Mechanisms of imidazoline I-2 receptor agonist-induced antinociception in rats

Abstract

BACKGROUND AND PURPOSEAlthough the antinociceptive efficacies of imidazoline I-2 receptor agonists have been established, the exact post-receptor mechanisms remain unknown. This study tested the hypothesis that monoaminergic transmission is critical for I-2 receptor agonist-induced antinociception.EXPERIMENTAL APPROACHvon Frey filaments were used to assess antinociceptive effects of two I-2 receptor agonists, 2-BFI and CR4056 on chronic constriction injury (CCI)-induced neuropathic pain or complete Freund's adjuvant (CFA)-induced inflammatory pain in rats. Rectal temperature was measured to assess hypothermic effects of 2-BFI. A two-lever drug discrimination paradigm in which rats were trained to discriminate 5.6 mg.kg(-1) 2-BFI (i.p.) from its vehicle was used to examine the discriminative stimulus effects of 2-BFI. In each experiment, pharmacological mechanisms were investigated by combining 2-BFI or CR4056 with various pharmacological manipulations of the monoaminergic system including selective reuptake inhibition, monoamine depletion and monoamine receptor antagonism.KEY RESULTSIn the CCI model, selective reuptake inhibitors of 5-HT (fluoxetine) or noradrenaline (desipramine), but not dopamine (GBR12909), enhanced 2-BFI-induced antinociception. Selective depletion of 5-HT or noradrenaline almost abolished 2-BFI-induced antinociception. 5-HT1A, 5-HT2A and (alpha 1)-adrenoceptor antagonists, but not other monoaminergic antagonists, attenuated 2-BFI and CR4056-induced antinociception in CCI and/or CFA models. However, none of these monoamine receptor antagonists significantly altered 2-BFI-induced hypothermia or discriminative stimulus effects.CONCLUSIONS AND IMPLICATIONSAntinociception induced by I-2 receptor agonists was mediated by serotonergic and noradrenergic mechanisms with 5-HT1A, 5-HT2A and (alpha 1)-adrenoceptor being particularly important. In contrast, the hypothermic and discriminative stimulus effects of I-2 receptor agonists were mediated by distinct, independent mechanisms.