepted November 11, 1997.
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Send reprint requests to: Christopher J. Evans, Ph.D., Department of Psychiatry, NPI/UCLA, 760 Westwood Plaza, Los Angeles, CA 90024-1759. E-mail: cevans{at}ucla.edu
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This work was supported by National Institute on Drug Abuse Grants DA05010 and DA00218. P.A.Z. is a Hatos Scholar and recipient of a predoctoral fellowship from the Howard Hughes Medical Institute. S.R.M. was funded by a postdoctoral fellowship from the National Institutes of Health. Flow cytometric analysis was performed in the Jonsson Comprehensive Cancer Center, which is partially supported by National Institutes of Health Grant CA16042.
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C.J.E. and M.v.Z. contributed equally to this report.
- The American Society for Pharmacology and Experimental Therapeutics
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