Glial TLR4 receptor as new target to treat neuropathic pain: Efficacy of a new receptor antagonist in a model of peripheral nerve injury in mice

Abstract

Neuropathic pain remains a prevalent clinical problem because it is often poorly responsive to the currently used analgesics, thus it is crucial the identification of new potential targets and drugs. Recent evidence indicated that microglial cells in the spinal cord are critically involved in the development and maintenance of neuropathic pain, with a pivotal role of toll-like receptor 4 (TLR4). Binding of an endogenous ligand to TLR4 might be considered an important step in the regulation of microglia activity in pain facilitation, suggesting that a mechanism aimed to inhibit such a binding could be effective against neuropathic pain. We have synthesized new ligands to TLR4 with antagonistic activity. In the present work we evaluated the efficacy of the most potent TLR4 antagonist synthesized by us (FP-1), administered in mice with painful neuropathy. The repeated treatment of neuropathic mice with FP-1 (5-10 mg/kg, i.p.) evoked a relief of both thermal hyperalgesia and mechanical allodynia, whereas the administration of the highest dose to TLR4 knockout neuropathic mice revealed that in the absence of TLR4 receptor, the compound lost its efficacy. As consequence of TLR4 binding, the repeated treatment with FP-1 prevented the activation of the transcription factor NF-kB and the TNFalpha overproduction in the spinal cord. Together, our findings support the previous evidence indicative for a contribution of glial TLR4 to the initiation of neuropathic pain, suggest it as potential innovative target to treat this debilitating disease, and propose FP-1 as lead compound for the development of new effective drugs.

Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon

“…In the CNS, TLR4 is expressed primarily by microglia 102 and is solely responsible for the biological activities of the endotoxin lipopolysaccharide (LPS) 103 . TLR4 is thought to have a broad role in pain as TLR4 loss-of-function mutant mice have reduced allodynia and/or hyperalgesia following transection of the L5 spinal nerve 104 or chronic constriction injury of the sciatic nerve 105 . However, in C3H/HeJ mice with a dominant-negative mutation of the Tlr4 gene (rendering TLR4 dysfunctional in this strain), only the males displayed reduced allodynia after nerve injury (as was previously reported in REF.…”

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

“…1 for summary). Furthermore, TLR4 blockade not only prevents the initial development of neuropathic pain (Tanga et al, 2005) but also reverses established neuropathic pain (Bettoni et al, 2008;Hutchinson et al, 2008c;Cao et al, 2009;Lan et al, 2010;Liu et al, 2010a;Saito et al, 2010;Wu et al, 2010). The nociceptive consequences of TLR4-induced central immune signaling are due, at least in part, to p38-dependent activation of reactive glial phenotypes (Liu et al, 2010a) and up-regulation of prosta-NEUROIMMUNOPHARMACOLOGIC IMPLICATIONS FOR OPIOID ANALGESIA glandin E2 and TNF-␣ (Saito et al, 2010).…”

Regulator of G Protein Signaling 10 (Rgs10) Expression Is Transcriptionally Silenced in Activated Microglia by Histone Deacetylase Activity

“…Microglial activation and, specifically, endogenous activation of microglial TLR4 receptors are directly implicated in the development of pain sensitization in the mouse pSNL model of neuropathic pain (Raghavendra et al, 2003;Bettoni et al, 2008). This suggests that the TLR4-mediated suppression of RGS10 we have observed in vitro may occur endogenously in the spinal cord following pSNL injury.…”

“…The pSNL model of injury-induced neuropathic pain results in robust microglial activation and spinal sensitization. During nerve injury-induced sensitization, endogenous mediators activate microglial TLR4 receptors, which trigger production of proinflammatory cytokines (Tanga et al, 2005;Bettoni et al, 2008;Wu et al, 2010). Blocking either microglial activation or endogenous TLR4 receptors has been shown to attenuate neuropathic pain (Raghavendra et al, 2003;Saito et al, 2010;Sorge et al, 2011;Yoon et al, 2012).…”