BIOLOGICAL PROFILE AND BIOAVAILABILITY OF IMIDAZOLINE COMPOUNDS AFFECT THEIR MODULATORY ACTIVITY ON MORPHINE TOLERANCE

Therapeutic use of opioids represents the standard of care in the treatment of severe chronic pain and cancer-related pain (1). Various α2-adrenoceptor agonists, devoid of α2 subtype selectivity (i.e. clonidine), have been clinically used in pain management but, due to its α2A subtype activation, they might be responsible for sedation and hypotension side effects. Moreover, to overcome the side effects of opiate drugs, the synergism with compounds interacting with imidazoline I2 receptors has been reported (2). The aim of the study was to compare the effects of the imidazoline compounds 1, 2, and 3 (Figure) on morphine tolerance in an animal model of inflammatory pain in rats. 1, 2, and 3 have been selected in that, although bearing a common scaffold, preferentially bind to α2-adrenoceptors, imidazoline I2 receptors, or both systems, respectively.These compounds have been tested in vivo in association with morphine, by measuring the paw withdrawal threshold to mechanical pressure. The sub-chronic 4 days treatment with 1-3, administered twice a day 15 min before each morphine administration significantly restored at day 4 the morphine analgesic response. The maximal activity of 2 was at t=45 min; instead that of 1 and 3 was at t=90 min. Since the different temporal profile on the tolerance reduction displayed by 1-3 might be associated not only to their different target profile, but also to their bioavailability, we developed an HPLC-mass spectrometry method for the determination of the ligand levels in the rat plasma. The mean serum concentration of 1 was determined to be maximum at 60 minutes (14.71 ng/ml); meanwhile that of 2 was maximal at 30 minutes (58.00 ng/ml). Therefore, this study highlights that both peculiar biological profile and bioavailability of such ligands complement each other to modulate the reduction of morphine tolerance.