In the context of neuropathic pain (NP), toll-like receptor member 4 (TLR4) is known to be expressed exclusively on spinal microglia and significantly up-regulated upon peripheral nerve injury. TLR4-knockout mice display reduced effects of chronic chonstriction injury (CCI) induced nerve damage. Similary, TLR4 loss-of-function mutant mice as well as TLR4 antisense oligonucleotide-treated rats both display attenuated neuropathic pain symptoms after nerve damage. Further, intrathecal administration of a TLR4 antagonist after CCI treatment results in relief of neuropathic pain symptoms. Many exogenous and endogenous ligands are known to stimulate TLR4-mediated signaling. However, both in vitro and in vivo studies involving spinal nerve ligation (SNL) treated animals implicate Fibronectin in neuropathic pain-related TLR4 signaling. Fibronectin is an extracellular matrix protein that is commonly produced in response to tissue injury. When administered intrathecally to intact rats, Fibronectin induces microglial up-regulation of the purigenic receptor, P2X4, and symptoms of neuropathic pain. This stimulation of P2X4 expression can be suppressed by interuption of Fibronectin binding the TLR4 receptor after SNL injury in rats.
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