Intrathecal siRNA against Toll-like receptor 4 reduces nociception in a rat model of neuropathic pain

Abstract

Background: Neuropathic pain is characterized by hyperalgesia, allodynia and spontaneous pain. It often occurs as a result of injury to peripheral nerves, dorsal root ganglions (DRG), spinal cord, or brain. Recent studies have suggested that Toll-like receptor 4 (TLR4) might play a role in neuropathic pain. Methodology/Principal Findings: In this study, we investigated the role of TLR4 in a rat chronic constriction injury (CCI) model and explored the feasibility of treating neuropathic pain by inhibiting TLR4. Our results demonstrated that intrathecal siRNA-mediated suppression of TLR4 attenuated CCI-induced mechanical allodynia and thermal hyperalgesia through inhibiting the activation of NF-κB p65 and production of proinflammatory cytokines (e.g., TNF-α and IL-1β). Conclusions/Significance: These findings suggest that suppression of TLR4 mediated by intrathecally administered siRNA may be a new strategy for the treatment of neuropathic pain.

Toll-like receptors in chronic pain

“…This work has been further replicated by laboratories world wide, demonstrating the key role of TLR4 in several preclinical models of neuropathic pain (Lan et al, 2010; Wu et al, 2010). Lan et al (2010) showed that TLR4 small interfering RNA (siRNA) administered intrathecally in rats prior to the development of allodynia induced with a bone cancer pain model displayed significantly attenuated behavioral hypersensitivity and decreased expression of spinal microglial markers and proinflammatory cytokines.…”

The essential roles of Toll-like receptor signaling pathways in sterile inflammatory diseases

“…Moreover, TLR signaling was also involved in neuroinflammation [158], since suppression of TLR4 by intrathecally administered siRNA could reduce neuropathic pain [159], while activation of TLR9 by intracerebroventricular administration of CpG might be an effective therapeutic strategy for Alzheimer's disease [160].…”

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).…”