Decoy peptide targeted to Toll-IL-1R domain inhibits LPS and TLR4-active metabolite morphine-3 glucuronide sensitization of sensory neurons

Yohance M. Allette, Youngsook Kim, Aaron L. Randolph, Jared A. Smith, Matthew S. Ripsch, Fletcher White

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Accumulating evidence indicates that Toll-like receptor (TLR) signaling adapter protein interactions with Toll/Interleukin-1 Receptor (TIR) domains present in sensory neurons may modulate neuropathic pain states. Following ligand interaction with TLRs, TIR serves to both initiate intracellular signaling and facilitate recruitment of signaling adapter proteins to the intracytoplasmic domain. Although TLR TIR is central to a number of TLR signaling cascades, its role in sensory neurons is poorly understood. In this study we investigated the degree to which TLR TIR decoy peptide modified to include a TAT sequence (Trans-Activator of Transcription gene in HIV; TAT-4BB) affected LPS-induced intracellular calcium flux and excitation in sensory neurons, and behavioral changes due to TLR4 active metabolite, morphine-3-glucuronide (M3G) exposure in vivo. TAT-4BB inhibited LPS-induced calcium changes in a majority of sensory neurons and decreased LPS-dependent neuronal excitability in small diameter neurons. Acute systemic administration of the TAT-4BB reversed M3G-induced tactile allodynia in a dose-dependent manner but did not affect motor activity, anxiety or responses to noxious thermal stimulus. These data suggest that targeting TLR TIR domains may provide novel pharmacological targets to reduce or reverse TLR4-dependent pain behavior in the rodent.

Original languageEnglish (US)
Article number3741
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Interleukin-1 Receptors
Toll-Like Receptors
Sensory Receptor Cells
Peptides
Calcium
Trans-Activators
Hyperalgesia
Neuralgia
Rodentia
Proteins
Motor Activity
Anxiety
Hot Temperature
morphine-3-glucuronide
HIV
Pharmacology
Ligands
Neurons
Pain
Genes

ASJC Scopus subject areas

  • General

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Decoy peptide targeted to Toll-IL-1R domain inhibits LPS and TLR4-active metabolite morphine-3 glucuronide sensitization of sensory neurons. / Allette, Yohance M.; Kim, Youngsook; Randolph, Aaron L.; Smith, Jared A.; Ripsch, Matthew S.; White, Fletcher.

In: Scientific Reports, Vol. 7, No. 1, 3741, 01.12.2017.

Research output: Contribution to journalArticle

Allette, Yohance M. ; Kim, Youngsook ; Randolph, Aaron L. ; Smith, Jared A. ; Ripsch, Matthew S. ; White, Fletcher. / Decoy peptide targeted to Toll-IL-1R domain inhibits LPS and TLR4-active metabolite morphine-3 glucuronide sensitization of sensory neurons. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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