Intestinal mucositis induced by 5-FU results in glial changes modified by analgesics via neuro-immune mechanisms

2017-10-23T02:14:52Z (GMT) by Juliana Bajic Alexandra Whittaker
Analgesic choice in oncology is problematic due to exacerbating gastrointestinal symptoms. Chemotherapy drugs induce intestinal mucositis, pain & often cognitive impairment (CICI). Neuro-immune glial cells, microglia and astrocytes are sensitive to peripheral inflammatory events & analgesics, modifying pain signalling and cognition. Glial reactivity may occur directly via central insults or indirectly via peripheral-to-central neuro-immune signalling pathways; cellular, humoral or neural pathways.

Research problem
- Chemotherapy induces intestinal mucositis, pain & CICI
- Whilst analgesics ameliorate pain, they may exacerbate chemotherapy-induced gut side-effects
- Analgesics may also modulate inflammatory responses and glial cell expression via neuro-immune signalling pathways

Hypothesis
- Glial changes will contribute to pain signalling and affect higher order brain regions involved in cognition via neuroimmune signalling mechanisms in rats with intestinal mucositis

Aims
- Characterise the effect of 3 analgesics on acute intestinal inflammation and neuro-immune mechanisms in a rat model of 5-fluorouracil (5-FU)-induced intestinal mucositis
- Assess acute intestinal mucositis via myeloperoxidase (MPO) activity in the jejunum & ileum of rats
- Quantify glial reactivity & pro-inflammatory response, determining neuro-immune pathway via a) humoral: hippocampal or b) neuronal: thoracic (T6-T9; innervated by small intestine)

Methods
- Female DA rats (n=8)
- I.P. administration of either saline or 5-FU (150mg/kg) in combination with 12 hourly doses of opioid derivatives (buprenorphine; BUP, 0.05kg/mg or tramadol; TRAM, 12.5mg/kg) or NSAID (carprofen; CARP, 15mg/kg)
- Rats were humanely euthanized at peak injury phase of intestinal mucositis (72h after saline or 5-FU administration)
- Intestinal sections were quantified using MPO assay & CNS sections using western blot staining for microglia (CD11b), astrocyte (glial fibrillary associated protein; GFAP) & interleukin-1 beta (IL-1β)
- All results p < 0.05 deemed significant

Discussion
BUP & TRAM may be more effective analgesic options in 5-FU-induced intestinal mucositis
- Attenuated acute intestinal inflammation (MPO activity)
- Increased hippocampal GFAP expression
- Co-administration of 5-FU returns GFAP increase to basal levels
- Thoracic IL-1β expression was increased in 5-FU treated rats, yet reduced in opioid analgesics
- CD11b changes were most evident in hippocampal and thoracic CARP groups
- Thoracic inflammatory effect was observed in CARP group
- Neuro-immune signalling pathways associated with the glial changes:
- Humoral (hippocampal) & neural (thoracic) pathways
- 5-FU induced an increase in thoracic GFAP expression (indicative of astrocyte activation), potentially enhancing pain signalling pathways as indicated by elevated IL-1β levels
- Intestinal histological score remained unchanged in opioid groups despite beneficial reduction in MPO activity