DECREASED SPINAL MORPHINE CLONIDINE ANTINOCICEPTIVE SYNERGISM IN MORPHINE-TOLERANT MICE

The antinociceptive interactions between spinally administered opioids and the alpha(2) agonist clonidine were examined in placebo and morph ine pellet-implanted mice using the tail flick test. In placebo pellet -implanted animals, coadministered morphine and clonidine produced a s ynergistic antinociceptive effect. In mice implanted with morphine pel lets, the synergism decreased to an additive interaction. The interact ions between clonidine and the mu agonist Tyr-D-Ala-Gly-N-Me-Phe-Gly-o l (DAMGO), the delta agonist D-Pen(2)-D-Pen(5)-Enkephalin (DPDPE), and the kappa agonist U50-488H were also synergistic in placebo pelleted animals. In morphine pellet treated mice the DPDPE/clonidine interacti on decreased to an antagonistic interaction, the DAMGO/clonidine remai ned synergistic and the U50-488H/clonidine interaction decreased to ad ditive. These results support the proposal that the morphine spinal/su praspinal synergism depends upon the interaction between spinal opioid and alpha(2) receptors and a decrease in this interaction is a mechan ism involved in development of tolerance to morphine. In addition, del ta and kappa receptors appeared to be more involved in the morphine/cl onidine decreased interaction than did mu opioid receptors.