Tolerance to
opioid administration represents a serious medical alert in different
chronic conditions. This study compares the effects of the
imidazoline compounds 1, 2, and 3 on
morphine tolerance in an animal model of inflammatory
pain in the rat. 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. Such compounds have been tested in vivo by measuring the paw withdrawal threshold to mechanical pressure after complete
Freund's adjuvant injection. To determine the
ligand levels in rat plasma, an HPLC-mass spectrometry method has been developed. All the compounds significantly reduced the induction of
morphine tolerance, showing different potency and duration of action. Indeed, the selective
imidazoline I2 receptor interaction (2) restored the
analgesic response by maintaining the same time-dependent profile observed after a single
morphine administration. Differently, the selective α2C-adrenoceptor activation (1) or the combination between α2C-adrenoceptor activation and
imidazoline I2 receptor engagement (3) promoted a change in the temporal profile of
morphine analgesia by maintaining a mild but long lasting
analgesic effect. Interestingly, the kinetics of compounds in rat plasma supported the pharmacodynamic data. Therefore, this study highlights that both peculiar
biological profile and bioavailability of such
ligands complement each other to modulate the reduction of
morphine tolerance. Based on these observations, 1-3 can be considered useful leads in the design of new drugs able to turn off the undesired tolerance induced by
opioids.