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.

Figure 1

Percentage of the maximum possible effects (%MPE) of fluoxetine (A, n = 6), desipramine (B, n = 5) or GBR12909 (C, n = 5) or 2‐BFI alone and in combination with fluoxetine (D), desipramine (E) or GBR12909 (F), on CCI‐induced mechanical nociception. Data shown are means ± SEM.

Figure 2

Percentage of the maximum possible effects (%MPE) of 2‐BFI on CCI‐induced mechanical nociception before and after treatment with pCPA and fenfluramine (A, n = 6) or DSP‐4 (B, n = 6). Data shown are means ± SEM.

Figure 3

Percentage of the maximum possible effects (%MPE) of 2‐BFI alone and in combination with WAY100635 (A, n = 6), MDL100907 (B, n = 5), SB242084 (C, n = 6), WB4101 (D, n = 5), yohimbine (E, n = 6), SCH23390 (F, n = 6) or raclopride (G, n = 6) on CCI‐induced mechanical nociception. Data shown are means ± SEM.

Figure 4

Percentage of the maximum possible effects (%MPE) of CR4056 alone and in combination with WAY100635 (A, n = 6), MDL100907 (B, n = 5), SB242084 (C, n = 6), WB4101 (D, n = 6), yohimbine (E, n = 5), SCH23390 (F, n = 5) or raclopride (G, n = 5) on CCI‐induced mechanical nociception. Data shown are means ± SEM.

Figure 5

Percentage of the maximum possible effects (%MPE) of 2‐BFI alone and in combination with WAY100635 (A, n = 6), MDL100907 (B, n = 6), SB242084 (C, n = 6), WB4101 (D, n = 6), yohimbine (E, n = 5), SCH23390 (F, n = 6) or raclopride (G, n = 6) on CFA‐induced mechanical nociception. Data shown are means ± SEM.

Figure 6

Hypothermic effects of 2‐BFI alone and in combination with WAY100635 (A, n = 6), MDL100907 (B, n = 6), SB242084 (C, n = 6), WB4101 (D, n = 7), SCH23390 (E, n = 7) or raclopride (F, n = 6). Data shown are means ± SEM of body temperature change from baseline.

Figure 7

Discriminative stimulus effects of 2‐BFI alone or in combination with WAY100635 (A), MDL100907 (B), SB242084 (C), WB4101 (D), yohimbine (E), raclopride (F) or SCH23390 (G) in rats discriminating 5.6 mg·kg⁻¹ 2‐BFI from its vehicle (n = 7). Upper graphs: substitution profiles of 2‐BFI or drug combinations. Data shown are means ± SEM of percentage of 2‐BFI‐appropriate lever responding. Lower graphs: response rate. Data shown are means ± SEM of the response rate (responses·s⁻¹). Shaded symbols are significantly different (P < 0.05) from 2‐BFI alone.

Figure 8

Discriminative stimulus effects of fluoxetine, desipramine, imipramine or GBR12909 alone (A) or 2‐BFI alone or in combination with fluoxetine (B), desipramine (C), imipramine (D) or GBR12909 (E) in rats discriminating 5.6 mg·kg⁻¹ 2‐BFI from its vehicle (n = 7). Upper graphs: substitution profiles of drugs or drug combinations. Data shown are means ± SEM of percentage of 2‐BFI‐appropriate lever responding. Lower graphs: response rate. Data shown are means ± SEM response rate (responses·s⁻¹). Shaded symbols are significantly different (P < 0.05) from vehicle (A) or 2‐BFI alone (B–E).

Figure 9

Diagram describing the probable mechanism of action of I₂ receptor agonists. Under normal conditions, monoamines such as 5‐HT and noradrenaline undergo reuptake and are metabolized by MAO enzymes (solid arrow). Administration of I₂ receptor agonists, and I₂ receptor activation, inhibits MAO activity and allows monoamine neurotransmitters to be repackaged, increasing their synaptic concentration (dashed arrows). The corresponding increased activation of certain downstream monoaminergic receptors (i.e. 5‐HT_1A, 5‐HT_2A and α₁‐adrenoceptors) leads to the production of analgesia.