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Systemic TAK-242 prevents intrathecal LPS evoked hyperalgesia in male, but not female mice and prevents delayed allodynia following intraplantar formalin in both male and female mice: The role of TLR4 in the evolution of a persistent pain state.

  • Sa, Woller
  • Sb, Ravula
  • Fc, Tucci
  • G, Beaton
  • M, Corr
  • Rr, Isseroff
  • Athena Soulika
  • M, Chigbrow
  • Ka, Eddinger
  • Tl, Yaksh
Published Article
Brain Behavior and Immunity
Publication Date
Aug 17, 2016
DOI: 10.1016/j.bbi.2016.03.026
PMID: 27044335
PMCID: PMC4917460
Soulika Lab - UC Davis dermatology-ucdavis


Objective: Pain resulting from local tissue injury or inflammation typically resolves with time. Frequently, however, this pain may unexpectedly persist, becoming a pathological chronic state. Increasingly, the innate and adaptive immune systems are being implicated in the initiation and maintenance of these persistent conditions. In particular, Toll-like receptor 4 (TLR4) signaling has been shown to mediate the transition to a persistent pain state in a sex-dependent manner. In the present work, we explored this contribution using the TLR4 antagonist, TAK-242. Methods: Male and female C57Bl/6 mice were given intravenous (IV), intrathecal (IT), or intraperitoneal (IP) TAK-242 prior to IT delivery of lipopolysaccharide (LPS), and tactile reactivity was assessed at regular intervals over 72-h. Additional groups of mice were treated with IP TAK-242 prior to intraplantar formalin, and flinching was monitored for 1-h. Tactile reactivity was assessed at 7-days after formalin delivery. Results: LPS evoked TNF release from male and female macrophages and RAW267.4 cells, which was blocked in a concentration dependent fashion by TAK-242. In vivo, IT LPS evoked tactile allodynia to a greater degree in male than female mice. TAK-242, given by all routes, prevented development of IT LPS-induced tactile allodynia in male animals, but did not reverse their established allodynia. TLR4 deficiency and TAK-242 treatment attenuated IT LPS-induced allodynia in male, but not female mice. In the formalin model, pre-treatment with TAK-242 did not affect Phase 1 or Phase 2 flinching, but prevented the delayed tactile allodynia in both male and unexpectedly in female mice (Phase 3). Conclusions: Together, these results suggest that TAK-242 is a TLR4 antagonist that has efficacy after systemic and intrathecal delivery and confirms the role of endogenous TLR4 signaling in triggering the development of a delayed allodynia in both male and female mice.

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