Toll-like receptor signaling regulates cisplatin-induced mechanical allodynia in mice

Abstract

Purpose Cisplatin treated mice develop a persistent pain state and a condition wherein otherwise innocuous tactile stimuli evoke pain behavior, e.g. tactile allodynia. The allodynia is associated with an up-regulation of Activation Transcription Factor 3 (ATF3) in the dorsal root ganglia (DRG), a factor, which is activated by Toll-like receptors (TLR). Accordingly, we sought to examine the role of the TLR signaling cascade on allodynia, weight and changes in DRG ATF3 in cisplatin-treated mice. Methods Cisplatin (2.3 mg/kg/day × 6 injections every other day) or vehicle was administered to male wild type (WT) C57BL/6, Tlr3−/−, Tlr4−/−, Myd88−/−, Triflps2 and Myd88/Triflps2 mice. We examined allodynia and body weight at intervals over 30 days, when we measured DRG ATF3 by immunostaining. Results i) WT cisplatin-treated mice showed tactile allodynia from day 3 through day 30. ii) The Myd88/Triflps2, mice did not show allodynia. iii) In Tlr3−/−, Tlr4−/−, and Myd88−/− mice, withdrawal thresholds were elevated towards normal versus WT cisplatin treated mice, but remained decreased as compared to vehicle mice. iv) In Triflps2 mice, cisplatin allodynia showed a delayed onset, but persisted. v) In Tlr3−/−, Tlr4−/−, Myd88−/−, and Myd88/Triflps2 mice, the increase in DRG ATF3 was abolished. vi) Weight loss occurred during cisplatin administration, which was exacerbated in mutant as compared to WT mice. Conclusions Cisplatin evoked a persistent allodynia and DRG ATF3 expression in WT mice, but these effects were reduced in mice with TLR signaling deficiency. TLR signaling may thus be involved in the mechanisms leading to the cisplatin-polyneuropathy.

Inhibition of Neuroinflammation by AIBP: Spinal Effects upon Facilitated Pain States

“…AIBP on the expression of several pain states known to be associated with neuraxial TLR4 signaling. Tlr4 gene knockout or mutant mice are fully protected from tactile allodynia in the models of facilitated pain tested below (Cao et al, 2009; Park et al, 2014; Saito et al, 2010; Sorge et al, 2011; Stokes et al, 2013a; Stokes et al, 2013b; Woller et al, 2015). Accordingly, we addressed the effects of i.t.…”

“…To address the functional impact of AIBP on TLR4 signaling, we took note of the evolving understanding of the role played by neuraxial TLR4 in regulating the development of facilitated pain states generated by tissue and nerve injury (Park et al, 2014; Saito et al, 2010; Sorge et al, 2011; Stokes et al, 2013b; Woller et al, 2015). TLR4 deficiency in mice prevents the tactile allodynia otherwise evolving over time after afferent activation, as observed with intraplantar formalin (Woller et al, 2016) or as seen with the chemotherapeutic agent cisplatin (Park et al, 2014; Woller et al, 2015).…”

“…TLR4 deficiency in mice prevents the tactile allodynia otherwise evolving over time after afferent activation, as observed with intraplantar formalin (Woller et al, 2016) or as seen with the chemotherapeutic agent cisplatin (Park et al, 2014; Woller et al, 2015). Tellingly, intrathecal (i.t.)…”

Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels

“…Hill et al (55) reported that just skin incision, without substantial nerve damage, causes an increase of ATF3, galanin, and other injury markers; ATF3 is found in 2.9% of DRG neurons after skin incision vs. 0.07% in controls. Up-regulation of such markers has been described in multiple conditions, including osteoarthritis, chemotherapy, and other noninvasive procedures, although osteoarthritis and chemotherapy are likely to damage nerves (56)(57)(58)(59)(60).…”

Chemotherapy-Induced Peripheral Neuropathy

“…Infiltration of macrophages in the DRG and antigen-presenting Langerhans cells in the skin has also been observed following the administration of paclitaxel. 115,260 Furthermore, modulation of known inflammatory signaling pathways, such as NFκB 141 and Toll-like receptor (TLR) signaling 261,262 attenuate the behavioral effects of chemotherapy administration in preclinical models. Indeed, paclitaxel administration to rats enhances the expression of the TLR4 in the DRG and spinal cord.…”