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The Journal of Neuroscience, April 12, 2006, 26(15):4118-4125; doi:10.1523/JNEUROSCI.0303-06.2006

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Behavioral/Systems/Cognitive
Separation of µ-Opioid Receptor Desensitization and Internalization: Endogenous Receptors in Primary Neuronal Cultures

Seksiri Arttamangkul,^1 * Maria Torrecilla,^1 * Kazuto Kobayashi,² Hideyuki Okano,^3,4 and John T. Williams¹

¹Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, ²Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University, School of Medicine, Fukushima 960-1295, Japan, ³Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, and ⁴Department of Physiology, Keio University, School of Medicine, Tokyo 160-8582, Japan

Correspondence should be addressed to John T. Williams, Vollum Institute, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Email: williamj{at}ohsu.edu

A close relationship between desensitization and internalization of µ-opioid receptors (MORs) has been proposed based on differential actions of series of agonists. The role that these two processes have in the development of tolerance and dependence to opioids has been a controversial subject that has been studied in a variety of model systems. Here, we examine desensitization and internalization of endogenous MORs simultaneously in primary cultures of locus ceruleus neurons using fluorescently tagged peptide agonists. With the use of two fluorescent opioid peptides, dermorphin-Bodipy Texas Red and dermorphin-Alexa594 (Derm-A594), desensitization was measured electrophysiologically and trafficking was followed by the accumulation of intracellular fluorescent puncta. Blocking endocytosis with concanavalin A eliminated the accumulation of fluorescent puncta but desensitization induced by Derm-A594 was unaffected. Likewise, after treatment with concanavalin A, there was no change in either desensitization or recovery from desensitization induced by [Met]⁵enkephalin. The results demonstrate that desensitization and the recovery from desensitization are not dependent on receptor internalization and suggest that the activity of endogenous MORs in primary neurons can be modulated at the level of the plasma membrane.

Key words: fluorescent-peptide; locus ceruleus; culture; concanavalin A; electrophysiology; two-photon microscopy

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Received Nov. 18, 2005; revised March 1, 2006; accepted March 2, 2006.

Correspondence should be addressed to John T. Williams, Vollum Institute, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Email: williamj{at}ohsu.edu

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