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Nociception in Drosophila Conclusion Bibliography Acknowledgements Modeling chemotherapy-induced neuropathic pain in Drosophila Abdulkarim Sankareh1, Jay Z Parrish2 1UW GenOM Project, 2Department of Biology, University of Washington, Seattle, WA Abstract Methods and Results: nociception in Drosophila Conclusion Chemotherapy-induced peripheral neuropathy Chemotherapy is a common method of cancer treatment, How do we assay mechanical nociception in How do we determine whether the behavior (CIPN) is a common side effect of many anticancer and results in Chemotherapy Induced Peripheral Drosophila larvae? responses reflect activation of nociceptors? drugs that is associated with a severe Neuropathy (CIPN) in 30-40% of patients (Staff, somatosensory pain syndrome. Previous studies 2017). CIPN is caused by the interaction between Vinca- have shown the utility of Drosophila in modelling alkaloid anti-cancer drugs and peripheral somatosensory chemotherapy induced neuropathic pain. These nociceptors, resulting in heightened nociceptive sensation in studies have demonstrated that acute Vinca-alkaloid the neurons (Boiko et al., 2017). The pathways through treatment results in augmented nociceptive function which Vinca-alkaloids achieve this effect are still poorly in Drosophila as well as in mice. In our research we understood. Here, we describe our attempts to use the fruit plan to use this model to understand the long and fly Drosophila as a genetically tractable model to dissect the short-term effects of Vinca-alkaloids on the peripheral acute and long-lasting effects of Vinca-alkaloids on nociception. We aim to use this model to understand nociceptive sensitivity. the effects of long-term exposure and the severity of Figure 2. Assay for mechanical nociception assay. the effects as a function of time. We hypothesize that Drosophila larvae elicit stereotypical rolling behavior when Wildtype Mechanical short- and long-term effects of vinblastine on pain Introduction stimulated with forces greater than ~40mN. involve distinct molecular and cellular mechanisms, Nociception is the sensory process that results in the 40 and the proposed studies will be the first step in subjective experience of ‘pain.' Because of its vital and testing this hypothesis. Figure 5. Genetic scheme for manipulating nociceptor broad role in animal biology, pain/nociception is a complex g 30 function. An adult female with the transgene directing physiological process. The powerful genetic toolkit, compact n i GAL4 expression in nociceptors (PPK-Gal4) is crossed to nervous system, and conservation of fundamental aspects d n males carrying the UAS.kir2.1 transgene. Progeny will of nervous system function make Drosophila melanogaster a o Acknowledgements p 20 express KIR2.1 in nociceptors, hyperpolarizing the neurons robust model system for studying nociception. Furthermore, s e and effectivelyMechanical silencing (80mN) them. Thank you to Dr. Parrish and the Parrish lab for prior studies have demonstrated that short-term treatment R ) providing the resources and tutelage for this project, the with Vinca-alkaloids potentiates nociception via the same % 10 80 ( University of Washington GenOM Project (NIH mechanism in Drosophila and mammals. 5R25HG007153‐07), the University of Washington g 60 Office of Research, and Lisa Peterson. 0 n i Figure 6. Mechanical 0 20 40 60 80 100 d n nociception of wild-type third o stimulus(mN) p 40 s instar larvae and the e experimental UAS.kir.2.1 with Figure 3. Larval behavioral response to mechanical R Bibliography force. Y(axis) shows the percentage of larvae that exhibit rolling ) a mechanical force of 80mN. % 20 Boiko, N., Medrano, G., Montano, E., Jiang, N., Williams, C.... & Eaton, B. ( responses and the X(axis) represents the force applied. (2017). TrpA1 activation in peripheral sensory neurons underlies the ionic basis of pain hypersensitivity in response to vinca alkaloids. PLoS 0 One, 12(10), e0186888. Boyette-Davis, J. A., Walters, E. T., & Dougherty, P. M. (2015). Mechanisms e p .1 involved in the development of chemotherapy-induced neuropathy. Pain ty r2 d i Management, 5(4), 285-296. il .k How do we assay thermal nociception in w S Chattopadhyay, A., Gilstrap, A. V., & Galko, M. J. (2012). Local and global A U methods of assessing thermal nociception in Drosophila larvae. Journal Drosophila larvae? of Visualized Experiments,(63). Hu, J., & Lewin, G. R. (2006). Mechanosensitive currents in the neurites of cultured mouse sensory neurons. The Journal of Physiology, 577(3), Testing vinblastine effects on nociceptive 815-828. sensitivity Im, S. H., & Galko, M. J. (2011). Pokes, sunburn, and hot sauce: Drosophila is an emerging model for the biology of nociception. Developmental Figure 7. Dynamics, 241(1), 16-262. Experimental Malik, B., & Stillman, M. (2008). Chemotherapy-induced peripheral neuropathy. Current Pain and Headache Reports,12(3), 165-174. plan for Montell, C. (2003). Faculty of 1000 evaluation for painless, a Drosophila studying long- gene essential for nociception. F1000 - Post-publication Peer and short-term Review of the Biomedical Literature. Staff, N. P., Grisold, A., Grisold, W., & Windebank, A. J. (2017). effects of Chemotherapy-induced peripheral neuropathy: A current review. Annals Vinca- of Neurology, 81(6), 772-781. alkaloids on Tsubouchi, A., Yano, T., Yokoyama, T. K., Murtin, C., Otsuna, H., & Ito, K. Figure 1. Comparative anatomy of Drosophila and mammalian (2017). Topological and modality-specific representation of nervous systems. A. The sensory neurons in adult Drosophila nociceptive somatosensory information in the fly brain. Science, 358(6363), 615- that are used for major somatosensory function including olfactory sensitivity 623. in Drosophila Zhang, H., & Dougherty, P. M. (2014). Enhanced excitability of primary stimuli reception. B. The corresponding set of somatosensory Figure 4. Thermal nociception of Drosophila larvae. sensory neurons and altered gene expression of neuronal ion channels neurons responsible for similar major somatosensory function in Larvae are stimulated with a heat probe calibrated to specific larvae. in dorsal root ganglion in paclitaxel-induced peripheral neuropathy. humans. C. The functionally similar neuronal structures in humans temperatures. Drosophila larvae are known to respond with Anesthesiology, 120(6), 1463-1475. and Drosophila make Drosophila melanogaster a suitable species the stereotypical rolling behavior when stimulated with to model nociception. temperatures ~43℃. University of Washington GenOM ALVA 2019.
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