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

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.

Macrophage Toll-like Receptor 9 Contributes to Chemotherapy-Induced Neuropathic Pain in Male Mice

“…The TLR family plays a critical role in innate immune responses by recognizing pathogen-associated molecular patterns and dangerassociated molecular patterns, signaling for the activation of host defense and inflammatory processes against infective pathogens and tissue injuries (Akira et al, 2006). Several TLRs, including TLR2 (Kim et al, 2007), TLR3 (Liu et al, 2012b), TLR4 (Tanga et al, 2005;Sorge et al, 2011;Li et al, 2014Li et al, , 2015a, TLR5 (Xu et al, 2015;Das et al, 2016), TLR7 (Park et al, 2014), and TLR8 (Zhang et al, 2018), as well as TLR signaling adaptor proteins, such as MyD88 (Stokes et al, 2013;Liu et al, 2014Liu et al, , 2016, have been implicated in pathological pain conditions via immune, glial, and neuronal regulatory mechanisms (for review, see Liu et al, 2012a;Nicotra et al, 2012;Bruno et al, 2018).…”

<p>Electroacupuncture Treatment Attenuates Paclitaxel-Induced Neuropathic Pain in Rats via Inhibiting Spinal Glia and the TLR4/NF-κB Pathway</p>

“…Both microglia and astrocytes express toll-like receptor 4 (TLR4) in the central nervous system. 19,20 TLR4 plays an essential role in the transition and induction of pain. It was reported that PTX treatment could result in increased expression of TLR4 and the activation of its downstream nuclear factor-κB (NF-κB) signaling pathway in the spinal cord, leading to the production of proinflammatory cytokines, 21,22 which, in turn, contributed to the occurrence and development of chemotherapy-induced neuropathic pain.…”

Evoked and spontaneous pain assessment during tooth pulp injury

“…We chose to assess the Toll-like Receptor 4 (Tlr4), transient receptor potential channels vanilloid 1 and ankyrin 1 (Trpv1 and Trpa1), and the mas-related G protein coupled receptor D (Mrgprd), because all are found in neurons that innervate the dental pulp 7,20,22,25-27 and could be involved in the development of either spontaneous or mechanical pain in the context of infection and injury. In particular, TLR4 is part of a larger class of receptors that recognize pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) 19 , and has known interactions with both TRPV1 and TRPA1 in the context of dental injury 20-23 . A direct role for Mrgprd in dental injury-related pain has not been established, but is possible given its expression in dental afferents 25 and its role in cutaneous mechanical pain perception 28 .…”

“…To begin to address this question, we examined the mRNA expression of Tlr4, trpv1, Trpa1, and Mrgprd using in situ hybridization at 24 hours following pulp exposure injury. A great deal of attention has been paid to TLR4 as a possible drug target for the treatment of inflammatory pain in various parts of the body 19 , but particularly in pulpitis given its role in recognizing molecular signals of bacterial presence and mechanical injury and upregulation in human pulpitis samples 20 . Furthermore, antagonism of TLR4 is associated with reversal of pain-associated behaviors in two different rat models of pulpitis 7,37 , including mechanical hypersensitivity in lightly anesthetized rats 37 .…”