MORPHINE TOLERANCE MODULATION INDUCED BY alpha2-ADRENERGIC OR/AND I2 IMIDAZOLINE BINDING SITES LIGANDS

The chronic use of opioids is often accompanied by development of tolerance, described as the need for increasing drug dosage to achieve the same effect. Previous studies demonstrated that both alpha2-adrenergic receptors (alpha2-AR) or I2 Imidazoline Binding Sites (I2-IBS) are involved in the modulation of morphine analgesia as well as tolerance and dependence. Our studies demonstrated that in molecular structures, sharing the common pharmacophore reported in figure 1, the bridge X determined the preferential recognition of a specific biological system. In particular, the -OCH(CH3)- bridge of 1 was suitable for alpha2-AR interaction, whereas the -CH2CH2- bridge (2) proved to be effective for I2-IBS. Interestingly, the -OCH2- bridge (3) was compatible with both systems. To assess the effects on tolerance to morphine, 1-3 were administered once daily for 4 days at a dose of 0.5 mg/Kg i.p. 15’ before the morphine s.c. After 4 days morphine was completely inactive. In contrast, 1-3, even though with different behaviour, significantly inibited morphine tolerance. In fact, 2 restored the lost morphine analgesic response in “neutral” mode, whereas 1 and 3 produced a temporal variation of morphine analgesic response extending its efficacy.