The α2 adrenergic receptor (AR) class of catecholamine/imidazoline (I) agonists, such as norepinephrine and clonidine, produce spinal antinociceptive synergy when co-administered with opioids. We have observed that intrathecally administered moxonidine, a selective I1/α2 (AR) agonist, produces antinociception. The present experiments tested moxonidine for ability 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 mice. Moxonidine, morphine, deltorphin II, and DAMGO inhibited substance P-elicited nociceptive behavior with full efficacy. Effective dose 50% (ED50) values were calculated and equi-effective dose ratios of the combinations moxonidine-morphine, moxonidine-deltorphin II, and moxonidine-DAMGO were determined. The interactions were tested by isobolographic analysis. The observed ED50 values of the combinations were statistically compared against their respective calculated theoretical additive ED50 values. The combinations of moxonidine-morphine and moxonidine-deltorphin II resulted in significant leftward shifts in the dose- response curves compared to those of each agonist administered separately. The ED50 values of the dose-response curves of these combinations were significantly less than the corresponding calculated theoretical additive ED50 values; these results indicated that moxonidine synergizes with both morphine and deltorphin II. In contrast, combining moxonidine with DAMGO did not increase the potencies of the agonists (in combination) when compared to the potencies of each agonist administered separately. These results indicated that the moxonidine-DAMGO interaction is subadditive. Collectively, these data demonstrate that moxonidine combined with some opioid agonists produces spinal antinociceptive synergy. Spinally administered moxonidine- opioid combinations may prove an effective therapeutic strategy to manage pain.