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Mechanical allodynia and enhanced responses to capsaicin are mediated by PI3K in a paclitaxel model of peripheral neuropathy
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SYSNO ASEP 0503873 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Mechanical allodynia and enhanced responses to capsaicin are mediated by PI3K in a paclitaxel model of peripheral neuropathy Author(s) Adámek, Pavel (FGU-C) RID, ORCID, SAI
Heleš, Mário (FGU-C) ORCID, RID, SAI
Paleček, Jiří (FGU-C) RID, ORCIDSource Title Neuropharmacology. - : Elsevier - ISSN 0028-3908
Roč. 146, Mar 1 (2019), s. 163-174Number of pages 12 s. Language eng - English Country NL - Netherlands Keywords pain ; neuropathy ; chemotherapy ; paclitaxel ; PI3K Subject RIV FH - Neurology OECD category Neurosciences (including psychophysiology R&D Projects GA18-09853S GA ČR - Czech Science Foundation (CSF) LQ1604 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Limited access Institutional support FGU-C - RVO:67985823 UT WOS 000457663900017 EID SCOPUS 85059310372 DOI 10.1016/j.neuropharm.2018.11.027 Annotation Paclitaxel chemotherapy treatment often leads to neuropathic pain resistant to available analgesic treatments. Recently spinal Toll-like receptor 4 (TLR4) and the transient receptor potential cation channel subfamily V member 1 (TRPV1) were identified to be involved in the pro-nociceptive effect of paclitaxel. The aim of this study was to investigate the role of phosphatidylinositol 3-kinase (PI3K) and serine/threonine kinases in this process, with the use of their antagonists (wortmannin, LY-294002, and staurosporine). The single paclitaxel administration (8 mg/kg i.p.) in mice induced robust mechanical allodynia measured as a reduced threshold to von Frey filament stimulation and generated reduced tachyphylaxis of capsaicin-evoked responses, recorded as changes in mEPSC frequency in patch-clamp recordings of dorsal horn neurons activity in vitro, for up to eight days. Paclitaxel application also induced increased Akt kinase phosphorylation in rat DRG neurons. All these paclitaxel-induced changes were prevented by the wortmannin in vivo pretreatment. Acute co-application of wortmannin or LY-294002 with paclitaxel in spinal cord slices also attenuated the paclitaxel effect on capsaicin-evoked responses. Staurosporine was effective in the acute in vitro experiments and on the first day after the paclitaxel treatment in vivo, but in contrast to wortmannin, it did not have a significant impact later. Our data suggest that the inhibition of PI3K signaling may help alleviate pathological pain syndromes in the paclitaxel-induced neuropathy. Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2020 Electronic address https://doi.org/10.1016/j.neuropharm.2018.11.027
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