Effects of the Transient Receptor Potential Vanilloid 1 receptor antagonist, SB366791, in thermal nociception and hyperalgesia

Khadija Alawi, Julie Keeble. King’s College London, London, United Kingdom.

The Transient Receptor Potential Vanilloid 1 (TRPV1) receptor is expressed predominantly on sensory nerve fibres and is activated by a variety of noxious stimuli including heat >43°C, protons and various inflammatory mediators. Therein, TRPV1 plays an integral role in the pain response. The current study aimed to determine the anti-nociceptive effect of the TRPV1 antagonist, SB366791 (Gunthorpe et al., 2004), in the mouse hind paw when administered via different routes and to subsequently determine the effect of this compound in carrageenan and lipopolysaccharide (LPS) -induced hind paw hyperalgesia.

Female, CD1 mice (Charles River, UK) were used for all experiments in accordance with the Scientific Procedures Act 1986. Mice were injected i.pl. with either the TRPV1 antagonist, SB366791 (2.5 μg), or vehicle (2% DMSO in 0.9% saline) into the ipsilateral paw while the contralateral paw was uninjected. Separate mice were injected i.p. with SB366791 (0.5 mg/kg) or vehicle (10 ml/kg). Thermal nociceptive responses in both paws were measured 30 min, 2 h and 4 h after injection of SB366791 or vehicle using the Hargreaves test. In subsequent experiments, carageenan (100 μg) or vehicle (saline) was either co-injected with SB336791 or vehicle i.pl. or, in animals treated i.p. with SB366791 or vehicle, carrageenan (100 μg) was injected i.pl. immediately after drug treatment. In further experiments, LPS (25 μg) or vehicle (saline) was injected in place of carrageenan. The maximum total volume injected i.pl. was 50 μl. Thermal nociceptive thresholds were measured at 2 h and 4 h after carrageenan; 1 h and 2 h after LPS.

Results show that i.pl. injection of SB366791 produced a significant (p<0.001) increase in the thermal nociceptive threshold within 30 min of administration. This anti-nociceptive effect was maintained for at least 4 h. SB366791 also caused a similar increase in the thermal nociceptive threshold when administered via the i.p. route (p<0.001) although a significant effect was not observed until 2 h. Both LPS and carrageenan cause a significant hyperalgesia (p<0.001) of the mouse hind paw at 1 and 2 h for LPS and 2 h and 4 h for carrageenan. Co-injection of LPS or carrageenan with SB366791 did not abolish thermal hyperalgesia at any time point. A similar profile of results was seen after i.p. injection of SB366791. All data was compared by ANOVA, n = 5-6 for each group.

In conclusion, this study has shown that doses of SB366791 that produce a significant anti-nociceptive effect against a thermal nociceptive do not prevent either carrageenan- or LPS-induced hyperalgesia in mice. In contrast, we have previously shown that TRPV1 receptor knockout mice do not exhibit carrageenan-induced thermal hyperalgesia of the hind paw (Keeble et al., 2005). It will be interesting to determine the effect of higher doses of the TRPV1 antagonist and results in TRPV1 knockout mice.

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Keeble et al. (2005). Arthritis Rheum. 52, 3248-3256.
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JK is funded by a Capacity Building Award in Integrative Mammalian Biology funded by the BBSRC, BPS, HEFCE, KTN, MRC and SFC.