Journal
NEUROPSYCHOPHARMACOLOGY
Volume 42, Issue 3, Pages 661-670Publisher
SPRINGERNATURE
DOI: 10.1038/npp.2016.131
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Funding
- National Institutes of Health [DA16272]
- Sigma Xi Scientific Research Society
- Georgia State University College of Arts and Sciences Dissertation Grant Award
- Georgia State University Center for Neuromics award
- Office of Research Infrastructure Programs [OD P51OD11132]
- Viral Vector Core of the Emory Neuroscience NINDS Core Facilities grant [P30NS055077]
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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 (soITNF), we demonstrate that solTNF mediates morphine tolerance induced by TLR4 signaling, stimulates neuroinflammation (increased IL-1 beta 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 presenting 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.
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