Activation of I2-imidazoline receptors enhances supraspinal morphine analgesia in mice:: a model to detect agonist and antagonist activities at these receptors

1 This work investigates the receptor acted upon by imidazoline compounds in the modulation of morphine analgesia. The effects of highly selective imidazoline ligands on the supraspinal antinociception induced by morphine in mice were determined. 2 Intracerebroventricular (i.c.v.) or subcutaneous (s.c.) administration of ligands selective for the I-2-imidazoline receptor, 2-BFI, LSL 60101, LSL 61122 and aganodine, and the non selective ligand agmatine, increased morphine antinociception in a dose-dependent manner. Neither moxonidine, a mixed I-1-imidazoline and alpha(2)-adrenoceptor agonist, RX821002, a potent alpha(2)-adrenoceptor antagonist that displays low affinity at I-2-imidazoline receptors, nor the selective non-imidazoline alpha(2)-adrenoceptor antagonist RS-15385-197, modified the analgesic responses to morphine. 3 Administration of pertussis toxin (0.25 mu g per mouse, i.c.v.) 6 days before the analgesic test blocked the ability of the I-2-imidazoline ligands to potentiate morphine antinociception. 4 The increased effect of morphine induced by I-2-imidazoline ligands (agonists) was completely reversed by idazoxan and BU 224. Identical results were obtained with IBI, which alkylates I-2-imidazoline binding sites. Thus, both agonist and antagonist properties of imidazoline ligands at the I-2-imidazoline receptors were observed. 5 Pre-treatment (30 min) with deprenyl, an irreversible inhibitor of monoamine oxidase B (IMAO-B), produced an increase of morphine antinociception. Clorgyline, an irreversible IMAO-B, given 30 min before morphine did not alter the effect of the opioid. At longer intervals (24 h) a single dose of either clorgyline or deprenyl reduced the density of I-2-imidazoline receptors and prevented the I-2- mediated potentiation of morphine analgesia. 6 These results demonstrate functional interaction between I-2-imidazoline and opioid receptors. The involvement of G(i)-G(o) transducer proteins in this modulatory effect is also suggested.