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J. Biol. Chem., Vol. 281, Issue 12, 8082-8089, March 24, 2006

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Identification of Morphine-6-glucuronide in Chromaffin Cell Secretory Granules^*

Yannick Goumon¹, Arnaud Muller, Elise Glattard, Céline Marban, Claire Gasnier, Jean-Marc Strub, Sylvette Chasserot-Golaz^¶, Olivier Rohr, George B. Stefano^||, Ingeborg D. Welters^**, Alain Van Dorsselaer, Françoise Schoentgen, Dominique Aunis, and Marie-Hélène Metz-Boutigue

From the Physiopathologie du Système Nerveux, INSERM U575, 67084 Strasbourg, France, the Laboratoire de Spectrométrie de Masse BioOrganique, CNRS UMR 7168/LC2, 67087 Strasbourg, France, the ^¶Laboratoire de Neurotransmission et Sécrétion Neuroendocrine, CNRS UPR 2356, 67084 Strasbourg, France, the ^||Neuroscience Research Institute, State University of New York, Old Westbury, New York, New York 11568, the ^**Department of Anesthesiology, Intensive Care, and Pain Medicine, Justus-Liebig-Universität, 35385 Giessen, Germany, and the Centre de Biophysique Moléculaire, CNRS UPR 4301, 45071 Orléans, France

We report for the first time that morphine-6-glucuronide, a highly analgesic morphine-derived molecule, is present in adrenal chromaffin granules and secreted from chromaffin cells upon stimulation. We also demonstrate that phosphatidylethanolamine-binding protein (alternatively named Raf-1 kinase inhibitor protein or RKIP) acts as an endogenous morphine-6-glucuronide-binding protein. An UDP-glucuronosyltransferase 2B-like enzyme, described to transform morphine into morphine-6-glucuronide, has been immunodetected in the chromaffin granule matrix, and morphine-6-glucuronide de novo synthesis has been characterized, demonstrating the possible involvement of intragranular UDP-glucuronosyltransferase 2B-like enzyme in morphine-6-glucuronide metabolism. Once secreted into the circulation, morphine-6-glucuronide may mediate several systemic actions (e.g. on immune cells) based on its affinity for µ-opioid receptors. These activities could be facilitated by phosphatidylethanolamine-binding protein (PEBP), acting as a molecular shield and preventing morphine-6-glucuronide from rapid clearance. Taken together, our data represent an important observation on the role of morphine-6-glucuronide as a new endocrine factor.

Received for publication, March 1, 2005 , and in revised form, January 5, 2006.

^* This work was supported by INSERM, Université Louis Pasteur Strasbourg, Ph.D. grants from the Région Alsace (to C. M.) and the French Ministère Délégué à la Recherche et à l'Enseignement Supérieur (to E. G. and A. M.), the Fondation pour la Recherche Médicale (to M.-H. M.-B.), the Ligue Contre le Cancer (to D. A.), and Hôpital Universitaire de Strasbourg Programme Hospitalier de Recherche Clinique 3150 (to M.-H. M.-B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: INSERM U575, 5, rue Blaise Pascal, 67084 Strasbourg, France. Tel.: 33-3-8845-6724; Fax: 33-3-8860-0806; E-mail: goumon{at}neurochem.u-strasbg.fr.

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