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Review
. 2018 Oct;159(10):1908-1915.
doi: 10.1097/j.pain.0000000000001306.

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

Kelly Bruno  1   2   3 , Sarah A Woller  1 , Yury I Miller  4 , Tony L Yaksh  1   5 , Mark Wallace  1   5 , Graham Beaton  5 , Krishnan Chakravarthy  1   2   5
Affiliations
Review

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

Kelly Bruno et al. Pain. 2018 Oct.

Abstract

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.

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Conflict of interest statement

Authorship Statement: The authors declare no conflict of interest with regards to this body of work.

Figures

Figure 1
Figure 1
TLR4 Activation Pathways.
See this image and copyright information in PMC

References

    1. Chaperonin 10 as a putative modulator of multiple Toll-like receptors for the treatment of inflammatory diseases. Expert Opinion on Therapeutic Patents. 2007;17:1299–1308.
    1. Abdollahi-Roodsaz S, Joosten LA, Roelofs MF, Radstake TR, Matera G, Popa C, van der Meer JW, Netea MG, van den Berg WB. Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum. 2007;56:2957–2967. - PubMed
    1. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature. 2007;406:782–787. - PubMed
    1. Andrade P, Hoogland G, Del Rosario JS, Steinbusch HW, Visser-Vandewalle V, Daemen MA. Tumor necrosis factor-alpha inhibitors alleviation of experimentally induced neuropathic pain is associated with modulation of TNF receptor expression. J Neurosci Res. 2014;92:1490–1498. - PubMed
    1. Bai L, Zhai C, Han K, Li Z, Qian J, Jing Y, Zhang W, Xu JT. Toll-like receptor 4-mediated nuclear factor-kappaB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats. Neurosci Bull. 2014;30:936–948. - PMC - PubMed