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

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 i...

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Bibliographic Details
Published in:The Journal of biological chemistry 2006-03, Vol.281 (12), p.8082-8089
Main Authors: Goumon, Yannick, Muller, Arnaud, Glattard, Elise, Marban, Céline, Gasnier, Claire, Strub, Jean-Marc, Chasserot-Golaz, Sylvette, Rohr, Olivier, Stefano, George B., Welters, Ingeborg D., Van Dorsselaer, Alain, Schoentgen, Françoise, Aunis, Dominique, Metz-Boutigue, Marie-Hélène
Format: Article
Language:English
Subjects:
Alkaloids - chemistry
Androgen-Binding Protein - metabolism
Animals
Blotting, Western
Cattle
Chemical Sciences
Chromaffin Cells - chemistry
Chromaffin Cells - metabolism
Chromaffin Granules - metabolism
Chromatography, Affinity
Chromatography, High Pressure Liquid
Electrophoresis, Agar Gel
Endocrine System - metabolism
Exocytosis
Glucuronosyltransferase - metabolism
Glycosylation
Humans
Immunohistochemistry
Immunoprecipitation
Mass Spectrometry
Medicinal Chemistry
Microscopy, Confocal
Microscopy, Fluorescence
Morphine - pharmacology
Morphine Derivatives - metabolism
Phosphatidylethanolamine Binding Protein - metabolism
Secretory Vesicles - metabolism
Subcellular Fractions
Time Factors
Trypsin - pharmacology
Uridine Diphosphate - chemistry
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M502298200