Characterization of the hypothermic effects of imidazoline I 2 receptor agonists in rats

BACKGROUND AND PURPOSE Imidazoline I 2 receptors have been implicated in several CNS disorders. Although several I 2 receptor agonists have been described, no simple and sensitive in vivo bioassay is available for studying I 2 receptor ligands. This study examined I 2 receptor agonist‐induced hypothermia as a functional in vivo assay of I 2 receptor agonism. EXPERIMENTAL APPROACH Different groups of rats were used to examine the effects of I 2 receptor agonists on the rectal temperature and locomotion. The pharmacological mechanisms were investigated by combining I 2 receptor ligands and different antagonists. KEY RESULTS All the selective I 2 receptor agonists examined (2‐BFI, diphenyzoline, phenyzoline, CR4056, tracizoline, BU224 and S22687, 3.2–56 mg·kg –1 , i.p.) dose‐dependently and markedly decreased the rectal temperature (hypothermia) in rats, with varied duration of action. Pharmacological mechanism of the observed hypothermia was studied by combining the I 2 receptor agonists (2‐BFI, BU224, tracizoline and diphenyzoline) with imidazoline I 2 receptor/ α 2 adrenoceptor antagonist idazoxan, selective I 1 receptor antagonist efaroxan, α 2 adrenoceptor antagonist/5‐HT 1A receptor agonist yohimbine. Idazoxan but not yohimbine or efaroxan attenuated the hypothermic effects of 2‐BFI, BU224, tracizoline and diphenyzoline, supporting the I 2 receptor mechanism. In contrast, both idazoxan and yohimbine attenuated hypothermia induced by the α 2 adrenoceptor agonist clonidine. Among all the I 2 receptor agonists studied, only S22687 markedly increased the locomotor activity in rats. CONCLUSIONS AND IMPLICATIONS Imidazoline I 2 receptor agonists can produce hypothermic effects, which are primarily mediated by I 2 receptors. These data suggest that I 2 receptor agonist‐induced hypothermia is a simple and sensitive in vivo assay for studying I 2 receptor ligands.