Differences in cisplatin‐induced mechanical allodynia in male and female mice

Chemotherapeutics have been reported to produce, equally in males and females, a peripheral polyneuropathy that can persist for months to years beyond cessation of treatment [Dougherty et al., 2007; Tofthagen et al., 2010; Mols et al., 2014] and has been reported to occur in 35–100% of people receiving treatment [Han and Smith, 2013]. Unfortunately, the severe pain associated with the polyneuropathy not only decreases quality of life, but also affects patient compliance and can limit clinical use. Understanding the mechanisms underlying the development of this pain state is important to further efforts to develop targets for therapeutic intervention. While the mechanisms underlying the polyneuropathy are complex, it is appreciated that the engagement of Toll-like receptors (TLRs) may facilitate pain development by inducing pro-inflammatory cytokine expression [Li et al., 2014; Liu et al., 2014; Park et al., 2014]. This induction occurs via different signaling cascades (Figure 1A). Activation of the Myeloid differentiation primary response gene 88 (MyD88) pathway leads to the activation of NFκB and the production of pro-inflammatory cytokines. Alternatively, activation of the TIR-domain-containing adaptor-inducing interferon-β (TRIF) adaptor protein results in production of type 1 interferon (IFN) and a delayed production of pro-inflammatory cytokines [O’Neill and Bowie, 2007]. All TLR activation leads to signaling through one of these two pathways and may play a role in cisplatin-induced pain. Figure 1 (a) Toll-like receptors (TLRs) signal through a MyD88-dependent and independent (TRIF) pathway. The MyD88-dependent pathway leads to the activation of NFκB and the induction of pro-inflammatory cytokines, such as TNF and IL-1β. (b) In ... A study by Park et al. showed that male mice deficient in both MyD88 and TRIF signaling do not develop tactile allodynia following cisplatin treatment [Park et al., 2014]. In addition, the group examined Myd88−/− and Triflps2 mice, revealing distinct roles of each pathway. For example, Triflps2 mice showed a delayed, but persistent tactile allodynia. In contrast, Myd8−/− mice showed a less severe allodynia. Furthermore, Li et al. [2014] found that paclitaxel-induced allodynia in rats was prevented by intrathecal administration of the TLR4 antagonist LPS-RS, and was transiently reversed by both LPS-RS and, to a lesser extent, by MIP, a MyD88 antagonist. Together, these results demonstrate a complex role of TLR signaling pathways in chemotherapeutic-induced polyneuropathy. It is well recognized that many chronic pain conditions affect females at a higher rate than males [Mogil, 2012], yet many experimental protocols only examine male mice. In addition, cisplatin is used for the treatment of a variety of female-specific cancers and females equally experience chemotherapeutic-induced polyneuropathies. This is important to note because recent work has made the case that spinal TLR4 signaling mediates pain associated with mononeuropathy in male, but not female, mice [Sorge et al., 2011]. Examining whether innate immune signaling plays an equal role in both sexes may point to important mechanistic differences underlying the development of persistent pain following administration of chemotherapeutic agents, and, potentially, the necessity to develop different therapeutic interventions for each sex. Accordingly, the current study examined the development of cisplatin-induced polyneuropathy in male and female wild type mice, and whether innate immune signaling is necessary for the induction and maintenance of pain in this model.