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ANESTHETIC PHARMACOLOGY

The µ Opioid Receptor Mediates Morphine-Induced Tumor Necrosis Factor and Interleukin-6 Inhibition in Toll-Like Receptor 2-Stimulated Monocytes

Marie-Pierre Bonnet, MD^*, Hélène Beloeil, MD, PhD^*, Dan Benhamou, MD^*, Jean-Xavier Mazoit, MD, PhD^*, and Karim Asehnoune, MD, PhD

From the *Hôpital Bicêtre, AP-HP, Le Kremlin-Bicêtre, cedex, France; and Hôpital Hotel-Dieu, Nantes, France.

Address correspondence and reprint requests to Marie-Pierre Bonnet, MD, Département d’Anesthésie Réanimation Chirurgicale, Groupement Hospitalier Universitaire Sud, Hôpital Bicêtre, 78, rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, cedex, France. Address e-mail to marie-pierre.bonnet{at}abc.aphp.fr.

BACKGROUND: Morphine possesses immunomodulatory effects but its intrinsic mechanisms, especially in the toll-like receptor 2 (TLR2) signaling pathway, are only partially understood. In this study, we evaluated the effects of morphine on tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-10 (IL-10) production in TLR2-stimulated human monocytes and identified the involvement of the different opioid receptors, and of the lymphocyte-to-monocyte contact.

METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from fresh blood by centrifugation on a density gradient. Monocytes were secondarily separated using a high-gradient magnetic cell sorting kit with specific anti-CD14 antibodies. Monocytes or PBMCs were pretreated with opioid receptors antagonists before being cultured with morphine and peptidoglycan (PGN) from Staphylococcus aureus (specific TLR2 agonist). The amount of TNF, IL-6, and IL-10 was measured in the supernatant enzyme-linked immunosorbent assay.

RESULTS: Proinflammatory cytokines: Morphine significantly inhibited the production of cytokines in a dose and concentration-dependent manner in PGN-stimulated monocytes. µ Opioid receptor activation specifically mediated this morphine-induced TNF and IL-6 inhibition in monocytes. Morphine significantly inhibited the TNF, but not the IL-6 production, in PGN-stimulated PBMCs. The µ opioid receptor was not involved in this morphine-induced TNF inhibition in PBMCs. Antiinflammatory cytokines: IL-10 was not a factor for the inhibition of TNF and IL-6 production after PGN stimulation in either monocytes or PBMCs cultures.

CONCLUSIONS: The µ opioid receptor mediates morphine-induced TNF and IL-6 inhibition in PGN-stimulated monocytes, but not in PBMCs. A direct monocyte-to-lymphocyte contact (PBMCs) alters the inhibitory effects of morphine observed on monocytes alone. IL-10 is not a factor for the inhibition of TNF or for IL-6 production. Interactions between TLR2 and µ opioid intracellular pathways remain to be studied to delineate these morphine immunosuppressive effects.

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