Toll-like Receptor 4 Mediates Morphine-Induced Neuroinflammation and Tolerance via Soluble Tumor Necrosis Factor Signaling

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2017-02, Vol.42 (3), p.661-670
• Main Authors: Eidson, Lori N, Inoue, Kiyoshi, Young, Larry J, Tansey, Malu G, Murphy, Anne Z
• Format: Article
• Language: English
• Subjects: Addictions; Animals; Chronic pain; Cytokines; Drug Tolerance - physiology; Glutamic Acid - metabolism; Homeostasis; Hypotheses; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - immunology; Male; Morphine; Morphine - pharmacology; Narcotics; Narcotics - pharmacology; Neurosciences; Original; Pain management; Peptides; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Signal Transduction - physiology; Toll-Like Receptor 4 - metabolism; Tumor Necrosis Factor-alpha - administration & dosage; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2016.131

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.