OP08 The hydrogen sulfide donor GYY4137 attenuates transient receptor potential vanilloid 1 (TRPV1) antagonist-mediated hyperthermia

Abstract

The transient receptor potential vanilloid 1 (TRPV1) ion channel is a member of the TRP superfamily of receptors and a well-known integrator of noxious stimuli. The expression of TRPV1 on primary sensory neurons has been very well characterised, however, recent studies have shown that they are also expressed in non-neuronal tissue [1] . Whilst TRPV1 antagonism is a promising analgesic strategy, early generation antagonists, such as JNJ17203212 [2] resulted in poorly-understood hyperthermia. Hydrogen sulfide (H 2 S) is a well-known vasodilator [3] , [4] , and inhalation of H 2 S can suspend animation, which includes a decreased body temperature [5] . We investigated whether the H 2 S donor GYY4137 [6] would attenuate the hyperthermia caused by JNJ17203212. Male CD1 mice (Charles River, 35–40 g) were used for all experiments in accordance with the Scientific Procedures Act (1986). Radiotelemetry devices allowed the measurement of temperature and activity of freely moving, conscious singly-housed mice in their home cages. Probes (TA-T10A, DSI, USA) were surgically implanted into the peritoneal cavity under 2–5% isoflurane anaesthesia. Preoperative analgesia was administered to aid recovery. Mice were left to recover for one week before temperature monitoring began. A 2-h baseline measurement was taken before i.p. treatment of the mice with either: 30 mg/kg JNJ17203212 ( n = 5), 50 mg/kg GYY4137 ( n = 5) or 11 mg/kg d , l - propargylglycine (PAG, n = 5) or vehicle (10 ml/kg). A pre-treatment of 50 mg/kg GYY4137 30 min before 30 mg/kg JNJ17203212 was performed to determine the effect of GYY4137 on JNJ17203212-mediated hyperthermia. Results were analysed using repeated measures 2-way ANOVA and expressed as mean ±SEM. JNJ17203212 (30 mg/kg) caused a significant increase in body temperature compared to vehicle (10%DMSO) treated mice at 2–3 h post administration ( n = 5, P P n = 4) and 50 mg/kg GYY4137 ( n = 4) treatment did not significantly change body temperature compared to vehicle (saline) treated mice). Treatment of mice with 50 mg/kg GYY4137 30 min before 30 mg/kg JNJ17203212 resulted in a reduction in amplitude of the JNJ17203212-mediated hyperthermia compared to saline-pre-treated mice ( n = 6, P This study provides an intriguing insight into a possible way of overcoming TRPV1 antagonist-induced hyperthermia. Under physiological conditions, GYY4137 and PAG did not affect core body temperature. The TRPV1 antagonist JNJ17203212 significantly increased body temperature of male CD1 mice compared to vehicle treated mice. The H 2 S donor GYY4137 reduced the JNJ17203212-mediated increase in body temperature. Further studies will determine whether GYY4137 will affect body temperature under pathological conditions and the mechanism involved in these changes.