Toll-like receptors and their role in persistent pain

Abstract

One of the fundamental mechanisms whereby the innate immune system coordinates inflammatory signal transduction is through Toll-like receptors (TLRs), which function to protect and defend the host organism by initiating inflammatory signaling cascades in response to tissue damage or injury. TLRs are positioned at the neuroimmune interface, and accumulating evidence suggests that the inflammatory consequences of TLR activation on glia (including microglia and astrocytes), sensory neurons, and other cell types can influence nociceptive processing and lead to states of exaggerated and unresolved pain. In this review, we summarize our current understanding of how different TLRs and their accessory or adaptor molecules can contribute to the development and maintenance of persistent pain. The challenges and opportunities of targeting TLRs for new treatment strategies against chronic pain are discussed, including the therapeutic context of TLR-mediated signaling in opioid analgesia and chemotherapy-induced pain. Considering the prevalence of persistent pain and the insufficient efficacy and safety of current treatment options, a deeper understanding of Toll-like receptors holds the promise of novel therapies for managing pathological pain.

Analgesic Effect of Toll-like Receptor 4 Antagonistic Peptide 2 on Mechanical Allodynia Induced with Spinal Nerve Ligation in Rats

“…Interestingly, TLR4 can also sense endogenous cellular components derived from injured tissues in vivo. In mouse models of neuropathic pain induced by CCI and SNL [10,11], TLR4 expression in microglia was notably increased in the dorsal horn of the spinal cord, in response to substances released from nerve terminals of damaged sensory neurons [7,8]. In this study, TLR4 was also upregulated in the spinal dorsal horn of rats with SNL.…”

“…In the context of neuropathic pain, TLR4 is upregulated exclusively on the surface of microglia in the spinal cord in animal models of neuropathic pain [6]. Upon peripheral nerve injury, endogenous TLR4 ligands such as extracellular matrix components and HMGB1 released from injured neurons may excite spinal microglia via TLR4 to secrete inflammatory molecules further complicating the condition [7,8]. These ligands can also exacerbate pain because TLR4 expressed on the surface of sensory neurons (small diameter, C-fibers) was suggested to be involved in pain conduction [9].…”

Cytokines in Pain: Harnessing Endogenous Anti-Inflammatory Signaling for Improved Pain Management

“…A common and unfortunate clinical side effect of chronic opioid use is the development of a paradoxical increase in pain sensitivity, termed opioid-induced hyperalgesia (195)(196)(197)(198)(199)(200)(201). Studies demonstrate in both humans and animal models that a number of key factors affect the development of opioid-induced hyperalgesia including anatomical projections from supra-spinal regions onto spinal pain projection neurons (an axonal route where pain facilitation can occur), variants in the mu-opioid receptor, sex differences, prior experience with pain, and even local activation of microglia and astrocytes (201). Given this work's emphasis on glial and immune factors, a brief review of the literature that supports opioid-induced hyperalgesia resulting from the production of pro-inflammatory immune mediators (e.g., cytokines, chemokines, and NO) that produce hyperalgesia (202) is provided below.…”

Global transcriptome analysis of rat dorsal root ganglia to identify molecular pathways involved in incisional pain

“…Activation of TLRs in glia, sensory neurons, and other cell types has been shown to alter nociceptive processing leading to pain. 41 Though our findings pinpoint TLR9 activation in the DRG as a contributing factor in a model of post-operative pain, this signaling mechanism has been postulated in neuropathic and inflammatory pain models. 42 , 43 Thus, TLR9 activity is likely a common mechanism in DRG that modulates pain signaling in multiple pain models.…”