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Treatment of Established Chemotherapy-Induced Peripheral Neuropathy: Basic Science and Animal Models

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Diagnosis, Management and Emerging Strategies for Chemotherapy-Induced Neuropathy

Abstract

Advancement of effective therapies to treat established CIPN will require a deeper understanding of CIPN pathomechanisms. Simplified models of CIPN have been developed using whole-animal systems, primary cultures, and immortalized cell lines to allow for detailed mechanistic studies. Recently, human stem-cell derived neuronal cultures have also allowed new opportunities to study CIPN. In this chapter, we provide an overview of studies that used model systems to investigate the treatment of established CIPN. We have divided the chapter into two main areas. First, there are studies that investigate CIPN-related nerve damage through the lens of neurogenesis, Schwann cells, and axonal regrowth. Next, we review model approaches to treat CIPN-related pain that have focused on voltage-gated ion channels, neuroinflammation, sphingosine metabolism, and endocannabinoids. The broad approaches that are being employed to study the treatment of established CIPN in model systems provide hope for future beneficial therapeutics.

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References

  1. Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, Chauhan C, Gavin P, Lavino A, Lustberg MB, Paice J, Schneider B, Smith ML, Smith T, Terstriep S, Wagner-Johnston N, Bak K, Loprinzi CL (2014) American Society of Clinical O. prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 32(18):1941–1967. Epub 2014/04/16. https://doi.org/10.1200/JCO.2013.54.0914

    Article  CAS  PubMed  Google Scholar 

  2. Currie GL, Angel-Scott HN, Colvin L, Cramond F, Hair K, Khandoker L, Liao J, Macleod M, McCann SK, Morland R, Sherratt N, Stewart R, Tanriver-Ayder E, Thomas J, Wang Q, Wodarski R, Xiong R, Rice ASC, Sena ES. Animal models of chemotherapy-induced peripheral neuropathy: A machine-assisted systematic review and meta-analysis. PLoS Biol. 2019;17(5):e3000243. https://doi.org/10.1371/journal.pbio.3000243. Epub 2019/05/21. PubMed PMID: 31107871; PMCID: PMC6544332

  3. Lu Y, Zhang P, Zhang Q, Yang C, Qian Y, Suo J, Tao X, Zhu J (2020) Duloxetine attenuates paclitaxel-induced peripheral nerve injury by inhibiting p53-related pathways. J Pharmacol Exp Ther 373(3):453–462. Epub 2020/04/03. https://doi.org/10.1124/jpet.120.265082

    Article  CAS  PubMed  Google Scholar 

  4. Mohiuddin MS, Himeno T, Inoue R, Miura-Yura E, Yamada Y, Nakai-Shimoda H, Asano S, Kato M, Motegi M, Kondo M, Seino Y, Tsunekawa S, Kato Y, Suzuki A, Naruse K, Kato K, Nakamura J, Kamiya H. Glucagon-like peptide-1 receptor agonist protects dorsal root ganglion neurons against oxidative insult. J Diabetes Res. 2019;2019:9426014. https://doi.org/10.1155/2019/9426014. Epub 2019/03/29. PubMed PMID: 30918901; PMCID: PMC6408997

  5. Klein R, Brown D, Turnley AM. Phenoxodiol protects against Cisplatin induced neurite toxicity in a PC-12 cell model. BMC Neurosci. 2007;8:61. https://doi.org/10.1186/1471-2202-8-61. Epub 2007/08/04. PubMed PMID: 17672914; PMCID: PMC1950519

  6. Chambers SM, Qi Y, Mica Y, Lee G, Zhang XJ, Niu L, Bilsland J, Cao L, Stevens E, Whiting P, Shi SH, Studer L. Combined small-molecule inhibition accelerates developmental timing and converts human pluripotent stem cells into nociceptors. Nat Biotechnol. 2012;30(7):715–20. https://doi.org/10.1038/nbt.2249. Epub 2012/07/04. PubMed PMID: 22750882; PMCID: 3516136

  7. Vojnits K, Mahammad S, Collins TJ, Bhatia M. Chemotherapy-induced neuropathy and drug discovery platform using human sensory neurons converted directly from adult peripheral blood. Stem Cells Transl Med. 2019;8(11):1180–91. https://doi.org/10.1002/sctm.19-0054. Epub 2019/07/28. PubMed PMID: 31347791; PMCID: PMC6811699

  8. Hooijmans CR, Draper D, Ergun M, Scheffer GJ. The effect of analgesics on stimulus evoked pain-like behaviour in animal models for chemotherapy induced peripheral neuropathy- a meta-analysis. Sci Rep. 2019;9(1):17549. https://doi.org/10.1038/s41598-019-54152-8. Epub 2019/11/28. PubMed PMID: 31772391; PMCID: PMC6879539

  9. Maruta T, Nemoto T, Hidaka K, Koshida T, Shirasaka T, Yanagita T, Takeya R, Tsuneyoshi I. Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain. PLoS One. 2019;14(11):e0225586. https://doi.org/10.1371/journal.pone.0225586. Epub 2019/11/26. PubMed PMID: 31765435; PMCID: PMC6876879

  10. Tsubota M, Fukuda R, Hayashi Y, Miyazaki T, Ueda S, Yamashita R, Koike N, Sekiguchi F, Wake H, Wakatsuki S, Ujiie Y, Araki T, Nishibori M, Kawabata A. Role of non-macrophage cell-derived HMGB1 in oxaliplatin- induced peripheral neuropathy and its prevention by the thrombin/thrombomodulin system in rodents: negative impact of anticoagulants. J Neuroinflammation. 2019;16(1):199. https://doi.org/10.1186/s12974-019-1581-6. Epub 2019/11/02. PubMed PMID: 31666085; PMCID: PMC6822350

  11. Janes K, Esposito E, Doyle T, Cuzzocrea S, Tosh DK, Jacobson KA, Salvemini D. A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways. Pain. 2014;155(12):2560–7. https://doi.org/10.1016/j.pain.2014.09.016. Epub 2014/09/23. PubMed PMID: 25242567; PMCID: PMC4529068

  12. Slivicki RA, Xu Z, Mali SS, Hohmann AG. Brain permeant and impermeant inhibitors of fatty-acid amide hydrolase suppress the development and maintenance of paclitaxel-induced neuropathic pain without producing tolerance or physical dependence in vivo and synergize with paclitaxel to reduce tumor cell line viability in vitro. Pharmacol Res. 2019;142:267–82. https://doi.org/10.1016/j.phrs.2019.02.002. Epub 2019/02/11. PubMed PMID: 30739035; PMCID: PMC6878658

  13. Alessandri-Haber N, Dina OA, Joseph EK, Reichling DB, Levine JD. Interaction of transient receptor potential vanilloid 4, integrin, and SRC tyrosine kinase in mechanical hyperalgesia. J Neurosci. 2008;28(5):1046–57. https://doi.org/10.1523/JNEUROSCI.4497-07.2008. Epub 2008/02/01. PubMed PMID: 18234883; PMCID: PMC6671413

  14. Lin H, Heo BH, Yoon MH. A new rat model of cisplatin-induced neuropathic pain. Korean J Pain. 2015;28(4):236–43. https://doi.org/10.3344/kjp.2015.28.4.236. Epub 2015/10/27. PubMed PMID: 26495078; PMCID: PMC4610937

  15. Zhang M, Du W, Acklin S, Jin S, Xia F. SIRT2 protects peripheral neurons from cisplatin-induced injury by enhancing nucleotide excision repair. J Clin Invest. 2020;130(6):2953–65. https://doi.org/10.1172/JCI123159. Epub 2020/03/07. PubMed PMID: 32134743; PMCID: PMC7260000

  16. Duggett NA, Flatters SJL. Characterization of a rat model of bortezomib-induced painful neuropathy. Br J Pharmacol. 2017;174(24):4812–25. https://doi.org/10.1111/bph.14063. Epub 2017/10/04. PubMed PMID: 28972650; PMCID: PMC5727311

  17. Boehmerle W, Huehnchen P, Peruzzaro S, Balkaya M, Endres M. Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice. Sci Rep. 2014;4:6370. https://doi.org/10.1038/srep06370. Epub 2014/09/19. PubMed PMID: 25231679; PMCID: PMC5377307

  18. Huehnchen P, Muenzfeld H, Boehmerle W, Endres M. Blockade of IL-6 signaling prevents paclitaxel-induced neuropathy in C57Bl/6 mice. Cell Death Dis. 2020;11(1):45. https://doi.org/10.1038/s41419-020-2239-0. Epub 2020/01/24. PubMed PMID: 31969555; PMCID: PMC6976596

  19. Miyano K, Shiraishi S, Minami K, Sudo Y, Suzuki M, Yokoyama T, Terawaki K, Nonaka M, Murata H, Higami Y, Uezono Y. Carboplatin enhances the activity of human transient receptor potential ankyrin 1 through the cyclic AMP-protein kinase A-A-Kinase Anchoring Protein (AKAP) pathways. Int J Mol Sci. 2019;20(13). https://doi.org/10.3390/ijms20133271. Epub 2019/07/07. PubMed PMID: 31277262; PMCID: PMC6651390

  20. Kawashiri T, Shimizu S, Shigematsu N, Kobayashi D, Shimazoe T (2019) Donepezil ameliorates oxaliplatin-induced peripheral neuropathy via a neuroprotective effect. J Pharmacol Sci 140(3):291–294. Epub 2019/08/05. https://doi.org/10.1016/j.jphs.2019.05.009

    Article  CAS  PubMed  Google Scholar 

  21. Fukuda M, Yamamoto A (2004) Effect of forskolin on synaptotagmin IV protein trafficking in PC12 cells. J Biochem 136(2):245–253. Epub 2004/10/22. https://doi.org/10.1093/jb/mvh116

    Article  CAS  PubMed  Google Scholar 

  22. Imai S, Koyanagi M, Azimi Z, Nakazato Y, Matsumoto M, Ogihara T, Yonezawa A, Omura T, Nakagawa S, Wakatsuki S, Araki T, Kaneko S, Nakagawa T, Matsubara K. Taxanes and platinum derivatives impair Schwann cells via distinct mechanisms. Sci Rep. 2017;7(1):5947. https://doi.org/10.1038/s41598-017-05784-1. Epub 2017/07/22. PubMed PMID: 28729624; PMCID: PMC5519765

  23. Blanchard JW, Eade KT, Szucs A, Lo Sardo V, Tsunemoto RK, Williams D, Sanna PP, Baldwin KK. Selective conversion of fibroblasts into peripheral sensory neurons. Nat Neurosci. 2015;18(1):25–35. https://doi.org/10.1038/nn.3887. Epub 2014/11/25. PubMed PMID: 25420069; PMCID: PMC4466122

  24. Hoelting L, Klima S, Karreman C, Grinberg M, Meisig J, Henry M, Rotshteyn T, Rahnenfuhrer J, Bluthgen N, Sachinidis A, Waldmann T, Leist M. Stem cell-derived immature human dorsal root ganglia neurons to identify peripheral neurotoxicants. Stem Cells Transl Med. 2016;5(4):476–87. https://doi.org/10.5966/sctm.2015-0108. Epub 2016/03/05. PubMed PMID: 26933043; PMCID: PMC4798731

  25. Rana P, Luerman G, Hess D, Rubitski E, Adkins K, Somps C (2017) Utilization of iPSC-derived human neurons for high-throughput drug- induced peripheral neuropathy screening. Toxicol In Vitro 45(Pt 1):111–118. Epub 2017/08/28. https://doi.org/10.1016/j.tiv.2017.08.014

    Article  CAS  PubMed  Google Scholar 

  26. Wheeler HE, Wing C, Delaney SM, Komatsu M, Dolan ME. Modeling chemotherapeutic neurotoxicity with human induced pluripotent stem cell-derived neuronal cells. PLoS One. 2015;10(2):e0118020. https://doi.org/10.1371/journal.pone.0118020. Epub 2015/02/18. PubMed PMID: 25689802; PMCID: PMC4331516

  27. Wing C, Komatsu M, Delaney SM, Krause M, Wheeler HE, Dolan ME. Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy. Stem Cell Res. 2017;22:79–88. https://doi.org/10.1016/j.scr.2017.06.006. Epub 2017/06/24. PubMed PMID: 28645005; PMCID: PMC5737666

  28. Starobova H, Vetter I. Pathophysiology of chemotherapy-induced peripheral neuropathy. Front Mol Neurosci. 2017;10:174. https://doi.org/10.3389/fnmol.2017.00174. Epub 2017/06/18. PubMed PMID: 28620280; PMCID: PMC5450696

  29. Hu LY, Mi WL, Wu GC, Wang YQ, Mao-Ying QL. Prevention and treatment for chemotherapy-induced peripheral neuropathy: therapies based on CIPN mechanisms. Curr Neuropharmacol. 2019;17(2):184–96. https://doi.org/10.2174/1570159X15666170915143217. Epub 2017/09/20. PubMed PMID: 28925884; PMCID: PMC6343206

  30. Wiszniak S, Schwarz Q. Notch signalling defines dorsal root ganglia neuroglial fate choice during early neural crest cell migration. BMC Neurosci. 2019;20(1):21. https://doi.org/10.1186/s12868-019-0501-0. Epub 2019/05/01. PubMed PMID: 31036074; PMCID: PMC6489353

  31. Czaja K, Fornaro M, Geuna S. Neurogenesis in the adult peripheral nervous system. Neural Regen Res. 2012;7(14):1047–54. https://doi.org/10.3969/j.issn.1673-5374.2012.14.002. Epub 2012/05/15. PubMed PMID: 25722694; PMCID: PMC4340017

  32. Muratori L, Ronchi G, Raimondo S, Geuna S, Giacobini-Robecchi MG, Fornaro M. Generation of new neurons in dorsal root Ganglia in adult rats after peripheral nerve crush injury. Neural Plast. 2015;2015:860546. https://doi.org/10.1155/2015/860546. Epub 2015/02/28. PubMed PMID: 25722894; PMCID: PMC4333329

  33. Chen L, Gong HY, Xu L. PVT1 protects diabetic peripheral neuropathy via PI3K/AKT pathway. Eur Rev Med Pharmacol Sci. 2018;22(20):6905–11. https://doi.org/10.26355/eurrev_201810_16160. Epub 2018/11/08

  34. Ceci ML, Mardones-Krsulovic C, Sanchez M, Valdivia LE, Allende ML. Axon-Schwann cell interactions during peripheral nerve regeneration in zebrafish larvae. Neural Dev. 2014;9:22. https://doi.org/10.1186/1749-8104-9-22. Epub 2014/10/19. PubMed PMID: 25326036; PMCID: PMC4214607

  35. Ducommun Priest M, Navarro MF, Bremer J, Granato M. Dynein promotes sustained axonal growth and Schwann cell remodeling early during peripheral nerve regeneration. PLoS Genet. 2019;15(2):e1007982. https://doi.org/10.1371/journal.pgen.1007982. Epub 2019/02/20. PubMed PMID: 30779743; PMCID: PMC6396928

  36. Hung HA, Sun G, Keles S, Svaren J. Dynamic regulation of Schwann cell enhancers after peripheral nerve injury. J Biol Chem. 2015;290(11):6937–50. https://doi.org/10.1074/jbc.M114.622878. Epub 2015/01/24. PubMed PMID: 25614629; PMCID: PMC4358118

  37. Wilcox MB, Laranjeira SG, Eriksson TM, Jessen KR, Mirsky R, Quick TJ, Phillips JB. Characterising cellular and molecular features of human peripheral nerve degeneration. Acta Neuropathol Commun. 2020;8(1):51. https://doi.org/10.1186/s40478-020-00921-w. Epub 2020/04/19. PubMed PMID: 32303273; PMCID: PMC7164159

  38. Mahar M, Cavalli V. Intrinsic mechanisms of neuronal axon regeneration. Nat Rev Neurosci. 2018;19(6):323–37. https://doi.org/10.1038/s41583-018-0001-8. Epub 2018/04/19. PubMed PMID: 29666508; PMCID: PMC5987780

  39. Fukuda Y, Li Y, Segal RA. A mechanistic understanding of axon degeneration in chemotherapy-induced peripheral neuropathy. Front Neurosci. 2017;11:481. https://doi.org/10.3389/fnins.2017.00481. Epub 2017/09/16. PubMed PMID: 28912674; PMCID: PMC5583221

  40. Hwang J, Namgung U. Cdk5 phosphorylation of STAT3 in dorsal root ganglion neurons is involved in promoting axonal regeneration after peripheral nerve injury. Int Neurourol J. 2020;24(Suppl 1):S19–27. https://doi.org/10.5213/inj.2040158.080. Epub 2020/06/03. PubMed PMID: 32482054; PMCID: PMC7285696

  41. Morales M, Avila J, Gonzalez-Fernandez R, Boronat L, Soriano ML, Martin-Vasallo P. Differential transcriptome profile of peripheral white cells to identify biomarkers involved in oxaliplatin induced neuropathy. J Pers Med. 2014;4(2):282–96. https://doi.org/10.3390/jpm4020282. Epub 2015/01/08. PubMed PMID: 25563226; PMCID: PMC4263976

  42. Flatters SJL, Dougherty PM, Colvin LA (2017) Clinical and preclinical perspectives on chemotherapy-induced peripheral neuropathy (CIPN): a narrative review. Br J Anaesth 119(4):737–749. Epub 2017/11/10. https://doi.org/10.1093/bja/aex229

    Article  CAS  PubMed  Google Scholar 

  43. Miyagi A, Kawashiri T, Shimizu S, Shigematsu N, Kobayashi D, Shimazoe T (2019) Dimethyl fumarate attenuates Oxaliplatin-induced peripheral neuropathy without affecting the anti-tumor activity of Oxaliplatin in rodents. Biol Pharm Bull 42(4):638–644. Epub 2019/04/02. https://doi.org/10.1248/bpb.b18-00855

    Article  CAS  PubMed  Google Scholar 

  44. Brandolini L, Castelli V, Aramini A, Giorgio C, Bianchini G, Russo R, De Caro C, d’Angelo M, Catanesi M, Benedetti E, Giordano A, Cimini A, Allegretti M. DF2726A, a new IL-8 signalling inhibitor, is able to counteract chemotherapy-induced neuropathic pain. Sci Rep. 2019;9(1):11729. https://doi.org/10.1038/s41598-019-48231-z. Epub 2019/08/15. PubMed PMID: 31409858; PMCID: PMC6692352

  45. Galley HF, McCormick B, Wilson KL, Lowes DA, Colvin L, Torsney C. Melatonin limits paclitaxel-induced mitochondrial dysfunction in vitro and protects against paclitaxel-induced neuropathic pain in the rat. J Pineal Res. 2017;63(4):e12444. https://doi.org/10.1111/jpi.12444. Epub 2017/08/24. PubMed PMID: 28833461; PMCID: PMC5656911

  46. Stage TB, Hu S, Sparreboom A, Kroetz DL (2020) Role of drug transporters in chemotherapy-induced peripheral neuropathy. Clin Transl Sci 3:1–8. https://doi.org/10.1111/cts.12915

    Article  CAS  Google Scholar 

  47. Leblanc AF, Sprowl JA, Alberti P, et al. OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity. J Clin Invest 2018;128(2):816–825. https://doi.org/10.1172/JCI96160

  48. Geisler S, Doan RA, Strickland A, Huang X, Milbrandt J, DiAntonio A. Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice. Brain. 2016;139(Pt 12):3092–108. https://doi.org/10.1093/brain/aww251. Epub 2016/11/01. PubMed PMID: 27797810; PMCID: PMC5840884

  49. Lazic A, Popovic J, Paunesku T, Woloschak GE, Stevanovic M. Insights into platinum-induced peripheral neuropathy-current perspective. Neural Regen Res. 2020;15(9):1623–30. https://doi.org/10.4103/1673-5374.276321. Epub 2020/03/27. PubMed PMID: 32209761; PMCID: PMC7437596

  50. Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S. The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases. J Adv Pharm Technol Res. 2011;2(4):236–40. https://doi.org/10.4103/2231-4040.90879. Epub 2012/01/17. PubMed PMID: 22247890; PMCID: PMC3255347

  51. Zhao X, Du W, Zhang M, Atiq ZO, Xia F. Sirt2-associated transcriptome modifications in cisplatin-induced neuronal injury. BMC Genomics. 2020;21(1):192. https://doi.org/10.1186/s12864-020-6584-2. Epub 2020/03/04. PubMed PMID: 32122297; PMCID: PMC7053098

  52. Kawashiri T, Miyagi A, Shimizu S, Shigematsu N, Kobayashi D, Shimazoe T (2018) Dimethyl fumarate ameliorates chemotherapy agent-induced neurotoxicity in vitro. J Pharmacol Sci 137(2):202–211. Epub 2018/07/26. https://doi.org/10.1016/j.jphs.2018.06.008

    Article  CAS  PubMed  Google Scholar 

  53. Ludman T, Melemedjian OK. Bortezomib-induced aerobic glycolysis contributes to chemotherapy-induced painful peripheral neuropathy. Mol Pain. 2019;15:1744806919837429. https://doi.org/10.1177/1744806919837429. Epub 2019/02/28. PubMed PMID: 30810076; PMCID: PMC6452581

  54. Majithia N, Temkin SM, Ruddy KJ, Beutler AS, Hershman DL, Loprinzi CL. National Cancer Institute-supported chemotherapy-induced peripheral neuropathy trials: outcomes and lessons. Support Care Cancer. 2016;24(3):1439–47. https://doi.org/10.1007/s00520-015-3063-4. Epub 2015/12/22. PubMed PMID: 26686859; PMCID: PMC5078987

  55. Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, Bressler LR, Fadul CE, Knox C, Le-Lindqwister N, Gilman PB, Shapiro CL, Alliance for clinical trials in O. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. Jama. 2013;309(13):1359–67. https://doi.org/10.1001/jama.2013.2813. PubMed PMID: 23549581; PMCID: PMC3912515

  56. Xiao W, Naso L, Bennett GJ (2008) Experimental studies of potential analgesics for the treatment of chemotherapy-evoked painful peripheral neuropathies. Pain Med 9(5):505–517. Epub 2008/09/09. https://doi.org/10.1111/j.1526-4637.2007.00301.x

    Article  PubMed  Google Scholar 

  57. Zhang H, Dougherty PM. Enhanced excitability of primary sensory neurons and altered gene expression of neuronal ion channels in dorsal root ganglion in paclitaxel-induced peripheral neuropathy. Anesthesiology. 2014;120(6):1463–75. https://doi.org/10.1097/ALN.0000000000000176. Epub 2014/02/19. PubMed PMID: 24534904; PMCID: PMC4031279

  58. Li Y, North RY, Rhines LD, Tatsui CE, Rao G, Edwards DD, Cassidy RM, Harrison DS, Johansson CA, Zhang H, Dougherty PM. DRG voltage- gated sodium channel 1.7 is upregulated in paclitaxel-induced neuropathy in rats and in humans with neuropathic pain. J Neurosci. 2018;38(5):1124–36. https://doi.org/10.1523/JNEUROSCI.0899-17.2017. Epub 2017/12/20. PubMed PMID: 29255002; PMCID: PMC5792474

  59. Thibault K, Calvino B, Dubacq S, Roualle-de-Rouville M, Sordoillet V, Rivals I, Pezet S (2012) Cortical effect of oxaliplatin associated with sustained neuropathic pain: exacerbation of cortical activity and down-regulation of potassium channel expression in somatosensory cortex. Pain 153(8):1636–1647. Epub 2012/06/02. https://doi.org/10.1016/j.pain.2012.04.016

    Article  CAS  PubMed  Google Scholar 

  60. Descoeur J, Pereira V, Pizzoccaro A, Francois A, Ling B, Maffre V, Couette B, Busserolles J, Courteix C, Noel J, Lazdunski M, Eschalier A, Authier N, Bourinet E. Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. EMBO Mol Med. 2011;3(5):266–78. https://doi.org/10.1002/emmm.201100134. Epub 2011/03/26. PubMed PMID: 21438154; PMCID: PMC3377073

  61. Nodera H, Spieker A, Sung M, Rutkove S (2011) Neuroprotective effects of Kv7 channel agonist, retigabine, for cisplatin-induced peripheral neuropathy. Neurosci Lett 505(3):223–227. Epub 2011/09/29. https://doi.org/10.1016/j.neulet.2011.09.013

    Article  CAS  PubMed  Google Scholar 

  62. Li Y, Tatsui CE, Rhines LD, North RY, Harrison DS, Cassidy RM, Johansson CA, Kosturakis AK, Edwards DD, Zhang H, Dougherty PM. Dorsal root ganglion neurons become hyperexcitable and increase expression of voltage-gated T-type calcium channels (Cav3.2) in paclitaxel- induced peripheral neuropathy. Pain. 2017;158(3):417–29. https://doi.org/10.1097/j.pain.0000000000000774. Epub 2016/12/03. PubMed PMID: 27902567; PMCID: PMC5303135

  63. Cai S, Tuohy P, Ma C, Kitamura N, Gomez K, Zhou Y, Ran D, Bellampalli SS, Yu J, Luo S, Dorame A, Ngan Pham NY, Molnar G, Streicher JM, Patek M, Perez-Miller S, Moutal A, Wang J, Khanna R (2020. Epub 2020/06/17) A modulator of the low-voltage activated T-type calcium channel that reverses HIV glycoprotein 120-, paclitaxel-, and spinal nerve ligation-induced peripheral neuropathies. Pain. https://doi.org/10.1097/j.pain.0000000000001955

  64. Bellampalli SS, Ji Y, Moutal A, Cai S, Wijeratne EMK, Gandini MA, Yu J, Chefdeville A, Dorame A, Chew LA, Madura CL, Luo S, Molnar G, Khanna M, Streicher JM, Zamponi GW, Gunatilaka AAL, Khanna R. Betulinic acid, derived from the desert lavender Hyptis emoryi, attenuates paclitaxel-, HIV-, and nerve injury-associated peripheral sensory neuropathy via block of N- and T-type calcium channels. Pain. 2019;160(1):117–35. https://doi.org/10.1097/j.pain.0000000000001385. Epub 2018/09/01. PubMed PMID: 30169422; PMCID: PMC6309937

  65. Makker PG, Duffy SS, Lees JG, Perera CJ, Tonkin RS, Butovsky O, Park SB, Goldstein D, Moalem-Taylor G. Characterisation of immune and Neuroinflammatory changes associated with chemotherapy-induced peripheral neuropathy. PLoS One. 2017;12(1):e0170814. https://doi.org/10.1371/journal.pone.0170814. Epub 2017/01/27. PubMed PMID: 28125674; PMCID: PMC5268425

  66. Shen Y, Zhang ZJ, Zhu MD, Jiang BC, Yang T, Gao YJ (2015) Exogenous induction of HO-1 alleviates vincristine-induced neuropathic pain by reducing spinal glial activation in mice. Neurobiol Dis 79:100–110. Epub 2015/05/10. https://doi.org/10.1016/j.nbd.2015.04.012

    Article  CAS  PubMed  Google Scholar 

  67. Robinson CR, Zhang H, Dougherty PM. Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy in the rat. Neuroscience. 2014;274:308–17. https://doi.org/10.1016/j.neuroscience.2014.05.051. Epub 2014/06/07. PubMed PMID: 24905437; PMCID: PMC4099296

  68. Zhou L, Hu Y, Li C, Yan Y, Ao L, Yu B, Fang W, Liu J, Li Y (2018) Levo- corydalmine alleviates vincristine-induced neuropathic pain in mice by inhibiting an NF-kappa B-dependent CXCL1/CXCR2 signaling pathway. Neuropharmacology 135:34–47. Epub 2018/03/09. https://doi.org/10.1016/j.neuropharm.2018.03.004

    Article  CAS  PubMed  Google Scholar 

  69. Brandolini L, Benedetti E, Ruffini PA, Russo R, Cristiano L, Antonosante A, d’Angelo M, Castelli V, Giordano A, Allegretti M, Cimini A. CXCR1/2 pathways in paclitaxel-induced neuropathic pain. Oncotarget. 2017;8(14):23188–201. https://doi.org/10.18632/oncotarget.15533. Epub 2017/04/21. PubMed PMID: 28423567; PMCID: PMC5410296

  70. Zhang H, Li Y, de Carvalho-Barbosa M, Kavelaars A, Heijnen CJ, Albrecht PJ, Dougherty PM. Dorsal root ganglion infiltration by macrophages contributes to paclitaxel chemotherapy-induced peripheral neuropathy. J Pain. 2016;17(7):775–86. https://doi.org/10.1016/j.jpain.2016.02.011. Epub 2016/03/17. PubMed PMID: 26979998; PMCID: PMC4939513

  71. Luo X, Huh Y, Bang S, He Q, Zhang L, Matsuda M, Ji RR. Macrophage toll-like receptor 9 contributes to chemotherapy-induced neuropathic pain in male mice. J Neurosci. 2019;39(35):6848–64. https://doi.org/10.1523/JNEUROSCI.3257-18.2019. Epub 2019/07/05. PubMed PMID: 31270160; PMCID: PMC6733562

  72. Li Y, Adamek P, Zhang H, Tatsui CE, Rhines LD, Mrozkova P, Li Q, Kosturakis AK, Cassidy RM, Harrison DS, Cata JP, Sapire K, Zhang H, Kennamer-Chapman RM, Jawad AB, Ghetti A, Yan J, Palecek J, Dougherty PM. The cancer chemotherapeutic paclitaxel increases human and rodent sensory neuron responses to TRPV1 by activation of TLR4. J Neurosci. 2015;35(39):13487–500. https://doi.org/10.1523/JNEUROSCI.1956-15.2015. Epub 2015/10/02. PubMed PMID: 26424893; PMCID: PMC4588613

  73. Li Y, Zhang H, Zhang H, Kosturakis AK, Jawad AB, Dougherty PM. Toll-like receptor 4 signaling contributes to Paclitaxel-induced peripheral neuropathy. J Pain. 2014;15(7):712–25. https://doi.org/10.1016/j.jpain.2014.04.001. Epub 2014/04/24. PubMed PMID: 24755282; PMCID: PMC4083500

  74. Chen Z, Doyle TM, Luongo L, Largent-Milnes TM, Giancotti LA, Kolar G, Squillace S, Boccella S, Walker JK, Pendleton A, Spiegel S, Neumann WL, Vanderah TW, Salvemini D. Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain. Proc Natl Acad Sci U S A. 2019;116(21):10557–62. https://doi.org/10.1073/pnas.1820466116. Epub 2019/05/10. PubMed PMID: 31068460; PMCID: PMC6534990

  75. Janes K, Little JW, Li C, Bryant L, Chen C, Chen Z, Kamocki K, Doyle T, Snider A, Esposito E, Cuzzocrea S, Bieberich E, Obeid L, Petrache I, Nicol G, Neumann WL, Salvemini D. The development and maintenance of paclitaxel-induced neuropathic pain require activation of the sphingosine 1-phosphate receptor subtype 1. J Biol Chem. 2014;289(30):21082–97. https://doi.org/10.1074/jbc.M114.569574. Epub 2014/05/31. PubMed PMID: 24876379; PMCID: PMC4110312

  76. Stockstill K, Wahlman C, Braden K, Chen Z, Yosten GL, Tosh DK, Jacobson KA, Doyle TM, Samson WK, Salvemini D. Sexually dimorphic therapeutic response in bortezomib-induced neuropathic pain reveals altered pain physiology in female rodents. Pain. 2020;161(1):177–84. https://doi.org/10.1097/j.pain.0000000000001697. Epub 2019/09/07. PubMed PMID: 31490328; PMCID: PMC6923586

  77. Deng L, Cornett BL, Mackie K, Hohmann AG. CB1 knockout mice unveil sustained CB2-mediated antiallodynic effects of the Mixed CB1/CB2 agonist CP55,940 in a mouse model of paclitaxel-induced neuropathic pain. Mol Pharmacol. 2015;88(1):64–74. https://doi.org/10.1124/mol.115.098483. Epub 2015/04/24. PubMed PMID: 25904556; PMCID: PMC4468646

  78. Uhelski ML, Khasabova IA, Simone DA. Inhibition of anandamide hydrolysis attenuates nociceptor sensitization in a murine model of chemotherapy-induced peripheral neuropathy. J Neurophysiol. 2015;113(5):1501–10. https://doi.org/10.1152/jn.00692.2014. Epub 2014/12/17. PubMed PMID: 25505113; PMCID: PMC4346731

  79. Mulpuri Y, Marty VN, Munier JJ, Mackie K, Schmidt BL, Seltzman HH, Spigelman I. Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation. Neuropharmacology. 2018;139:85–97. https://doi.org/10.1016/j.neuropharm.2018.07.002. Epub 2018/07/08. PubMed PMID: 29981335; PMCID: PMC6883926

  80. King KM, Myers AM, Soroka-Monzo AJ, Tuma RF, Tallarida RJ, Walker EA, Ward SJ. Single and combined effects of Delta(9) – tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy- induced neuropathic pain. Br J Pharmacol. 2017;174(17):2832–41. https://doi.org/10.1111/bph.13887. Epub 2017/05/27. PubMed PMID: 28548225; PMCID: PMC5554313

  81. Vera G, Cabezos PA, Martin MI, Abalo R (2013) Characterization of cannabinoid-induced relief of neuropathic pain in a rat model of cisplatin- induced neuropathy. Pharmacol Biochem Behav 105:205–212. Epub 2013/03/05. https://doi.org/10.1016/j.pbb.2013.02.008

    Article  CAS  PubMed  Google Scholar 

  82. Khasabova IA, Khasabov S, Paz J, Harding-Rose C, Simone DA, Seybold VS. Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy. J Neurosci. 2012;32(20):7091–101. https://doi.org/10.1523/JNEUROSCI.0403-12.2012. Epub 2012/05/18. PubMed PMID: 22593077; PMCID: PMC3366638

  83. Segat GC, Manjavachi MN, Matias DO, Passos GF, Freitas CS, Costa R, Calixto JB (2017) Antiallodynic effect of beta-caryophyllene on paclitaxel- induced peripheral neuropathy in mice. Neuropharmacology 125:207–219. Epub 2017/07/22. https://doi.org/10.1016/j.neuropharm.2017.07.015

    Article  CAS  PubMed  Google Scholar 

  84. Deng L, Guindon J, Cornett BL, Makriyannis A, Mackie K, Hohmann AG. Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. Biol Psychiatry. 2015;77(5):475–87. https://doi.org/10.1016/j.biopsych.2014.04.009. Epub 2014/05/24. PubMed PMID: 24853387; PMCID: PMC4209205

  85. Tonello R, Lee SH, Berta T (2019) Monoclonal antibody targeting the matrix metalloproteinase 9 prevents and reverses paclitaxel-induced peripheral neuropathy in Mice. J Pain 20(5):515–527. https://doi.org/10.1016/j.jpain.2018.11.003. Epub 2018/11/25. PubMed PMID: 30471427; PMCID: PMC6511475

    Article  CAS  PubMed  Google Scholar 

  86. Krukowski K, Ma J, Golonzhka O, Laumet GO, Gutti T, van Duzer JH, Mazitschek R, Jarpe MB, Heijnen CJ, Kavelaars A (2017) HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy. Pain 158(6):1126–1137. https://doi.org/10.1097/j.pain.0000000000000893. Epub 2017/03/08. PubMed PMID: 28267067; PMCID: PMC5435512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ramakrishna C, Corleto J, Ruegger PM, Logan GD, Peacock BB, Mendonca S, Yamaki S, Adamson T, Ermel R, McKemy D, Borneman J, Cantin EM (2019) Dominant role of the gut microbiota in chemotherapy induced neuropathic pain. Sci Rep. 9(1):20324. https://doi.org/10.1038/s41598-019-56832-x. Epub 2020/01/01. PubMed PMID: 31889131; PMCID: PMC6937259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Slivicki RA, Mali SS, Hohmann AG (2019) Voluntary exercise reduces both chemotherapy-induced neuropathic nociception and deficits in hippocampal cellular proliferation in a mouse model of paclitaxel-induced peripheral neuropathy. Neurobiol Pain 6:100035. https://doi.org/10.1016/j.ynpai.2019.100035. Epub 2019/09/19. PubMed PMID: 31528755; PMCID: PMC6739464

    Article  PubMed  PubMed Central  Google Scholar 

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  1. Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain

    Manuel Morales

  2. Mayo Clinic, Rochester, MN, USA

    Nathan P. Staff

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  1. Yale University School of Medicine, New Haven, CT, USA

    Maryam Lustberg

  2. Mayo Clinic, Rochester, MN, USA

    Charles Loprinzi

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Morales, M., Staff, N.P. (2021). Treatment of Established Chemotherapy-Induced Peripheral Neuropathy: Basic Science and Animal Models. In: Lustberg, M., Loprinzi, C. (eds) Diagnosis, Management and Emerging Strategies for Chemotherapy-Induced Neuropathy. Springer, Cham. https://doi.org/10.1007/978-3-030-78663-2_6

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