Descending serotonergic pain modulation during chemotherapy-induced neuropathy: the role of spinal 5-HT3 receptor
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1
Department of Biomedicine, Faculty of Medicine, University of Porto, Portugal
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2
i3S, Instituto de Investigação e Inovação em Saúde, Portugal
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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
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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