Mechanisms of imidazoline I-2 receptor agonist-induced antinociception in rats
Siemian, J. N., Wang, K., Zhang, Y., & Li, J-X. (2018). Mechanisms of imidazoline I-2 receptor agonist-induced antinociception in rats: Involvement of monoaminergic neurotransmission. British Journal of Pharmacology, 175(9), 1519-1534. DOI: 10.1111/bph.14161
BACKGROUND AND PURPOSE: Although studies have established the antinociceptive efficacies of imidazoline I2receptor (I2R) agonists, its exact post-receptor mechanism remains unknown. This study tested the hypothesis that monoaminergic transmission is critical for I2R agonist-induced antinociception.
EXPERIMENTAL APPROACH: The von Frey filament test was used to examine the antinociceptive effects of the I2R 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 measurement was used to investigate the hypothermic effects of 2-BFI. A two-lever drug discrimination paradigm in which rats were trained to discriminate 5.6 mg/kg 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 RESULTS: In CCI model, selective reuptake inhibitors of serotonin (fluoxetine) and norepinephrine (desipramine) but not dopamine (GBR12909) enhanced 2-BFI-induced antinociception. Selective depletion of serotonin or norephinephrine nearly abolished 2-BFI-induced antinociception. 5-HT1A, 5-HT2A, and α1-adrenergic receptor antagonists but not other monoaminergic antagonists attenuated 2-BFI and CR4056-induced antinociception in CCI and/or CFA models. In contrast, none of these monoamine receptor antagonists significantly altered 2-BFI-induced hypothermia or discriminative stimulus effects.
CONCLUSIONS AND IMPLICATIONS: I2R agonist-induced antinociception is mediated by serotonergic and noradrenergic mechanisms with 5-HT1A, 5-HT2A, and α1-adrenergic receptors being particularly important. In contrast, the hypothermic and discriminative stimulus effects of I2R agonists are mediated by distinct, independent mechanisms.