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Brain Behav Immun. 2016 Aug;56:271-80. doi: 10.1016/j.bbi.2016.03.026. Epub 2016 Apr 1.

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.

Author information

1
Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA; Department of Medicine, Division of Rheumatology, Allergy, and Immunology, University of California San Diego, La Jolla, CA, USA. Electronic address: swoller@ucsd.edu.
2
Epigen Biosciences Inc., 10225 Barnes Canyon Road, Suite A104, San Diego, CA 92121, USA. Electronic address: sravula@epigenbiosciences.com.
3
Epigen Biosciences Inc., 10225 Barnes Canyon Road, Suite A104, San Diego, CA 92121, USA. Electronic address: ftucci@epigenbiosciences.com.
4
Epigen Biosciences Inc., 10225 Barnes Canyon Road, Suite A104, San Diego, CA 92121, USA. Electronic address: gbeaton@epigenbiosciences.com.
5
Department of Medicine, Division of Rheumatology, Allergy, and Immunology, University of California San Diego, La Jolla, CA, USA. Electronic address: mpcorr@ucsd.edu.
6
Department of Dermatology, School of Medicine, University of California, Davis, CA, USA. Electronic address: rrisseroff@ucdavis.edu.
7
Department of Dermatology, School of Medicine, University of California, Davis, CA, USA; Shriners Hospital for Children, Northern California, Sacramento, CA, USA. Electronic address: asoulika@ucdavis.edu.
8
Department of Dermatology, School of Medicine, University of California, Davis, CA, USA. Electronic address: mchigbrow@ucdavis.edu.
9
Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA. Electronic address: keddinger@ucsd.edu.
10
Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA. Electronic address: tyaksh@ucsd.edu.

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.

KEYWORDS:

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

PMID:
27044335
PMCID:
PMC4917460
DOI:
10.1016/j.bbi.2016.03.026
[Indexed for MEDLINE]
Free PMC Article

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