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Several studies have demonstrated synergistic antinociception following low-dose administration of morphine and alpha-2 adrenergic agonists at the spinal level. This study was carried out in order to identify the opiate subtypes that are likely to be involved in such synergistic suppression of noxiously evoked activity of wide-dynamic-range (WDR) neurons in the dorsal horn of the spinal cord. We also examined the effect of opiate antagonists and alpha-2 adrenergic antagonists on the suppression produced by opiate or alpha-2 adrenergic agonists. Extracellular activity of single WDR neurons in the spinal dorsal horn, which was evoked by a radiant heat stimulus (51° C), was recorded in decerebrate, spinally transected cats. Agonists were administered spinally and antagonists intravenously. In the synergism study, ineffective doses of the moderately selective mu agonist morphine (25 μg), the delta agonist DADL (20 μg), and the selective delta agonist DPDPE (30 μg), when combined with an ineffective dose of the alpha-2 adrenergic agonist clonidine (5 μg) produced significant synergistic suppression of noxiously evoked WDR neuronal activity. However, the ineffective or slightly effective dose of the selective mu agonist DAGO (1 or 1.5 μg, respectively) did not show any synergistic action with clonidine. Furthermore, the synergism between morphine and clonidine was reversed by the selective delta antagonist ICI 174,864. We interpret these results to indicate that opiates interact at spinal delta receptors to produce a synergistic suppression of evoked WDR neuronal activity in the presence of spinal clonidine. An alternative explanation is that ICI 174,864 may interact in some way with alpha-adrenergic systems. There was no statistically significant cross antagonism when naloxone or ICI 174,864 was used to reverse clonidine suppression or when the alpha-2 adrenergic antagonist yohimbine was used to reverse opiate suppression.