Efficacy of the TRPV1 antagonist SB-705498 in an MRI guinea pig model of rhinitis

Rationale: Antagonism of nasal TRPV1 receptors is a potential target for inhibition of symptoms associated with rhinitis. Here, we explore the pharmacology of SB-705498 on the contralateral nasal secretory response to ipsilateral nasal capsaicin challenge in the guinea pig. Methods: Experiments were conducted on intranasally sensitised guinea pigs. Absolute nasal fluid volumes were measured using MRI techniques that provide images of the total nasal cavity of the guinea pig. Animals were pre-treated with SB-705498 or vehicle (-1, -6 and -24h) and MRI scanned to produce first a baseline measurement and then a further measurement at 10 minutes post capsaicin challenge (0.3mM; 50ul). Results: 1 hour pre-treatment with SB-705498 resulted in approximately 50% inhibition of the secretory response at 10mg/kg (oral; p<0.05), 1mg/kg (intranasal suspension; p<0.005) and 0.1mg/kg (intranasal particle reduced suspension; p<0.0005). At 12 hour pre-treatment, approximately 60% inhibition (p < 0.0001) was observed with SB-705498 at 1mg/kg (intranasal particle reduced suspension); at 24h this had reduced to ∼50% inhibition (p<0.01). Conclusion: These studies demonstrate that SB-705498 inhibits capsaicin-induced intranasal parasympathetic responses in guinea pig. Topical application of SB-705498 was associated with a approximately 10-fold reduction in total dose compared with oral administration. In addition, particle reduction of SB-705498 was associated with a further improvement in intranasal potency.