Sarah A Woller1, Satheesh B Ravula2, Fabio C Tucci3, Graham Beaton4, Maripat Corr5, R Rivkah Isseroff6, Athena M Soulika7, Marianne Chigbrow8, Kelly A Eddinger9, Tony L Yaksh10. 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.
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. TLR4deficiency 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: Jennifer A Stokes; Jonathan Cheung; Kelly Eddinger; Maripat Corr; Tony L Yaksh Journal: J Neuroinflammation Date: 2013-12-09 Impact factor: 8.322
Authors: Sarah A Woller; Soo-Ho Choi; Eun Jung An; Hann Low; Dina A Schneider; Roshni Ramachandran; Jungsu Kim; Yun Soo Bae; Dmitri Sviridov; Maripat Corr; Tony L Yaksh; Yury I Miller Journal: Cell Rep Date: 2018-05-29 Impact factor: 9.423
Authors: Sarah A Woller; Cody Ocheltree; Stephanie Y Wong; Anthony Bui; Yuya Fujita; Gilson Gonçalves Dos Santos; Tony L Yaksh; Maripat Corr Journal: Brain Behav Immun Date: 2018-11-19 Impact factor: 7.217
Authors: Xiangrong Cui; Xuan Jing; Susan K Lutgendorf; Catherine S Bradley; Andrew Schrepf; Bradley A Erickson; Vincent A Magnotta; Timothy J Ness; Karl J Kreder; Michael A O'Donnell; Yi Luo Journal: Am J Physiol Renal Physiol Date: 2019-05-15