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1

Quantitative Analysis of Opioids

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All the solvents used in this study were high-performance liquid chromatography (HPLC) grade and were purchased from BDH (Poole, UK). Ammonium formate was obtained from Sigma Aldrich (Steinheim, Germany). Morphine, 6-MAM, codeine, 6-AC, and their corresponding internal standards were purchased from Lipomed (Arlesheim, Switzerland). SPE cartridges (Clean Screen®, CSDAU203) were obtained from United Chemical Technologies (Bristol, PA, USA). Stomach wall tissues were homogenized using Stomacher® 400 and Stomacher 80 bags (dimensions: 101 × 152 mm with filter) purchased from Seward limited company (West Sussex, UK).
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2

Quantification of Opioid Compounds

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Morphine, Morphine-d3, 6-MAM, 6-monoacetylMorphine-d3 (6-MAM-d3), codeine, codeine-d3, and 6-AC were purchased from Lipomed (Arlesheim, Switzerland). Methanol (HPLC grade), acetonitrile (HPLC grade), ammonium carbonate, formic acid, and ammonium hydroxide were obtained from BDH (Poole, UK). Ammonium formate was obtained from Sigma-Aldrich (Steinheim, Germany). Clean Screen® solid phase extraction (SPE) cartridges (CSDAU203) were obtained from United Chemical Technologies (Bristol, PA, USA).
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3

Radioligand Binding Assay Protocol

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[3H]-Clonidine (61.3 Ci/mmol) was purchased from Perkin Elmer (Courtaboeuf, France). Specs compounds (AE; AF; AG; AI; AK; AN; AO; AP) were purchased from Specs (Delft, The Netherlands). 6-monoacetylmorphine, codeine, cocaethylene, norcocaine, desomorphine, dihydromorphine, hydrocodone, hydromorphone, norbuprenorphine, oxycodone, and oxymorphone were obtained from Lipomed (Euromedex, Souffelweyersheim, France) and heroin, methadone, and morphine from Francopia (Paris, France). Methylenedioxy-methylamphetamine (MDMA, ecstasy) was synthetized by Dr H. Galons from the chemistry department of Paris University. All other chemicals were purchased from Sigma (St Quentin Fallavier, France) except diphenhydramine (Inresa, Strasbourg, France), cocaine (Cooper, Melun, France), and D617 (Carbosynth, Campton, UK).
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Radioligand Binding Assay Protocol

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Buprenorphine, citalopram, codeine, dextromethorphan, dihydrocodeine, fentanyl, heroin (diacetylmorphine, diamorphine), 6‐acetylmorphine (6‐mono‐acetylmorphine), hydrocodone, hydromorphone, mazindol, MDMA, methadone, morphine, oxycodone, oxymorphone, pethidine (meperidine), tramadol, O‐desmethyl‐cistramadol, tapentadol, venlafaxine and fluoxetine were purchased from Lipomed (Arlesheim, Switzerland). Mianserin, nisoxetine, pargyline, pindolol and spiperone were supplied by Sigma‐Aldrich (Buchs, Switzerland). D(S)‐methadone and l(R)‐methadone were obtained from Alsachim (Illkirch Graffenstaden, France). The HPLC purity of all of the substances was >98%. [3H]‐8‐OH‐DPAT, [3H]‐ketanserin and [3H]‐mesulergine were supplied by Perkin‐Elmer.
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5

Quantification of Drug Concentrations

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Amphetamine, methAmphetamine, MDMA, MDEA, MDA, morphine, codeine, 6-MAM, cocaine and BE (Lipomed, Weil am Rhein, Germany) were dissolved in a solution of 0.9 % NaCl (B. Braun, Melsungen, Germany) and diluted. The mouth rinse solution in study A had a concentration of 1.0 μg/ml. The incubation drug solution in study B had a concentration of 10 μg/ml.
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