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. Author manuscript; available in PMC: 2014 May 1.
Published in final edited form as: Pain. 2013 Jan 30;154(5):733–742. doi: 10.1016/j.pain.2013.01.012

Figure 9. Schematic of the TLR cascades emphasized in the present work.

Figure 9

Endogenous ligands present in the injured and inflamed system activate resident TLRs, localized to glia and/or neurons. Based on the effects of IT TLR ligands, it is hypothesized that TLRs signaling through TIRAP and MyD88 lead to NFκB mediated cytokine (TNF) release and to a TNF dependent allodynia (e.g. TLR2 and TLR4). However, TLR3 leads to a TNF independent allodynia and IFNβ production. Based on the effects of Ifnar−/− mice, the increased IFNβ production regulates the allodynic actions mediated by TIRAP (TLR2/TLR4 activation) and induced by IT TLR3-L. As TLR4 activated both TRIF and TIRAP signaling, the net allodynic effect reflects the facilitation mediated by spinal TNF release and the inhibition initiated by TRIF mediated IFNβ production.