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Mechanisms of imidazoline I 2 receptor agonist‐induced antinociception in rats: involvement of monoaminergic neurotransmission
Author(s) -
Siemian Justin N,
Wang Kaixuan,
Zhang Yanan,
Li JunXu
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14161
Subject(s) - monoaminergic , pharmacology , agonist , reboxetine , desipramine , chemistry , serotonergic , dopamine , serotonin , receptor , medicine , endocrinology , reuptake inhibitor , antidepressant , hippocampus
Background and Purpose Although 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 Approach von 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 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 α 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 Implications Antinociception induced by I 2 receptor agonists was mediated by serotonergic and noradrenergic mechanisms with 5‐HT 1A , 5‐HT 2A and α 1 ‐adrenoceptor being particularly important. In contrast, the hypothermic and discriminative stimulus effects of I 2 receptor agonists were mediated by distinct, independent mechanisms.