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.

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.

• Authors: Sarah A Woller, Satheesh B Ravula, Fabio C Tucci, Graham Beaton, Maripat Corr, R Rivkah Isseroff, Athena M Soulika, Marianne Chigbrow, Kelly A Eddinger, Tony L Yaksh
• Journal: Brain, behavior, and immunity (Brain Behav Immun) Vol. 56 Pg. 271-80 (08 2016) ISSN: 1090-2139 [Electronic] Netherlands
• PMID: 27044335 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Disinfectants
• Lipopolysaccharides
• Sulfonamides
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
• Formaldehyde

Topics

• Animals
• Behavior, Animal
• Chronic Pain (chemically induced, prevention & control)
• Disease Models, Animal
• Disinfectants (administration & dosage, pharmacology)
• Female
• Formaldehyde (administration & dosage, pharmacology)
• Hyperalgesia (chemically induced, prevention & control)
• Lipopolysaccharides (administration & dosage, pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• RAW 264.7 Cells
• Sex Factors
• Signal Transduction (drug effects, physiology)
• Sulfonamides (administration & dosage, pharmacology)
• Toll-Like Receptor 4 (antagonists & inhibitors, deficiency)
• Tumor Necrosis Factor-alpha (drug effects)