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

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