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Targeting toll-like receptor-4 (TLR4)—an emerging therapeutic target for persistent pain states

Bruno, Kellya,b,c; Woller, Sarah A.a; Miller, Yury I.d; Yaksh, Tony L.a,e; Wallace, Marka,e; Beaton, Grahame; Chakravarthy, Krishnana,b,e,*

doi: 10.1097/j.pain.0000000000001306
Comprehensive Review
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Global Year 2018

Toll-like receptors (TLRs) are a family of pattern recognition receptors that initiate signaling in innate and adaptive immune pathways. The highly conserved family of transmembrane proteins comprises an extracellular domain that recognizes exogenous and endogenous danger molecules and an ectodomain that activates downstream pathways in response. Recent studies suggest that continuous activation or dysregulation of TLR signaling may contribute to chronic disease states. The receptor is located not only on inflammatory cells (meningeal and peripheral macrophages) but on neuraxial glia (microglia and astrocytes), Schwann cells, fibroblasts, dorsal root ganglia, and dorsal horn neurons. Procedures blocking TLR functionality have shown pronounced effects on pain behavior otherwise observed in models of chronic inflammation and nerve injury. This review addresses the role of TLR4 as an emerging therapeutic target for the evolution of persistent pain and its role in noncanonical signaling, mediating anomalous pro-algesic actions of opiates. Accordingly, molecules targeting inhibition of this receptor have promise as disease-modifying and opioid-sparing alternatives for persistent pain states.

aDepartment of Anesthesiology and Pain Medicine, University of California San Diego Health Sciences, La Jolla, CA, United States

bVA San Diego Healthcare System, San Diego, CA, United States

cCenter for Excellence in Stress and Mental Health, VA San Diego Healthcare System, San Diego, CA, United States

dDepartment of Medicine, University of California San Diego Health Science, La Jolla, CA, United States

eDouleur Therapeutics, San Diego, CA, United States

Corresponding author. Address: Department of Anesthesiology, University of California San Diego Health Sciences, 3350 La Jolla Village Dr, San Diego, CA 92161, United States. Tel.: 716-908-2392; fax: (858) 657-6035. E-mail address: kvchakravarthy@ucsd.edu (K. Chakravarthy).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received March 13, 2018

Received in revised form May 17, 2018

Accepted May 29, 2018

© 2018 International Association for the Study of Pain
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