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

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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 (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.

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Acknowledgments

This work was supported by Grants from National Institutes of Health: NS16541 and DA02110.

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Authors and Affiliations

  1. Department of Anesthesiology and Pain Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea

    Hue Jung Park

  2. Department of Anesthesiology, Anesthesia Research Lab 0818, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA, 92093-0818, USA

    Jennifer A. Stokes & Tony L. Yaksh

  3. Division of Rheumatology, Allergy, and Immunology, University of California, San Diego, La Jolla, CA, USA

    Maripat Corr

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  1. Hue Jung Park
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Correspondence to Tony L. Yaksh.

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Park, H.J., Stokes, J.A., Corr, M. et al. Toll-like receptor signaling regulates cisplatin-induced mechanical allodynia in mice. Cancer Chemother Pharmacol 73, 25–34 (2014). https://doi.org/10.1007/s00280-013-2304-9

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  • DOI: https://doi.org/10.1007/s00280-013-2304-9

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