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Published on: March 16, 2018
Toll-like receptor signaling regulates cisplatin-induced mechanical allodynia in mice
Hue Jung Park1, Jennifer A Stokes, Maripat Corr
1Department of Anesthesiology and Pain Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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.
Insights
Toll-like receptor (TLR) signaling is implicated in cisplatin-induced tactile allodynia, a persistent pain state. Blocking TLR signaling in mice significantly reduced pain behaviors and dorsal root ganglia ATF3 expression, suggesting TLRs contribute to chemotherapy-induced pain.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Cisplatin chemotherapy can induce neuropathic pain, characterized by tactile allodynia.
- Activation transcription factor 3 (ATF3) in dorsal root ganglia (DRG) is upregulated in cisplatin-induced allodynia.
- Toll-like receptors (TLRs) are known to activate ATF3.
Purpose of the Study:
- To investigate the role of the Toll-like receptor (TLR) signaling pathway in cisplatin-induced tactile allodynia.
- To examine the impact of TLR signaling on body weight changes and DRG ATF3 expression in cisplatin-treated mice.
Main Methods:
- Cisplatin or vehicle was administered to wild-type (WT) and various TLR-deficient mice (Tlr3-/-, Tlr4-/-, Myd88-/-, Trif (lps2), and Myd88/Trif (lps2)).
- Tactile allodynia and body weight were monitored over 30 days.
- DRG ATF3 expression was measured by immunostaining.
Main Results:
- WT mice developed persistent tactile allodynia and increased DRG ATF3 expression after cisplatin treatment.
- Mice deficient in both Myd88 and Trif (Myd88/Trif (lps2)) showed no allodynia.
- TLR signaling deficiencies (Tlr3-/-, Tlr4-/-, Myd88-/-) partially reduced allodynia and abolished DRG ATF3 upregulation.
- Weight loss was exacerbated in cisplatin-treated mutant mice compared to WT mice.
Conclusions:
- Cisplatin induces persistent allodynia and DRG ATF3 expression in WT mice.
- TLR signaling plays a significant role in mediating cisplatin-induced neuropathic pain.
- Targeting TLR signaling pathways may offer a therapeutic strategy for chemotherapy-induced polyneuropathy.
