A Conserved Pain Syndrome Resulting from the Acute Activation of TrpA1 by Chemotherapy Drugs

Abstract

Treatment with anti‐cancer drugs are often compromised by a peripheral pain syndrome referred to as chemotherapy induced peripheral neuropathy (CIPN). Currently there is no treatment for CIPN and the cellular mechanisms underlying the effects of anti‐cancer drugs on sensory neuron function are not well described. Mitochondria dysfunction, axonal degeneration, reduced sensory innervation, and altered gene expression have all been observed in somatosensory neurons from animal models; but it should be noted that these outcomes are the result of prolonged systemic administration of anti‐cancer drugs and do not necessarily represent the early formative events associated with the initiation of CIPN. Here we show that acute exposure to vinca alkaloids and taxanes result in an immediate pain syndrome in both flies and mice that is consistent with the direct activation of peripheral nociceptors. Electrophysiological analyses of polymodal Class IV dendrite arborization (C4da) sensory neurons in Drosophila reveals that vinca alkaloids and taxol specifically activate the transient receptor potential cation channel A1 (TrpA1) resulting in the activation of these sensory neurons. Furthermore, TrpA1 mutant mice and flies have reduced pain in response to vinca alkaloid exposure consistent with the acute activation of TrpA1 by these chemotherapy drugs being sufficient to generate CIPN across phyla. Targeted expression of dTrpA1 in C4da neurons rescues the pain phenotype in dTrpA1 mutants. These findings represent the first demonstration of direct excitation of sensory neurons by CIPN causing chemotherapy drugs, and identify TrpA1 as an important target during the pathogenesis of CIPN.Support or Funding InformationThis work was funded by a CPRIT IIRG grant (RP150408) and a NIH/NCI R21 grant (CA194138) to J. D. Stockand and B. A. EatonThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.