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Induction of Opioid Receptor Function by Up-Regulation of Membrane Receptors in Mouse Primary Afferent Neurons

Department of Psychiatry and Biobehavioral Sciences, Center for Health Sciences, University of California, Los Angeles, California (W.W., N.T.M., C.J.E.); Psychology Department, University of California, Los Angeles, Los Angeles, California (M.S.); Institute of Genetics and Molecular and Cellular Biology, Centre National de la Recherche Scientifique/Institut National de la Sante et de la Recherche Medicale/Université Louis Pasteur, Illkirch, France (B.L.K.); and Departments of Pharmacology & Physiology and Anesthesiology & Critical Care Medicine, the George Washington University, Washington, DC (T.G.H.)

It is not clear whether primary afferent neurons express functional cell-surface opioid receptors. We examined receptor coupling to Ca²⁺ channels in mouse dorsal root ganglion neurons under basal conditions and after receptor up-regulation. [D-Ala²,Phe⁴,Gly⁵-ol]-enkephalin (DAMGO), [D-Ala²,D-Leu⁵]-enkephalin (DADLE), trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl) benzene-acetamide methanesulfonate (U-50,488H; 1 µM), and baclofen (50 µM) inhibited Ca²⁺ currents, whereas the -selective ligands [D-Pen²,Pen⁵]-enkephalin (DPDPE) and deltorphin II (1 µM) did not. The effect of DADLE (1 µM) was blocked by the µ-antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂ (CTAP; 300 nM) but not by the -antagonist Tyr-1,2,3,4-tetrahydroisoquinoline-Phe-Phe-OH (300 nM), implicating µ receptors. Despite a lack of functional receptors, flow cytometry revealed cell-surface receptors. We used this approach to identify conditions that up-regulate receptors, including µ receptor gene deletion in dorsal root ganglion neurons of µ-/- mice and 18-h incubation of µ+/+ neurons with CTAP followed by brief (10-min) DPDPE exposure. Under these conditions, the expression of cell-surface receptors was up-regulated to 149 ± 9 and 139 ± 5%, respectively; furthermore, DPDPE and deltorphin II (1 µM) inhibited Ca²⁺ currents in both cases. Viral replacement of µ receptors in µ-/- neurons reduced receptor expression to µ+/+ levels, restored the inhibition of Ca²⁺ currents by DAMGO, and abolished receptor coupling. Our observations suggest that receptor-Ca²⁺ channel coupling in primary afferent fibers may have little functional significance under basal conditions in which µ receptors predominate. However, up-regulation of cell-surface receptors induces their coupling to Ca²⁺ channels. Pharmacological approaches that increase functional receptor expression may reveal a novel target for analgesic therapy.

Address correspondence to: Dr. Tim G. Hales, Department of Pharmacology and Physiology, Medical Center, The George Washington University, 2300 Eye Street NW, Washington, DC 20037. E-mail: phmtgh{at}gwumc.edu.

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