Assessment of 5-HT7Receptor Agonists Selectivity Using Nociceptive and Thermoregulation Tests in Knockout versus Wild-Type Mice

Alex Brenchat,Daniel Zamanillo,Maria Rocasalbas,Michel Hamon,Luz Romero,José Miguel Vela

doi:10.1155/2012/312041

Abstract

No study has ever examined the effect of 5-HT7 receptor agonists on nociception by using 5-HT7 receptor knockout mice. Basal sensitivity to noxious heat stimuli and formalin-induced nociception in both phase I and II of the formalin test did not differ in 5-HT7 receptor knockout mice and paired wild-type controls. Similarly, there was no significant difference in basal body temperature between both genotypes. Subcutaneous administration of 5-HT7 receptor agonists AS-19 (10 mg/kg), E-57431 (10 mg/kg), and E-55888 (20 mg/kg) significantly reduced formalin-induced licking/biting behavior during the phase II of the test in wild-type but not in 5-HT7 receptor knockout mice. At these active analgesic doses, none of the three 5-HT7 receptor agonists modified the basal body temperature neither in wild-type nor in 5-HT7 receptor knockout mice. However, a significant decrease in body temperature was observed at a higher dose (20 mg/kg) of AS-19 and E-57431 in both genotypes. Our data strongly suggest that the 5-HT7 receptor agonists AS-19, E-57431, and E-55888 produce antinociception in the formalin test by activating 5-HT7 receptors. These results also strengthen the idea that the 5-HT7 receptor plays a role in thermoregulation, but by acting in concert with other receptors.

Highlights

The 5-HT7 receptor has been cloned from different genomes and its binding profile is consistent across species and between cloned and native receptors [1, 2]
Our data strongly suggest that the 5-HT7 receptor agonists AS-19, E-57431, and E-55888 produce antinociception in the formalin test by activating 5-HT7 receptors
To further assess the in vivo specificity of the 5-HT7 receptor agonists used in this study, we examined in 5-HT7 receptor knockout mice, the effects of the 5-HT7 receptor agonists AS-19, E-57431, and E-55888 on both formalininduced nociception and body temperature

Summary

Introduction

The 5-HT7 receptor has been cloned from different genomes and its binding profile is consistent across species and between cloned and native receptors [1, 2]. Considerable efforts have focused on the development of selective 5-HT7 receptor agonists and antagonists. Regarding 5-HT7 receptor agonists, AS-19 [8, 9], MSD-5a [10], LP-44 [11], LP-211 [12], E-55888 [13], and E-57431 [14] have been developed Most of these agonists display rather modest selectivity because their affinity for the 5-HT7 type is only 11fold higher than for 5-HT1D in case of AS-19 [13], 28.6-fold higher than for 5-HT1A in case of MSD-5a [10], and 33-fold higher than for dopamine D2 receptor [15], and 5-14-fold higher than for 5-HT1B, 5-HT2B, 5-HT2C, and 5-HT5A in case of LP-211 [16].

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Conclusion