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

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• 作者：Francesco Gentili ; Claudia Cardinaletti ; Antonio Carrieri ; Francesca Ghelfi ; Laura Mattioli ; Marina Perfumi ; Cristian Vesprini ; Maria Pigini
• 关键词：Morphine analgesia modulation ; I₂-IBS (I₂-imidazoline binding sites) ; I₂-IBS ligands ; Phenyzoline ; Diphenyzoline
• 刊名：European Journal of Pharmacology
• 出版年：2006
• 出版时间：28 December 2006
• 年：2006
• 卷：553
• 期：1-3
• 页码：73-81
• 全文大小：445 K

文摘

Some studies, suggesting the involvement of I₂-imidazoline binding sites (I₂-IBS) in morphine analgesia modulation, prompted us to examine on mice antinociceptive assays the effect produced by 1 (phenyzoline), that in view of its high I₂-IBS affinity and high I₂-IBS selectivity with regard to I₁-IBS, α₂-adrenoreceptors and μ-opioid receptors might be considered the first interesting I₂-IBS ligand. The study was also applied to its ortho phenyl derivative 2 (diphenyzoline), designed and prepared in order to produce a possible modification of the biological profile of 1. Diphenyzoline (2) retains a significant I₂-IBS selectivity with regard to I₁-IBS, α₂-adrenoreceptors and μ-opioid receptors. Moreover, by the functional assays 1 and 2 proved inactive at all α₂-adrenoreceptors subtypes up to 10^{− 3} M. As expected, phenyzoline and diphenyzoline, which are structurally related, highlighted an interesting “positive” or “negative”, respectively, morphine analgesia modulatory effect. In fact, 1 (s.c. 10 mg/kg) enhanced morphine analgesia (60 % and 40 % in mouse tail-flick and mouse hot-plate, respectively), while 2 (s.c. 10 mg/kg) decreased it (− 41 % and − 20 % , respectively). The ability to decrease morphine analgesia had never been observed before in I₂-IBS ligands. These effects were not affected by i.p. treatment of animals with yohimbine (a selective α₂-adrenoreceptor antagonist, 0.625 mg/kg) or efaroxan (an I₁-IBS/α₂-adrenoreceptor antagonist, 1.0 mg/kg). In contrast, they were completely reversed by i.p. treatment of animals with idazoxan (an I₂-IBS/α₂-adrenoreceptor antagonist, 2 mg/kg). Moreover, compound 2, in mouse tail-flick test, was able to potentiate by 23 % the naloxone-induced decrease of morphine analgesia. Therefore, the results of this study indicate the crucial involvement of I₂-IBS in the morphine analgesia modulatory effects of 1 and 2.