The Effects Of The TRPA1 Antagonists TCS5861528 And HC030031 On Core Body Temperature And Activity Of Conscious Mice

Maria Fernandes, Julie Keeble. Institute of Pharmaceutical Sciences, King’s College London, London SE1 9NH, UK.

The Transient Receptor Potential Ankyrin 1 (TRPA1) receptor is closely related to Transient Receptor Potential Vanilloid (TRPV1) receptor. Both of these channels are expressed predominantly on sensory nerve fibres and are activated by a variety of noxious stimuli. Therein, these channels play an integral role in the pain response and, thus, have been highlighted as therapeutic targets for the treatment of pain. However, some TRPV1 antagonists cause hyperthermia in humans and animals, that is associated with increased thermogenesis and decreased cutaneous blood flow (Steiner et al., 2007). Our previous studies have shown that this is not the case with the TRPV1 antagonist SB366791 (Fernandes et al., 2011). We hypothesised that TRPA1 antagonists may also have a thermoneutral profile. The present study has therefore investigated the effect of the TRPA1 antagonists TCS5861528 (Wei et al., 2011) and HC030031 (Eid et al., 2008) in core body temperature and activity in mice.

Male, CD1 mice (30-40g, Charles River, UK) were used for all experiments under Home Office Licence in accordance with the Scientific Procedures Act 1986. Animals were housed under controlled conditions (12 hours light:dark cycle - lights on at 0700; 21±2°C; 40-50% humidity) with free access to food and water. Body temperature and activity were measured using radiotelemetry via intraperitoneally implanted transmitters (TA-T20A, DSI). Briefly, mice were anaesthetised (3-5% isoflurane) after preoperative analgesia (10ug/kg buprenorphine) before a midline incision was made in the abdominal cavity. The transmitter was implanted before suturing the abdominal wall and skin and mice were left to recover for at least one week. Mice were then orally dosed with TCS5861528 (10 mg/kg), HC030031 (100mg/kg) or vehicle control (2% DMSO, 10 ml/kg) after a one-hour baseline recording. Dosing was consistently carried out between 1200 and 1300 in order that the effects of treatment could be observed during the day (light phase:0700 to 1900) and night (dark phase: 1900 and 0700) cycles.

Both core body temperature and activity were significantly higher in the dark phase than the light phase (2-way ANOVA, P<0.001, n = 5) for all treatment groups; however neither TCS5861528 nor HC030031 had a significant effect on core body temperature or activity during either day or night cycles (vs baseline; 2-way ANOVA, P>0.05, n = 5).

Thus, to conclude, the TRPA1 antagonists used in these studies do not have an effect on core body temperature. This may be that TRPA1 does not play a role in basal control of thermoregulation, or that TCS5861528 and HC030031, like SB366791, do not block the precise mechanism involved in temperature adaptation.

Eid et al. (2008) Mol Pain, 4:48

Fernandes et al. (2011) Inflamm. Res. 60 (Suppl 1):S205

Steiner et al. (2007) J Neurosci, 27:7459-68.

Wei et al. (2011) Pain, 152(3):582-91