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| 183P London, UK Pharmacology 2017 |
Streptozocin-diabetic rats show reduced hyperthermic effects but maintained anti-allodynia responses to the TRPV1 antagonist ABT-102 throughout nine days of dosing
Introduction: The clinical development of TRPV1 antagonists was halted by hyperthermic responses, modulated by a peripheral on-target mechanism of action, vasoconstriction and thermogenesis (1). Peripheral TRPV1 function is differentially regulated during diabetes (2) which led to the hypothesis that 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 streptozotocin (STZ) induced diabetic rat model.
Method: Male Wistar rats (325-425g) were administered a single i.p. injection of 65mgkg-1 STZ (n=30) or 20mM citrate buffer (pH4.5,sham n=16). 100% of STZ rats developed hyperglycaemia (29.1 ± 0.8mMol/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 transponders. By 14 days post STZ-injection 93% (n=27) diabetic animals developed significant sensory static allodynia (84.6 ± 1.7% change from baseline ***p<0.001) and were randomly allocated into vehicle (0.5% methylcellulose), ABT-102 (10.44mgkg-1) and pregabalin (30mgkg-1) treatment groups (p.o.daily for 9 days).Temperatures were recorded over 9 days. Evoked static allodynia responses were measured 2 hours post-dose, days 1, 3, 8. Data are given as mean±SEM (n animals) and analysis was performed using repeated measures ANOVA with post hoc Bonferroni.
Results: In sham rats, ABT-102 caused a significant hyperthermic effect that persisted for 9 days (0.84±0.2 °C n=8, *p<0.05 day 1; 0.88±0.3 °C n=8, **p<0.01 day 9). In STZ-diabetic rats, ABT-102 caused a hyperthermic effect on day 1 which reduced from day 2-9 (+1.13±0.14 °C n=9 *p<0.05 day 1; +0.18±0.15 °C n=9, ns day 9). 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 day 8).
Conclusions: Daily administration of the TRPV1 antagonist ABT-102 over 9 days did not cause significant hyperthermia 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.
References:
(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