RATIONALERecent research has established the imidazoline I₂ receptor as a promising target for the development of novel analgesics. However, despite an increasing understanding of imidazoline I₂ receptor-mediated behavioral effects, little is known about post-I₂-receptor signaling mechanisms.OBJECTIVEThis study examined the effects of several inhibitors of Ca²⁺ signaling mechanisms on two behavioral effects of the prototypical imidazoline I₂ receptor ligand 2-(2-benzofuranyl)-2-imidazoline (2-BFI).METHODSThe von Frey filament test was used to examine the antinociceptive effects of 2-BFI in complete Freund's adjuvant (CFA)-induced inflammatory pain in rats. A two-lever drug discrimination paradigm in which rats were trained to discriminate 5.6 mg/kg (intraperitoneally) 2-BFI from its vehicle was used to examine the discriminative stimulus effects of 2-BFI.RESULTSThe L-type Ca²⁺ channel blockers verapamil and nimodipine, the calmodulin antagonist W-7, and the internal Ca²⁺ release inhibitor ryanodine all attenuated the antinociceptive effects of 2-BFI. Oxycodone- and acetaminophen-induced antinociception was unaffected by pretreatment with the Ca²⁺ channel blockers. Rats learned to reliably discriminate 5.6 mg/kg 2-BFI from saline. The I₂ receptor agonists BU224, RS45041, tracizoline, and CR4056 all fully substituted for 5.6 mg/kg 2-BFI while idazoxan, S22687, 2,5-dimethoxy-4-methylamphetamine (DOM), and phenyzoline produced partial or no substitution. Verapamil, nimodipine, and W-7 did not alter the discriminative stimulus effects of 2-BFI.CONCLUSIONThese results indicate that the antinociceptive effects of 2-BFI involve intracellular Ca²⁺ elevation and/or downstream Ca²⁺/calmodulin signaling, whereas the discriminative stimulus effects of 2-BFI are mediated by a distinct, independent mechanism.

01 Jul 2012·British Journal of Pharmacology

Characterization of the hypothermic effects of imidazoline I₂receptor agonists in rats

Article

Author: An, Xiao-Fei ; Zhang, Yanan ; Pigini, Maria ; Li, Jun-Xu ; Thorn, David A.

BACKGROUND AND PURPOSEImidazoline I2receptors have been implicated in several CNS disorders. Although several I2receptor agonists have been described, no simple and sensitivein vivobioassay is available for studying I2receptor ligands. This study examined I2receptor agonist‐induced hypothermia as a functionalin vivoassay of I2receptor agonism.EXPERIMENTAL APPROACHDifferent groups of rats were used to examine the effects of I2receptor agonists on the rectal temperature and locomotion. The pharmacological mechanisms were investigated by combining I2receptor ligands and different antagonists.KEY RESULTSAll the selective I2receptor 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 I2receptor agonists (2‐BFI, BU224, tracizoline and diphenyzoline) with imidazoline I2receptor/ α2adrenoceptor antagonist idazoxan, selective I1receptor antagonist efaroxan, α2adrenoceptor antagonist/5‐HT1Areceptor agonist yohimbine. Idazoxan but not yohimbine or efaroxan attenuated the hypothermic effects of 2‐BFI, BU224, tracizoline and diphenyzoline, supporting the I2receptor mechanism. In contrast, both idazoxan and yohimbine attenuated hypothermia induced by the α2adrenoceptor agonist clonidine. Among all the I2receptor agonists studied, only S22687 markedly increased the locomotor activity in rats.CONCLUSIONS AND IMPLICATIONSImidazoline I2receptor agonists can produce hypothermic effects, which are primarily mediated by I2receptors. These data suggest that I2receptor agonist‐induced hypothermia is a simple and sensitivein vivoassay for studying I2receptor ligands.

25 Jan 2012·NeuroReportQ4 · MEDICINE

Effects of imidazoline I2 receptor ligands on acute nociception in rats

Q4 · MEDICINE

Article

Author: Del Bello, Fabio ; Sampson, Cristal ; Li, Jun-Xu ; Zhang, Yanan

This study examined the antinociceptive effects of seven imidazoline I2 receptor ligands in a rat warm water tail withdrawal procedure (46 and 50 °C). Agmatine, 2-BFI, phenyzoline, and diphenyzoline produced a significant antinociceptive activity at 46 °C. BU224, S22687, and idazoxan had no effect at 46 °C up to doses that altered the locomotor activity. None of the drugs showed antinociceptive activity at 50 °C. It is suggested that I2 receptor agonists have antinociceptive activity for acute phasic pain under weak noxious stimulus, and the effects are efficacy-dependent. These data explain the findings that I2 receptor agonists enhance the antinociceptive effects of opioids and support developing higher-efficacy I2 receptor agonists for the treatment of pain.

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Indication	Highest Phase	Country/Location	Organization	Date
Pain	Discovery	France	Servier Pharmaceuticals LLC	-

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