Characterization of the hypothermic effects of imidazoline I₂ receptor agonists in rats

Abstract

BACKGROUND AND PURPOSEImidazoline I2 receptors have been implicated in several CNS disorders. Although several I2 receptor agonists have been described, no simple and sensitive in vivo bioassay is available for studying I2 receptor ligands. This study examined I2 receptor agonist-induced hypothermia as a functional in vivo assay of I2 receptor agonism. EXPERIMENTAL APPROACHDifferent groups of rats were used to examine the effects of I2 receptor agonists on the rectal temperature and locomotion. The pharmacological mechanisms were investigated by combining I2 receptor ligands and different antagonists. KEY RESULTSAll the selective I2 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 I2 receptor agonists (2-BFI, BU224, tracizoline and diphenyzoline) with imidazoline I2 receptor/ a2 adrenoceptor antagonist idazoxan, selective I1 receptor antagonist efaroxan, a2 adrenoceptor antagonist/5-HT1A receptor agonist yohimbine. Idazoxan but not yohimbine or efaroxan attenuated the hypothermic effects of 2-BFI, BU224, tracizoline and diphenyzoline, supporting the I2 receptor mechanism. In contrast, both idazoxan and yohimbine attenuated hypothermia induced by the a2 adrenoceptor agonist clonidine. Among all the I2 receptor agonists studied, only S22687 markedly increased the locomotor activity in rats. CONCLUSIONS AND IMPLICATIONSImidazoline I2 receptor agonists can produce hypothermic effects, which are primarily mediated by I2 receptors. These data suggest that I2 receptor agonist-induced hypothermia is a simple and sensitive in vivo assay for studying I2 receptor ligands. Abbreviations

Inhibitory effects of imidazoline receptor ligands on basal and kainic acid-induced neurotoxic signalling in mice

“…Below: representative immunoblots for p-JNK and JNK in mouse HC after acute IR ligands. Note: efaroxan, moxonidine and idazoxan, but not LSL61122 (delayed hypothermic effects; seeThorn et al, 2012) significantly reduced the animal's rectal temperature at 60 minutes after administration (−1.1ºC to −1.7ºC, n=5; at least p<0.05); efaroxan, contrary to the data shown above, completely antagonised the moxonidine-induced hypothermia (p<0.05).…”

“…Garau et al, 2013;Haxhiu et al, 1994;Kim et al, 2011;Sánchez-Blázquez et al, 2000;Thorn et al, 2012), and efaroxan (I 1 -IR) and idazoxan (I 2 -IR) as IR antagonists to prevent the effects of moxonidine and LSL61122, respectively (e.g. see Cambridge and Robinson, 2005;Haxhiu et al, 1994;Sánchez-Blázquez et al, 2000).…”

Behavioral effects of the imidazoline I2 receptor ligand BU99006 in rats

“…While some drugs, such as idazoxan (Sanchez-Blazquez et al, 2000; Thorn et al, 2012; Tonello et al, 2012) and BU224 (Sanchez-Blazquez et al, 2000; Bhalla et al, 2013) have been shown to attenuate the effects of I 2 receptor agonists such as 2-BFI and CR4056, those compounds have also been shown to have agonist effects in some assays, suggesting that they have low efficacy at I 2 receptors. For example, both 2-BFI and BU224 increase rotational behaviors in rats with nigrostriatal lesions (MacInnes and Duty, 2004).…”

“…Although BU99006 binds selectively to I 2 receptors, its efficacy at these receptors has not been determined; however, to the extent that BU99006 has little or no efficacy, it might be a useful tool for selectively blocking other I 2 receptor ligands (Tyacke et al, 2002). This study examined the effects of BU99006, alone and in combination with I 2 receptor agonist 2-BFI, in two behavioral assays that are sensitive to I 2 receptor agonists, hypothermia and 2-BFI discrimination (Thorn et al, 2012; MacInnes and Handley, 2002). If BU99006 is an I 2 receptor antagonist, it is expected that it does not produce hypothermia or increase 2-BFI-associated lever responding as I 2 receptor agonists do (Thorn et al, 2012; MacInnes and Handley, 2002).…”

“…This study examined the effects of BU99006, alone and in combination with I 2 receptor agonist 2-BFI, in two behavioral assays that are sensitive to I 2 receptor agonists, hypothermia and 2-BFI discrimination (Thorn et al, 2012; MacInnes and Handley, 2002). If BU99006 is an I 2 receptor antagonist, it is expected that it does not produce hypothermia or increase 2-BFI-associated lever responding as I 2 receptor agonists do (Thorn et al, 2012; MacInnes and Handley, 2002). In contrast, it is expected that BU99006 should attenuate the effects of 2-BFI in these assays.…”