Inhibition of Inflammation-Induced Thermal Hypersensitivity by Sumatriptan through Activation of 5-HT1B/1D Receptors

Abstract

Migraine is effectively treated by drugs acting via 5-HT1B/1D receptors; however, the antinociceptive effects of such agents have not been fully investigated, particularly in models in which sensitization may be present. The aim of these studies was to evaluate the effects of the 5-HT1B/1D receptor agonist sumatriptan in specific models of pain states: a mouse model of inflammation-induced thermal hyperalgesia and a rat model of nerve injury-induced thermal hyperalgesia. In female mice, following intraplantar injection of carrageenan 225 min earlier, sumatriptan (300 μg/kg intraperitoneally; ip) increased paw withdrawal latency (PWL) from 3.1 ± 0.4 s in the saline group to 5.6 ± 0.9 s, measured 240 min postcarrageenan (P < 0.05 ANOVA followed by post hoc Dunnett's test). A similar effect was seen in male mice. Sumatriptan was also effective in male mice when given ip and subcutaneously 15 min precarrageenan, with a maximum effect at 30 μg/kg (ip latency 7.4 ± 1.3 s compared to saline group, 2.6 ± 0.7 s; iv latency 5.9 ± 0.8 s compared to saline group, 2.9 ± 0.3 s; P < 0.05 ANOVA followed by post hoc Dunnett's test). The number of mice required to give a response that could be reliably attributed to sumatriptan (number needed to treat) was calculated using discriminant analysis and found to be 2.6. The ability of sumatriptan to attenuate the carrageenan-induced reduction in PWL was blocked by the mixed 5-HT1B/1D receptor antagonist GR-127935 (3 mg/kg ip) but not by the 5-HT1B receptor antagonist SB-224289 (10 mg/kg ip). Sumatriptan had no effect on thermal hyperalgesia induced by sciatic nerve ligation in the rat at any time point. These data demonstrate that sumatriptan attenuates the hypersensitivity to noxious thermal stimuli induced by intraplantar carrageenan.