Moxonidine, a selective imidazoline/alpha(2) adrenergic receptor agonist, synergizes with morphine and deltorphin II to inhibit substance P-induced behavior in mice

The alpha(2) adrenergic receptor (AR) class of catecholamine/imidazoline (I ) agonists, such as norepinephrine and clonidine, produce spinal antinocice ptive synergy when co-administered with opioids. We have observed that intr athecally administered moxonidine, a selective I-1/alpha(2) (AR) agonist, p roduces antinociception. The present experiments tested moxonidine for abil ity to synergize with morphine, deltorphin II, and DAMGO (Tyr-D-Ala-NMe-Phe -Gly(ol)) to inhibit substance P-elicted nociceptive behavior in Institute of Cancer Research (ICR) mice. Moxonidine, morphine, deltorphin II, and DAM GO inhibited substance P-elicited nociceptive behavior with full efficacy. Effective dose 50% (ED50) values were calculated and equi-effective dose ra tios of the combinations moxonidine-morphine, moxonidine-deltorphin II, and moxonidine-DAMGO were determined. The interactions were tested by isobolog raphic analysis. The observed ED50 values of the combinations were statisti cally compared against their respective calculated theoretical additive ED5 0 values. The combinations of moxonidinemorphine and moxonidine-deltorphin II resulted in significant leftward shifts in the dose-response curves comp ared to those of each agonist administered separately. The ED50 values of t he dose-response curves of these combinations were significantly less than the corresponding calculated theoretical additive ED50 values; these result s indicated that moxonidine synergizes with both morphine and deltorphin II . In contrast, combining moxonidine with DAMGO did not increase the potenci es of the agonists (in combination) when compared to the potencies of each agonist administered separately. These results indicated that the moxonidin e-DAMGO interaction is subadditive. Collectively, these data demonstrate th at moxonidine combined with some opioid agonists produces spinal antinocice ptive synergy. Spinally administered moxonidine-opioid combinations may pro ve an effective therapeutic strategy to manage pain. (C) 2000 International Association for the Study of Pain. Published by Elsevier Science B.V.