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. 1. 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]. In recent years, considerable efforts have focused on the development of selective 5-HT7 receptor agonists and antagonists. To date, the search for 5-HT7 receptor antagonists has led to the discovery of LY215840 [3], SB-258719 [4], DR4004 [5], SB-269970 [6], and SB-656104-A [7]. 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. However, most of these agonists display rather modest selectivity because their affinity for the 5-HT7 type is only 11-fold 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]. Indeed, among 5-HT7 receptor agonists, only E-55888 and E-57431 seem to have a satisfactory selectivity with affinity for the 5-HT7 receptor 280-fold higher than for 5-HT1A and 112.7-fold higher than for 5-HT1D, respectively [13] (see Table 1). When tested in a functional assay, 5-HT7 receptor agonists concentration dependently increased cAMP
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