Involvement of I2-imidazoline binding sites in positive and negative morphine analgesia modulatory effects

Gentili, Francesco; Cardinaletti, Claudia; Carrieri, Antonio; Ghelfi, Francesca; Mattioli, Laura; Perfumi, Marina; Vesprini, Cristian; Pigini, Maria

doi:10.1016/j.ejphar.2006.09.031

Cited by 34 publications

(44 citation statements)

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“…These findings suggest that BU224 may be a low efficacy I 2 receptor agonist, although other mechanisms cannot be ruled out under certain conditions (Min et al, 2013). Phenyzoline, 4,5-dihidro-2-(2-phenylethyl)-1H-imidazole, is a recently described selective I 2 receptor ligand, which shows remarkable receptor binding selectivity for I 2 receptors over I 1 and α 2 adrenoceptors (Gentili et al, 2006). Our receptor binding screening results confirmed its pharmacological selectivity (Table 1).…”

Section: Introductionmentioning

confidence: 99%

“…Our receptor binding screening results confirmed its pharmacological selectivity (Table 1). Functionally, phenyzoline increases morphine-induced antinociception and produces hypothermia, and both of the effects are mediated through I 2 receptors (Gentili et al, 2006; Thorn et al, 2012). These results suggest that phenyzoline may have higher efficacy than BU224 on I 2 receptors.…”

Section: Introductionmentioning

confidence: 99%

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Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats

Qiu

Zhang

2015

European Journal of Pharmacology

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Although imidazoline I2 receptor ligands have been used as discriminative stimuli, the role of efficacy of I2 receptor ligands as a critical determinant in drug discrimination has not been explored. This study characterized the discriminative stimulus effects of selective imidazoline I2 receptor ligands BU224 (a low-efficacy I2 receptor ligand) and phenyzoline (a higher efficacy I2 receptor ligand) in rats. Two groups of male Sprague-Dawley rats were trained to discriminate 5.6 mg/kg BU224 or 32 mg/kg phenyzoline (i.p.) from their vehicle in a two-lever food-reinforced drug discrimination procedure, respectively. All rats acquired the discriminations after an average of 18 (BU224) and 56 (phenyzoline) training sessions, respectively. BU224 and phenyzoline completely substituted for one another symmetrically. Several I2 receptor ligands (tracizoline, CR4056, RS45041, and idazoxan) all occasioned > 80% drug-associated lever responding in both discriminations. The I2 receptor ligand 2-BFI and a monoamine oxidase inhibitor harmane occasioned > 80% drug-associated lever responding in rats discriminating BU224. Other drugs that occasioned partial or less substitution to BU224 cue included clonidine, methamphetamine, ketamine, morphine, methadone and agmatine. Clonidine, methamphetamine and morphine also only produced partial substitution to phenyzoline cue. Naltrexone, dopamine D2 receptor antagonist haloperidol and serotonin (5-HT) 2A receptor antagonist MDL100907 failed to alter the discriminative stimulus effects of BU224 or phenyzoline. Combined, these results are the first to demonstrate that BU224 and phenyzoline can serve as discriminative stimuli and that the low-efficacy I2 receptor ligand BU224 shares similar discriminative stimulus effects with higher-efficacy I2 receptor ligands such as phenyzoline and 2-BFI.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats

Qiu

Zhang

2015

European Journal of Pharmacology

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“…2-BFI also enhances the antinociceptive effects of opioids through I 2 receptor agonism [11]. Phenyzoline has B800-fold selectivity and diphenyzoline has 45-fold selectivity at I 2 receptors over a 2 adrenoceptors and their effects in modulating morphine antinociception are mediated by I 2 receptors [10]. BU224 has more than 1000-fold selectivity for I 2 receptors over a 2 adrenoceptors and is a lowefficacy I 2 receptor agonist [21].…”

Section: Discussionmentioning

confidence: 98%

“…It is worth noting that when studying the effects of I 2 receptor ligands for acute phasic pain, all previous studies used highly intense noxious stimuli (e.g. radiant heat or Z 501C water) [8,10,11]. Thus, it is possible that I 2 receptor ligands indeed have weak antinociceptive effects for acute phasic pain, and that previous negative findings are due to the high-intensity painful stimuli used.…”

Section: Introductionmentioning

confidence: 95%

“…Interestingly, although I 2 receptor ligands alone are generally inactive in animal models of acute phasic pain, they consistently enhance the antinociceptive effects of opioids [8][9][10][11]. It is worth noting that when studying the effects of I 2 receptor ligands for acute phasic pain, all previous studies used highly intense noxious stimuli (e.g.…”

Section: Introductionmentioning

confidence: 98%

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Effects of imidazoline I2 receptor ligands on acute nociception in rats

et al. 2012

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This study examined the antinociceptive effects of seven imidazoline I2 receptor ligands in a rat warm water tail withdrawal procedure (46 and 50 °C). Agmatine, 2-BFI, phenyzoline, and diphenyzoline produced a significant antinociceptive activity at 46 °C. BU224, S22687, and idazoxan had no effect at 46 °C up to doses that altered the locomotor activity. None of the drugs showed antinociceptive activity at 50 °C. It is suggested that I2 receptor agonists have antinociceptive activity for acute phasic pain under weak noxious stimulus, and the effects are efficacy-dependent. These data explain the findings that I2 receptor agonists enhance the antinociceptive effects of opioids and support developing higher-efficacy I2 receptor agonists for the treatment of pain.

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The Versatile 2‐Substituted Imidazoline Nucleus as a Structural Motif of Ligands Directed to the Serotonin 5‐HT_1A Receptor

et al. 2016

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The involvement of the serotonin 5‐HT1A receptor (5‐HT1A‐R) in the antidepressant effect of allyphenyline and its analogues indicates that ligands bearing the 2‐substituted imidazoline nucleus as a structural motif interact with 5‐HT1A‐R. Therefore, we examined the 5‐HT1A‐R profile of several imidazoline molecules endowed with a common scaffold consisting of an aromatic moiety linked to the 2‐position of an imidazoline nucleus by a biatomic bridge. Our aim was to discover other ligands targeting 5‐HT1A‐R and to identify the structural features favoring 5‐HT1A‐R interaction. Structure–activity relationships, supported by modeling studies, suggested that some structural cliché such as a polar function and a methyl group in the bridge, as well as proper steric hindrance in the aromatic area of the above scaffold, favored 5‐HT1A‐R recognition and activation. We also highlighted the potent antidepressant‐like effect (mouse forced swimming test) of (S)‐(+)‐19 [(S)‐(+)‐naphtyline] at very low dose (0.01 mg kg−1). This effect was clearly mediated by 5‐HT1A, as it was significantly reduced by pretreatment with the 5‐HT1A antagonist WAY100635.

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Involvement of I2-imidazoline binding sites in positive and negative morphine analgesia modulatory effects

Cited by 34 publications

References 42 publications

Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats

Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats

Effects of imidazoline I2 receptor ligands on acute nociception in rats

The Versatile 2‐Substituted Imidazoline Nucleus as a Structural Motif of Ligands Directed to the Serotonin 5‐HT_1A Receptor

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Involvement of I2-imidazoline binding sites in positive and negative morphine analgesia modulatory effects

Cited by 34 publications

References 42 publications

Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats

Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats

Effects of imidazoline I2 receptor ligands on acute nociception in rats

The Versatile 2‐Substituted Imidazoline Nucleus as a Structural Motif of Ligands Directed to the Serotonin 5‐HT1A Receptor

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The Versatile 2‐Substituted Imidazoline Nucleus as a Structural Motif of Ligands Directed to the Serotonin 5‐HT_1A Receptor