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

Some studies, suggesting the involvement Of I-2-imidazoline binding sites (I-2-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 I-2-IBS affinity and high I-2-IBS selectivity with regard to I,IBS, alpha(2)-adrenoreceptors and mu-opioid receptors might be considered the first interesting I-2-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 I-2-IBS selectivity with regard to I-1-IBS, (alpha(2)-adrenoreceptors and mu-opioid receptors. Moreover, by the functional assays I and 2 proved inactive at all alpha(2)-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, I (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 I-2-IBS ligands. These effects were not affected by i.p. treatment of animals with yohimbine (a selective alpha(2)-adrenoreceptor antagonist, 0.625 mg/kg) or efaroxan (an I-1-IBS/alpha(2)-adrenoreceptor antagonist, 1.0 mg/kg). In contrast, they were completely reversed by i.p. treatment of animals with idazoxan (an I-2-IBS/alpha(2)-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 I-2-IBS in the morphine analgesia modulatory effects of I and 2. (c) 2006 Elsevier B.V. All rights reserved.