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

Sarah A. Woller, Satheesh B. Ravula, Fabio C. Tucci, Graham Beaton, Maripat Corr, Roslyn Rivkah Isseroff, Athena Soulika, Marianne Chigbrow, Kelly A. Eddinger, Tony L. Yaksh

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)271-280
Number of pages10
JournalBrain, Behavior, and Immunity
Volume56
DOIs
StatePublished - Aug 1 2016

Fingerprint

Toll-Like Receptor 4
Hyperalgesia
Formaldehyde
Lipopolysaccharides
Pain
Touch
ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
Immune System
Macrophages
Maintenance
Inflammation
Wounds and Injuries
Therapeutics

Keywords

  • Formalin
  • LPS
  • Mouse
  • Tactile allodynia
  • TAK-242
  • TLR4
  • TNF

ASJC Scopus subject areas

  • Immunology
  • Behavioral Neuroscience
  • Endocrine and Autonomic Systems

Cite this

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. / Woller, Sarah A.; Ravula, Satheesh B.; Tucci, Fabio C.; Beaton, Graham; Corr, Maripat; Isseroff, Roslyn Rivkah; Soulika, Athena; Chigbrow, Marianne; Eddinger, Kelly A.; Yaksh, Tony L.

In: Brain, Behavior, and Immunity, Vol. 56, 01.08.2016, p. 271-280.

Research output: Contribution to journalArticle

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abstract = "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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AU - Woller, Sarah A.

AU - Ravula, Satheesh B.

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AU - Beaton, Graham

AU - Corr, Maripat

AU - Isseroff, Roslyn Rivkah

AU - Soulika, Athena

AU - Chigbrow, Marianne

AU - Eddinger, Kelly A.

AU - Yaksh, Tony L.

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