title: Mu opioid receptor activation modulates Toll like receptor 4 in murine macrophages.
abstract: Opioids have been shown to affect both innate and adaptive immunity. We previously showed that morphine affects the macrophage production of pro-inflammatory cytokines after LPS in a NFkB dependent manner. Toll like receptors (TLRs) play a crucial role in the signaling pathways which lead to NFkB activation. TLR4 is considered the Lipopolysaccaride (LPS) receptor. The data here presented show that, in murine macrophages, morphine impacts on the immune function acting on the early step of pathogen recognition. Morphine, when added to RAW 264.7 cells and when injected into mice (s.c. 20mg/kg) is in fact able to decrease TLR4 both at mRNA and protein level in RAW cells and peritoneal macrophages. In the same cells, the mu opioid receptor (MOR) antagonist Naltrexone increases TLR4 levels, thus suggesting a role of the endogenous opioid system in TLR4 regulation. The effect of the two drugs is moreover lost in case of co-administration. Experiments with MOR KO mice and with DAMGO (MOR specific agonist) confirm that the effect of morphine on TLR4 mRNA in peritoneal macrophages is due to the MOR activation. Moreover the effect on TLR4 is blocked by PTX thus indicating the involvement of a G(i) protein after MOR binding. This work unveils a clear link between MOR activation and TLR4, suggesting a new possible mechanism at the basis of the peripheral immunosuppressive effect of opioids.
authors.affiliation: Dipartimento di Farmacologia Chemioterapia e Tossicologia medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Franchi
authors.forename: Sarah
authors.initials: S
authors.lastname: Moretti
authors.forename: Mara
authors.initials: M
authors.lastname: Castelli
authors.forename: Donatella
authors.initials: D
authors.lastname: Lattuada
authors.forename: Cinzia
authors.initials: C
authors.lastname: Scavullo
authors.forename: Alberto E
authors.initials: AE
authors.lastname: Panerai
authors.forename: Paola
authors.initials: P
authors.lastname: Sacerdote
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009271:Naltrexone / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D007166:Immunosuppressive Agents; D017450:Receptors, Opioid, mu; D051197:Toll-Like Receptor 4; D009271:Naltrexone; D009020:Morphine