Top

Cancer Chemotherapy and Pharmacology

Published in:

01-01-2014 | Original Article

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

Authors: Hue Jung Park, Jennifer A. Stokes, Maripat Corr, Tony L. Yaksh

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2014

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.

Trigg ME, Higa GM (2010) Chemotherapy-induced nausea and vomiting: antiemetic trials that impacted clinical practice. J Oncol Pharm Pract 16(4):233–244. doi:10.1177/1078155209354655 PubMedCrossRef

Windebank AJ, Grisold W (2008) Chemotherapy-induced neuropathy. J Peripher Nerv Syst 13(1):27–46. doi:10.1111/j.1529-8027.2008.00156.x PubMedCrossRef

McKeage MJ (1995) Comparative adverse effect profiles of platinum drugs. Drug Saf 13(4):228–244PubMedCrossRef

Park SB, Krishnan AV, Lin CS, Goldstein D, Friedlander M, Kiernan MC (2008) Mechanisms underlying chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies. Curr Med Chem 15(29):3081–3094PubMedCrossRef

Park HJ, Stokes JA, Pirie E, Skahen J, Shtaerman Y, Yaksh TL (2013) Persistent hyperalgesia in the cisplatin-treated mouse as defined by threshold measures, the conditioned place preference paradigm, and changes in dorsal root ganglia activated transcription factor 3: the effects of gabapentin, ketorolac, and etanercept. Anesth Analg 116(1):224–231. doi:10.1213/ANE.0b013e31826e1007 PubMedCentralPubMedCrossRef

Peters CM, Jimenez-Andrade JM, Kuskowski MA, Ghilardi JR, Mantyh PW (2007) An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat. Brain Res 1168:46–59. doi:10.1016/j.brainres.2007.06.066 PubMedCentralPubMedCrossRef

Hai T, Wolford CC, Chang YS (2010) ATF3, a hub of the cellular adaptive-response network, in the pathogenesis of diseases: is modulation of inflammation a unifying component? Gene Expr 15(1):1–11PubMedCrossRef

Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34(5):637–650. doi:10.1016/j.immuni.2011.05.006 PubMedCrossRef

O’Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7(5):353–364. doi:10.1038/nri2079 PubMedCrossRef

10.

Boivin A, Pineau I, Barrette B, Filali M, Vallieres N, Rivest S, Lacroix S (2007) Toll-like receptor signaling is critical for Wallerian degeneration and functional recovery after peripheral nerve injury. J Neurosci 27(46):12565–12576. doi:10.1523/JNEUROSCI.3027-07.2007 PubMedCrossRef

11.

Lehnardt S (2010) Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 58(3):253–263. doi:10.1002/glia.20928 PubMed

12.

Liu T, Gao YJ, Ji RR (2012) Emerging role of Toll-like receptors in the control of pain and itch. Neurosci Bull 28(2):131–144. doi:10.1007/s12264-012-1219-5 PubMedCentralPubMedCrossRef

13.

Stokes JA, Corr M, Yaksh TL (2013) Spinal Toll-like receptor signaling and nociceptive processing: regulatory balance between TIRAP and TRIF cascades mediated by TNF and IFNbeta. Pain. doi:10.1016/j.pain.2013.01.012 PubMed

14.

Vera G, Chiarlone A, Martin MI, Abalo R (2006) Altered feeding behaviour induced by long-term cisplatin in rats. Auton Neurosci 126–127:81–92. doi:10.1016/j.autneu.2006.02.011 PubMedCrossRef

15.

Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63. doi:10.1016/0165-0270(94)90144-9 PubMedCrossRef

16.

Abalo R, Cabezos PA, Vera G, Lopez-Perez AE, Martin MI (2013) Cannabinoids may worsen gastric dysmotility induced by chronic cisplatin in the rat. Neurogastroenterol Motil 25 (5):373–382, e292. doi:10.1111/nmo.12073

17.

Jack CS, Arbour N, Manusow J, Montgrain V, Blain M, McCrea E, Shapiro A, Antel JP (2005) TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol 175(7):4320–4330. http://www.jimmunol.org/content/175/7/4320 PubMed

18.

Qi J, Buzas K, Fan H, Cohen JI, Wang K, Mont E, Klinman D, Oppenheim JJ, Howard OM (2011) Painful pathways induced by TLR stimulation of dorsal root ganglion neurons. J Immunol 186(11):6417–6426. doi:10.4049/jimmunol.1001241 PubMedCentralPubMedCrossRef

19.

Kuang X, Huang Y, Gu HF, Zu XY, Zou WY, Song ZB, Guo QL (2012) Effects of intrathecal epigallocatechin gallate, an inhibitor of Toll-like receptor 4, on chronic neuropathic pain in rats. Eur J Pharmacol 676(1–3):51–56. doi:10.1016/j.ejphar.2011.11.037 PubMedCrossRef

20.

Hai T, Hartman MG (2001) The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis. Gene 273(1):1–11. doi:10.1016/S0378-1119(01)00551-0 PubMedCrossRef

21.

Ivanavicius SP, Ball AD, Heapy CG, Westwood FR, Murray F, Read SJ (2007) Structural pathology in a rodent model of osteoarthritis is associated with neuropathic pain: increased expression of ATF-3 and pharmacological characterisation. Pain 128(3):272–282. doi:10.1016/j.pain.2006.12.022 PubMedCrossRef

22.

Jimenez-Andrade JM, Peters CM, Mejia NA, Ghilardi JR, Kuskowski MA, Mantyh PW (2006) Sensory neurons and their supporting cells located in the trigeminal, thoracic and lumbar ganglia differentially express markers of injury following intravenous administration of paclitaxel in the rat. Neurosci Lett 405(1–2):62–67. doi:10.1016/j.neulet.2006.06.043 PubMedCrossRef

23.

Khasabova IA, Khasabov S, Paz J, Harding-Rose C, Simone DA, Seybold VS (2012) Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy. J Neurosci 32(20):7091–7101. doi:10.1523/JNEUROSCI.0403-12.2012 PubMedCentralPubMedCrossRef

24.

Braz JM, Basbaum AI (2010) Differential ATF3 expression in dorsal root ganglion neurons reveals the profile of primary afferents engaged by diverse noxious chemical stimuli. Pain 150(2):290–301. doi:10.1016/j.pain.2010.05.005 PubMedCentralPubMedCrossRef

25.

Cao H, Zhang YQ (2008) Spinal glial activation contributes to pathological pain states. Neurosci Biobehav Rev 32(5):972–983. doi:10.1016/j.neubiorev.2008.03.009 PubMedCrossRef

26.

Sung YJ, Chiu DT, Ambron RT (2006) Activation and retrograde transport of protein kinase G in rat nociceptive neurons after nerve injury and inflammation. Neuroscience 141(2):697–709. doi:10.1016/j.neuroscience.2006.04.033 PubMedCrossRef

27.

Cavassani KA, Ishii M, Wen H, Schaller MA, Lincoln PM, Lukacs NW, Hogaboam CM, Kunkel SL (2008) TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J Exp Med 205(11):2609–2621. doi:10.1084/jem.20081370 PubMedCentralPubMedCrossRef

28.

Erridge C (2010) Endogenous ligands of TLR2 and TLR4: agonists or assistants? J Leukoc Biol 87(6):989–999. doi:10.1189/jlb.1209775 PubMedCrossRef

29.

Marsh BJ, Williams-Karnesky RL, Stenzel-Poore MP (2009) Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience 158(3):1007–1020. doi:10.1016/j.neuroscience.2008.07.067 PubMedCentralPubMedCrossRef

30.

Rivest S (2009) Regulation of innate immune responses in the brain. Nat Rev Immunol 9(6):429–439. doi:10.1038/nri2565 PubMedCrossRef

31.

Shichita T, Hasegawa E, Kimura A, Morita R, Sakaguchi R, Takada I, Sekiya T, Ooboshi H, Kitazono T, Yanagawa T, Ishii T, Takahashi H, Mori S, Nishibori M, Kuroda K, Akira S, Miyake K, Yoshimura A (2012) Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nat Med 18(6):911–917. doi:10.1038/nm.2749 PubMedCrossRef

32.

Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11(2):155–161. doi:10.1038/ni.1836 PubMedCentralPubMedCrossRef

33.

Yanai H, Ban T, Wang Z, Choi MK, Kawamura T, Negishi H, Nakasato M, Lu Y, Hangai S, Koshiba R, Savitsky D, Ronfani L, Akira S, Bianchi ME, Honda K, Tamura T, Kodama T, Taniguchi T (2009) HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature 462(7269):99–103. doi:10.1038/nature08512 PubMedCrossRef

34.

Zhang J, Takahashi HK, Liu K, Wake H, Liu R, Maruo T, Date I, Yoshino T, Ohtsuka A, Mori S, Nishibori M (2011) Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats. Stroke 42(5):1420–1428. doi:10.1161/STROKEAHA.110.598334 PubMedCrossRef

35.

Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464(7285):104–107. doi:10.1038/nature08780 PubMedCentralPubMedCrossRef

36.

Shibasaki M, Sasaki M, Miura M, Mizukoshi K, Ueno H, Hashimoto S, Tanaka Y, Amaya F (2010) Induction of high mobility group box-1 in dorsal root ganglion contributes to pain hypersensitivity after peripheral nerve injury. Pain 149(3):514–521. doi:10.1016/j.pain.2010.03.023 PubMedCrossRef

37.

Badary OA, Awad AS, Sherief MA, Hamada FM (2006) In vitro and in vivo effects of ferulic acid on gastrointestinal motility: inhibition of cisplatin-induced delay in gastric emptying in rats. World J Gastroenterol 12(33):5363–5367PubMed

38.

Isambert N, Fumoleau P, Paul C, Ferrand C, Zanetta S, Bauer J, Ragot K, Lizard G, Jeannin JF, Bardou M (2013) Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors. BMC Cancer 13:172. doi:10.1186/1471-2407-13-172 PubMedCentralPubMedCrossRef

39.

Sussman DA, Santaolalla R, Strobel S, Dheer R, Abreu MT (2012) Cancer in inflammatory bowel disease: lessons from animal models. Curr Opin Gastroenterol 28(4):327–333. doi:10.1097/MOG.0b013e328354cc36 PubMedCentralPubMedCrossRef

40.

Biron CA (2001) Interferons alpha and beta as immune regulators–a new look. Immunity 14(6):661–664. doi:10.1016/S1074-7613(01)00154-6 PubMedCrossRef

Title: Toll-like receptor signaling regulates cisplatin-induced mechanical allodynia in mice
Authors: Hue Jung Park
Jennifer A. Stokes
Maripat Corr
Tony L. Yaksh
Publication date: 01-01-2014
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2014
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-013-2304-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2014

Open-label, randomized, single-dose, crossover study to evaluate the pharmacokinetics and safety differences between two docetaxel products, CKD-810 and Taxotere injection, in patients with advanced solid cancer

Safety and pharmacology of gemcitabine and capecitabine in patients with advanced pancreatico-biliary cancer and hepatic dysfunction

Mechanisms of action of tasquinimod on the tumour microenvironment

Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients

A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC)

Longitudinal assessment of TUBB3 expression in non-small cell lung cancer patients

Keynote webinar | Spotlight on antibody–drug conjugates in cancer