Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice

Background: spinal toll-like receptors (tlrs) and signaling intermediaries have been implicated in persistent pain states. we examined the roles of two major tlr signaling pathways and selected tlrs in a mononeuropathic allodynia. methods: l5 spinal nerve ligation (snl) was performed in wild type (wt,c57bl/6) male and female mice and in male tlr2-/-tlr3-/-,tlr4-/-,tlr5-/-,myd88-/-,triflps2,myd88/triflps2,tnf-/-,and ifnar1-/- mice. we also examined l5 ligation in tlr4-/- female mice. we examined tactile allodynia using von frey hairs. iba-1 (microglia) and gfap (astrocytes) were assessed in spinal cords by immunostaining. tactile thresholds were analyzed by 1- and 2-way anova and the bonferroni post hoc test was used. results: in wt male and female mice,snl lesions resulted in a persistent and robust ipsilateral,tactile allodynia. in males with tlr2,3,4,or 5 deficiencies,tactile allodynia was significantly,but incompletely,reversed (approximately 50%) as compared to wt. this effect was not seen in female tlr4-/- mice. increases in ipsilateral lumbar iba-1 and gfap were seen in mutant and wt mice. mice deficient in myd88,or myd88 and trif,showed an approximately 50% reduction in withdrawal thresholds and reduced ipsilateral iba-1. in contrast,trif and interferon receptor null mice developed a profound ipsilateral and contralateral tactile allodynia. in lumbar sections of the spinal cords,we observed a greater increase in iba-1 immunoreactivity in the trif-signaling deficient mice as compared to wt,but no significant increase in gfap. removing myd88 abrogated the contralateral allodynia in the trif signaling-deficient mice. conversely,ifnβ,released downstream to trif signaling,administered intrathecally,temporarily reversed the tactile allodynia. conclusions: these observations suggest a critical role for the myd88 pathway in initiating neuropathic pain,but a distinct role for the trif pathway and interferon in regulating neuropathic pain phenotypes in male mice. © 2013 stokes et al.; licensee biomed central ltd.