Effects of imidazoline I2 receptor agonists and morphine on schedule-controlled responding in rats

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Abstract

Accumulating evidence indicates that imidazoline I2 receptor agonists enhance the antinociceptive effects of opioids and therefore may be suitable for combination therapy with opioids for pain treatment. However, little is known of the effects of I2 receptor agonists on other behavioral effects of opioids. This study used schedule-controlled responding and dose-addition analyses to examine interactions between the μ opioid receptor agonist morphine and two imidazoline I2 receptor agonists, 2-BFI and BU224. In 8 rats responding under a fixed ratio 10 schedule of food presentation, morphine (3.2–17.8 mg/kg), 2-BFI (3.2–17.8 mg/kg), and BU224 (5.6–17.8 mg/kg) each dose-dependently decreased responding. The addition of fixed proportions of 2-BFI or BU224 shifted the morphine dose–effect curves leftward. The interactions between morphine and 2-BFI or BU224 were infra-additive when the same proportions of morphine and I2 receptor agonists were mixed; however, the interaction between morphine and I2 receptor agonists was additive when the drugs were mixed at other proportions. These results provide quantitative evidence that I2 receptor agonists do not enhance the response rate-decreasing effect of morphine and suggest that the enhancement of morphine antinociception is selective. Together, these results further support the therapeutic potential of combining I2 receptor agonists and opioids for pain control.

Highlights

► Imidazoline I2 receptor agonists decreased food-maintained responding. ► I2 receptor agonists and morphine produced additive or infra-additive interactions in decreasing food-maintained responding. ► The nature of the interaction depended on the proportions of morphine and I2 receptor agonists in the mixture. ► That I2 receptor agonists enhance the antinociceptive but not response-decreasing effects of morphine supports combining I2 agonists and morphine for pain treatment.

Introduction

Pain remains a global health care challenge and imparts significant economic cost to society. Opioids are the drugs of choice for many painful conditions, particularly moderate to severe pain. However, the clinical use of opioids comes with many untoward effects, including pruritus, physical dependence and constipation, which are especially problematic during repeated opioid use (Annemans, 2011). Combined, these untoward effects limit adequate treatment in a large population of pain patients, and novel strategies that retain the therapeutic (analgesic) activities with decreased untoward effects are welcome in the clinic.

First proposed as binding sites that recognize drugs with an imidazoline structure like the α2 adrenoceptor agonist and imidazoline ligand, clonidine (Bousquet et al., 1984), imidazoline receptors have now been recognized to include at least three subtypes: I1, I2 and I3 receptors (Eglen et al., 1998). Importantly, emerging evidence suggests that imidazoline I2 receptors may be involved in depression, opioid addiction and pain modulation (Garcia-Sevilla et al., 1999, Li and Zhang, 2011, Wu et al., 2008). For instance, I2 receptors have attracted increasing attention as a candidate drug target of analgesics (Li and Zhang, 2011). Preclinical studies have shown that the purported endogenous imidazoline receptor ligand, agmatine, and selective I2 receptor agonists such as 2-BFI and BU224 have significant antinociceptive effects for acute and persistent pains (Fairbanks et al., 2000, Li et al., 2011c, Sampson et al., 2012). Moreover, the selective I2 receptor agonist CR4056 demonstrated marked anti-hyperalgesic activity for inflammatory and neuropathic pain in rats and this compound is currently under Phase I clinical trial (Ferrari et al., 2011). When used in combination, agmatine and I2 receptor agonists such as 2-BFI, BU224 and CR4056 consistently increased the antinociceptive effects of the opioid morphine and the interaction was supra-additive (synergistic) (Ferrari et al., 2011, Li et al., 2011c, Thorn et al., 2011). These findings, combined with the fact that I2 receptor ligands markedly attenuate the development of tolerance to morphine antinociception (Boronat et al., 1998) and inhibit the physical withdrawal syndrome (Hudson et al., 1999), strongly support the notion of combining I2 receptor agonists and opioids for pain treatment (Li and Zhang, 2011).

Combination therapy is a valid strategy for clinical pain management (Raffa et al., 2010, Smith, 2008). The justification of combination therapy for pain treatment is that the combined drugs should either increase the therapeutic effects without simultaneously increasing the untoward effects, or retain the therapeutic effects but decrease the untoward effects, or a combination of both. Indeed, some drug combinations such as oxycodone and acetaminophen (Percocet®) have long been used clinically for pain control and others such as opioids and α2 adrenoceptor agonists have also shown promising utility (Andrieu et al., 2009). However, although I2 receptor agonists and morphine have demonstrated antinociceptive synergy (Ferrari et al., 2011, Li et al., 2011c, Thorn et al., 2011), no study has examined the interactions between selective I2 receptor ligands and opioids using other behavioral endpoints than antinociception. This is particularly important because a simultaneous enhancement of all the pharmacological (therapeutic and untoward) effects of opioids by I2 receptor ligands will not yield a useful combination therapy. Therefore, this study aimed to examine the effects of I2 receptor agonists and the opioid, morphine, alone or in combination, on food-maintained operant responding in rats. Food-maintained operant responding procedure was selected for this study because it is often used as reference readout to differentiate pharmacological specificity of analgesics (e.g., antinociception vs. general behavioral suppression) and because it generates highly replicable and quantitative data (Banks et al., 2010, Li et al., 2010, Stevenson et al., 2005).

Section snippets

Subjects

Eight adult male Sprague–Dawley rats (Harlan, Indianapolis, IN) weighing 250–275 g upon arrival were housed individually on a 12/12-h light/dark cycle (experiments conducted during the light period). Access to food was limited to 10 g/day for several days to facilitate lever press training. Thereafter body weights were allowed to increase at an age appropriate rate and then maintained at 340–350 g by providing standard rodent chow in the home cage after daily sessions. Rats had free access to

Results

The group average control response rates (± SEM) for the 6 cycles comprising a session were as follows: 0.81 ± 0.09, 0.84 ± 0.09, 0.83 ± 0.10, 0.86 ± 0.07, 0.84 ± 0.13 and 0.81 ± 0.12 responses/s. An acute injection of 2-BFI and BU224 dose-dependently decreased responding throughout the 6-cycle, 90-min session (Fig. 1). Two-way ANOVA revealed a main effect for time after injection (F [5, 140] = 14.30, P < 0.0001, 2-BFI; F [5, 140] = 3.28, P < 0.001, BU224), for dose (F [3, 140] = 34.49, P < 0.0001, 2-BFI; F [3, 140] = 

Discussion

The primary findings of the current study were that the compounds with high affinity for I2 receptors dose-dependently decreased food-maintained operant responding and, at certain proportions, produced infra-additive interactions with morphine in rats. Although more work is needed, these data suggest that I2 receptor agonists do not simultaneously increase all the behavioral effects of morphine. Rather, I2 receptor agonists have certain selectivity in increasing morphine antinociception.

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