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 ₂receptor 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.