Mechanisms of imidazoline I₂ receptor agonist-induced antinociception in rats: involvement of monoaminergic neurotransmission.

ABSTRACT:

Background and purpose

Although the antinociceptive efficacies of imidazoline I₂ receptor agonists have been established, the exact post-receptor mechanisms remain unknown. This study tested the hypothesis that monoaminergic transmission is critical for I₂ receptor agonist-induced antinociception.

Experimental approach

von Frey filaments were used to assess antinociceptive effects of two I₂ 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 results

In 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-HT_1A , 5-HT_2A and α₁ -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 implications

Antinociception induced by I₂ receptor agonists was mediated by serotonergic and noradrenergic mechanisms with 5-HT_1A , 5-HT_2A and α₁ -adrenoceptor being particularly important. In contrast, the hypothermic and discriminative stimulus effects of I₂ receptor agonists were mediated by distinct, independent mechanisms.

SUBMITTER: Siemian JN 

PROVIDER: S-EPMC5900992 | biostudies-literature |

REPOSITORIES: biostudies-literature