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

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 (TLRs). 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 ^-/-, Trif ^lps2 and Myd88/Trif ^lps2 mice. We examined allodynia and body weight at intervals over 30 days, when we measured DRG ATF3 by immunostaining. Results: (1) WT cisplatin-treated mice showed tactile allodynia from day 3 through day 30. (2) The Myd88/Trif ^lps2 mice did not show allodynia. (3) In Tlr3 ^-/-, Tlr4 ^-/-, and Myd88 ^-/- mice, withdrawal thresholds were elevated toward normal versus WT cisplatin-treated mice, but remained decreased as compared to vehicle mice. (4) In Trif ^lps2 mice, cisplatin allodynia showed a delayed onset, but persisted. (5) In Tlr3 ^-/-, Tlr4 ^-/-, Myd88 ^-/-, and Myd88/Trif ^lps2 mice, the increase in DRG ATF3 was abolished. (6) 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.