Cancer chemotherapeutics in early life alter spinal nociceptive processing in the adult

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCB238

Poster Communications: Cancer chemotherapeutics in early life alter spinal nociceptive processing in the adult

J. Lloyd1, R. Hulse1, C. Greenspoon1, G. J. Hathway1

1. university of Nottingham, Nottingham, Nottinghamshire, United Kingdom.

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Survivability of paediatric cancers has tripled since the 1970s, however treatment comes with severe side effects[GH1] . Cisplatin is a front line treatment for solid state tumours yet its’ main dose-limiting effect is chemotherapy induced peripheral neuropathy (CIPN) that negatively effects quality of life for decades[GH2] . This can be especially damaging in children, where early life insults can fundamentally alter the development of spinal nociceptive pathways. This study aimed to determine the extent of changes in developing spinal nociceptive pathways following chemotherapeutic treatment in early life. All animal use procedures were specifically licenced by the UK Home Office. Sprague Dawley rats pups of both sexes were given 1mg/kg cisplatin (CIS) (0.5mg/ml) (n=3) or vehicle (VEH) (n=4) via intraperitoneal (IP) injections for 5 days from postnatal day 7 to 11. On postnatal day 45 animals were perfusion fixed using 4% paraformaldehyde. Spinal cords were removed and immunohistochemistry performed on 40µm sections of the lumbar enlargement. Antibodies for neuronal and glial targets involved in nociceptive pathways used were: neurones (NeuN), Microglia (IBA1), astrocytes (GFAP), peptidergic neurones (CGRP), non-peptidergic neurones (IB4), peptidergic nerve growth factor receptors (TrkA), peptidergic interneurones (vGLUT2) and neurofiliment 200 (NF200). The dorsal horn (DH) was imaged on a confocal microscope and regions of interest (ROI) in laminae I-V analysed using ImageJ and Graphpad Prism. Comparisons between groups (CIS vs VEH) were made using Students t-Test. There were no significant differences between CIS and VEH groups in NeuN (CIS=17.8±0.6, VEH=16.8±0.7, p=0.3) CGRP (CIS=43.7±3.1, VEH=42.9±2.6, p=0.3) staining. However, there were significant increases in TrkA (CIS=93.54±41.8, VEH=59.2±2.8, p=0.0001), vGLUT2 (CIS=43.8±0.2, VEH=26.7±0.1, p=0.0001) and IB4 (CIS=27.9±1.2, VEH=23.6±0.9, p=0.0001) staining, as well as NF200 (CIS=36.3±0.7, VEH=18.1±0.3, p=0.0001), suggestive of neuronal sprouting. Over the entire DH IBA1 did not show any significant changes (CIS=3.2±0.1, VEH=2.9±0.1, p=0.1). However, in laminae V specifically, there was an increase in IBA1 in CIS treated rats (CIS=2.7±0.2, VEH=2.2±0.1, p=0.02). There was a significant decrease in GFAP in CIS animals (CIS=6.6±0.1, VEH=9.2±0.1, p=0.0001). Cancer chemotherapeutic treatment in early life significantly alters the structure and function of spinal nociceptive networks in later life. These changes explain the altered sensory and pain perceptual changes experienced by cancer survivors and indicate alterations in other central nervous system structures.



Where applicable, experiments conform with Society ethical requirements.

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