title: Toll-like receptor 2 is required for opioids-induced neuronal apoptosis.
abstract: Toll-like receptor 2 (TLR2), a key immune receptor in the TLR family, is widely expressed in various systems, including the immune and nervous systems and plays a critical role in controlling innate and adaptive immune responses. We previously reported that opioids inhibit cell growth and trigger apoptosis. However, the underlying mechanism by which TLR2 mediates apoptosis in response to opioids is not yet known. Here we show that chronic morphine treatment in primary neurons dramatically increased the expression of TLR2 at both the messenger RNA and protein levels. In addition, TLR2 deficiency significantly inhibited chronic morphine-induced apoptosis in primary neurons. Activation of caspase-3 after morphine treatment is impaired in TLR2 deficient primary neurons. Moreover, morphine treatment failed to induce an increased level of phosphorylated glycogen synthase kinase 3 beta (GSK3beta) in TLR2 deficient primary neurons, suggesting an involvement of GSK3beta in morphine-mediated TLR2 signaling. These results thus demonstrate that opioids prime neurons to undergo apoptosis by inducing TLR2 expression. Our data suggest that inhibition of TLR2 is capable of preventing opioids-induced damage to neurons.
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiuli
authors.initials: X
authors.lastname: Sun
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Hanley
authors.forename: Gene
authors.initials: G
authors.lastname: LeSage
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shenggang
authors.initials: S
authors.lastname: Sun
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.forename: Deling
authors.initials: D
authors.lastname: Yin
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000096:biosynthesis; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D009020:Morphine; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3