Descending serotonergic pain modulation during chemotherapy-induced neuropathy: the role of spinal 5-HT3 receptor

Abstract

Event Abstract Back to Event Descending serotonergic pain modulation during chemotherapy-induced neuropathy: the role of spinal 5-HT3 receptor José T. Da Costa-Pereira1, 2, 3, Isabel Martins1, 2, 3 and Isaura Tavares1, 2, 3* 1 Department of Biomedicine, Faculty of Medicine, University of Porto, Portugal 2 i3S, Instituto de Investigação e Inovação em Saúde, Portugal 3 Instituto de Biologia Molecular e Celular (IBMC), Portugal Chemotherapeutics drugs are the most common cytostatic agents used in cancer treatment. Chemotherapy-induced neuropathy (CIN) is a common complication of cancer treatment and neuropathic pain arises frequently as side effect. The mechanisms underlying pain during CIN are starting to be uncovered namely the alterations induced by cytostatics at the peripheral nervous system. However, the effects of cytostatics at the central nervous system remain poorly understood. This experimental work aimed to study the effects of the cytostatic drug paclitaxel on i) the serotonin levels in spinal cord, ii) the contribution of the main serotonergic brainstem area, rostroventromedial medulla (RVM); and iii) the role of the spinal 5-HT3 receptor (5HT3-R). Male Wistar rats were injected with paclitaxel (2.0 mg/kg) or the vehicle solution (4% dimethyl sulfoxide; DMSO) in four alternate days. The spinal serotonin content was assessed by high performance liquid chromatography with electrochemical detection (HPLC-ED). The main source of serotoninergic innervation of the spinal cord (the RVM) was studied through the double immunodetection of phosphorylated extracellular signal-regulated kinase (pERK) and tryptophan hydroxylase (TpH) in RVM sections. To study the role of the 5HT3-R, we assessed the effects of the intrathecal administration of 5HT3-R antagonist ondansetron, on mechanical and thermal sensitivity using, respectively, the von Frey and cold plate tests. We further measured the spinal expression of the 5HT3-R by immunohistochemistry and western-blotting. Paclitaxel-treated animals presented a higher basal serotonin content in spinal dorsal horn accompanied by an increased co-localization of pERKs – TpH in RVM. The mechanical and thermal sensitivities were reversed by the blockade of 5HT3-R in spinal cord with ondansetron. The 5HT3-R expression was increased in superficial dorsal horn in paclitaxel-treated animals. Our results indicate that paclitaxel-induced CIN is associated with an increase of spinal serotonin along with an higher activation of serotonergic RVM neurons and spinal 5HT3-R expression which constitute the trigger for descending serotonergic facilitation. The antinociceptive effect of ondansetron in paclitaxel-treated animals point to the pronociceptive role of spinal 5HT3-R. Targeting the descending serotonergic system along with a decrease of the function of spinal 5HT3-R may be important to treat pain during CIN. Acknowledgements Norte 2020/NORTE-01-0145-FEDER-000008; NORTE-08-5369-FSE-000026 Keywords: paclitaxel-induced neuropathic pain, RVM, 5-HT3 receptor, Spinal Cord, Serotonin Conference: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019. Presentation Type: Oral presentation Topic: Sensory Processing Citation: Da Costa-Pereira JT, Martins I and Tavares I (2019). Descending serotonergic pain modulation during chemotherapy-induced neuropathy: the role of spinal 5-HT3 receptor. Front. Cell. Neurosci. Conference Abstract: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019). doi: 10.3389/conf.fncel.2019.01.00029 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 22 Feb 2019; Published Online: 27 Sep 2019. * Correspondence: Prof. Isaura Tavares, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal, isatav@med.up.pt Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers José T Da Costa-Pereira Isabel Martins Isaura Tavares Google José T Da Costa-Pereira Isabel Martins Isaura Tavares Google Scholar José T Da Costa-Pereira Isabel Martins Isaura Tavares PubMed José T Da Costa-Pereira Isabel Martins Isaura Tavares Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.