title: Toll-like Receptor 4 Mediates Morphine-Induced Neuroinflammation and Tolerance via Soluble Tumor Necrosis Factor Signaling.
abstract: Opioid tolerance and the potential for addiction is a significant burden associated with pain management, yet its precise underlying mechanism and prevention remain elusive. Immune signaling contributes to the decreased efficacy of opioids, and we recently demonstrated that Toll-like receptor 4 (TLR4)-mediated neuroinflammation in the periaqueductal gray (PAG) drives tolerance. Tumor necrosis factor (TNF), a product of TLR4 signaling, promotes inflammation and facilitates glutamatergic signaling, key components of opioid tolerance. Therefore, we hypothesize that TLR4-mediated opioid tolerance requires TNF signaling. By expression of a dominant-negative TNF peptide via lentiviral vector injection in rat PAG to sequester soluble TNF (solTNF), we demonstrate that solTNF mediates morphine tolerance induced by TLR4 signaling, stimulates neuroinflammation (increased IL-1β and TLR4 mRNA), and disrupts glutamate reuptake (decreased GLT-1 and GLAST mRNA). We further demonstrate the efficacy of the brain-permeant PEGylated version of the anti-solTNF peptide, XPro1595, injected systemically, to normalize morphine-induced CNS neuroinflammation and morphine- and endotoxin-induced changes in glutamate transport, effectively preserving the efficacy of morphine analgesia and eliminating tolerance. Our findings provide a novel pharmacological target for the prevention of opioid-induced immune signaling, tolerance, and addiction.
authors.affiliation: Neuroscience Institute, Petit Science Center, Georgia State University, Atlanta GA, USA.
authors.forename: Lori N
authors.initials: LN
authors.lastname: Eidson
authors.affiliation: Center for Translational Social Neuroscience, Yerkes National Primate Research Center, Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Center for Translational Social Neuroscience, Yerkes National Primate Research Center, Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Young
authors.affiliation: Department of Physiology, Emory University, Atlanta, GA, USA.
authors.forename: Malu G
authors.initials: MG
authors.lastname: Tansey
authors.affiliation: Neuroscience Institute, Petit Science Center, Georgia State University, Atlanta GA, USA.
authors.forename: Anne Z
authors.initials: AZ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D004361:Drug Tolerance / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D009294:Narcotics; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C540591:XENP 1595; D018698:Glutamic Acid; D009020:Morphine