Introduction: The clinical development of TRPV1 antagonists has been halted by hyperthermic responses, believed to be modulated by a peripheral on-target mechanism of action (1). Recent reports (2) and in-house data suggest that TRPV1 function is downregulated peripherally during diabetes which has led to the hypothesis that administration of TRPV1 antagonists would not cause hyperthermia in diabetics and therefore could potentially be used to treat painful diabetic neuropathy. The aim of this study was to investigate whether an analgesic dose of the selective TRPV1 antagonist ABT-102 would cause hyperthermia in a streptozocin (STZ) induced diabetic rat model. Method: This work was conducted in accordance with guidelines established by the Animals (Scientific Procedures) Act 1986 / ASPA Amendment Regulations 2012. Male Wistar rats (325-425g) were administered a single i.p. injection of 65mgkg STZ (n=30) or 20mM citrate buffer (pH4.5, sham, n=16). 100% of STZ rats developed hyperglycaemia (29.1 0.8 mMol/L, p<0.001) by day 7. Evoked static allodynia (Von Frey paw withdrawal threshold, PWT) was evaluated using Dixon’s up-down method (3) and body temperature was recorded using s.c. implanted IPTT-300 microchip transponders. By 14 days post STZ injection 93% (n=27) diabetic animals developed significant sensory static allodynia (had 84.6 1.7% change from baseline,***p<0.001) and were randomly allocated into vehicle (0.5% methylcellulose), ABT-102 (10.44mg/kg) and pregabalin (30mg/kg) treatment groups (p.o.daily for 9 days). Temperature measurements were recorded pre-dose and at 0.5,1,1.5,2,3,4,5,6 hours post dose on days 1-9. Evoked static allodynia responses were measured 2 hours post-dose, on days 1, 3 and 8. Data are given as mean±SEM (n animals) and analysis was performed using repeated measures ANOVA followed by post hoc Bonferroni. Results: In STZ-diabetic rats, administration of ABT-102 over 9 days resulted in significant analgesia (PWT 11.1±2.5g, n=9) versus vehicle (2.2±0.4g n=9, *p<0.05 at day 8) with a temperature rise from baseline, only significant on day 1 (1.13±0.14 ºC n=9, *p<0.05 at 2 hours post dose day 1; 0.18±0.15 ºC n=9, ns at day 9). In control rats, ABT-102 caused a significant hyperthermic effect that persisted for 9 days (0.84±0.2 ºC n=8, *p<0.05 at day 1; 0.88±0.3 ºC n=8, **p<0.01 at day 9). Conclusion: Daily administration of the TRPV1 antagonist ABT-102 over 9 days did not cause significant hyperthemia in STZ-diabetic rats from days 2-9, but did significantly reverse the static allodynia associated with diabetic neuropathy (in line with pregabalin efficacy), confirming the hypothesis that TRPV1 function is altered peripherally in diabetes. These data demonstrate that there is a potential for treatment of diabetic neuropathy by TRPV1 antagonists. (1) Gavva NR. (2009) The Open Drug Discovery Journal 1:1-35 (2) DelloStitto DJ. et al. (2016) Basic Research in Cardiology 111:21 (3) Dixon WJ. (1980) Ann Rev Pharmacol Toxicol. 20: 441-62.
|Publication status||Published - 11 Dec 2017|
|Event||British Pharmacological Society Winter Meeting, 2017 - Queen Elizabeth II Conference Centre, London, United Kingdom|
Duration: 11 Dec 2017 → 13 Dec 2017
|Conference||British Pharmacological Society Winter Meeting, 2017|
|Period||11/12/17 → 13/12/17|