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| 147P London, UK Pharmacology 2017 |
The role of rage in the pathogenesis of inflammatory pain in an acute model of inflammation
Introduction: Advanced glycation end products (AGEs) contribute to inflammatory conditions, including obesity and diabetes, through the perpetuation of cellular dysfunction. The receptor for AGEs (RAGE) is widely known to mediate the inflammatory cascade. The aim of this study was to investigate whether RAGE expression is altered in response to inflammation in a rodent model of acute inflammation and pain hypersensitivity, and if pharmacological blockade of RAGE activity with a RAGE V-domain blocker (FPS-ZM1) has anti-inflammatory and analgesic effects.
Method: Responses to thermal and mechanical stimulation of the hindpaw and paw oedema were measured in adult male Wistar rats in response to intra-dermal (50 μl) injection of carrageenan (3%) or vehicle (n=6/group) into the left hindpaw. Animals were euthanized 6 h post-carrageenan and spinal cord, white adipose tissue (WAT) and serum collected and analysed for expression of RAGE using real-time PCR and ELISA. A second study measured the effect of treatment with FPS-ZM1 dissolved in DMSO (10 mg/kg; i.p.) or vehicle (50:50 DMSO/H2O) 15 mins pre- or 3 hours post-carrageenan injection, on thermal and mechanical nociceptive responses and paw oedema over 24 h (n=6-12/group). Data were analysed using an ANOVA with post-hoc Tukey’s test (p < 0.05 considered significant). All procedures meet requirements of the Animals Scientific Procedures Act 1986 or amendment regulations 2012 for work performed in the UK.
Results: Carrageenan induced significant paw oedema (139.8 ± 12.51 vs. 0.42 ± 7.38, n=6; p < 0.001) and thermal (12.02 ± 0.09 vs. 7.48 ± 1.63, n=6; p < 0.001) and mechanical (47.78 ± 0.71 vs. 30.2 ± 6.83, n=6; p < 0.001) hypersensitivity in the injected paw at 6 h. RAGE mRNA and protein were detected in spinal cord and WAT, but levels were unchanged post-carrageenan. A significant decrease was detected in RAGE protein levels in serum (10785 ± 2340 vs 2930 ± 316; p < 0.05). Treatment with FPS-ZM1 15 mins pre- or 3 h post-carrageenan injection failed to attenuate carrageenan-induced paw oedema or hypersensitivity.
Conclusions: The altered expression of RAGE in the serum in response to acute inflammation suggests that this cytokine may serve as a useful biomarker for monitoring acute inflammation. However, given that levels of RAGE were unchanged in spinal cord in response to carrageenan and that FPS-ZM1 had no effect on inflammation or pain hypersensitivity in this model, this study suggests that contribution of RAGE to central inflammation and pathogenesis of pain may be limited.