Agonists at ␦, , and opioid receptors produce interacting effects in rodents and nonhuman primates. To further evaluate the determinants of these interactions, this study examined the effects of mixtures of ␦ ϩ and ␦ ϩ agonists in rhesus monkeys (n ϭ 4 -5) using two behavioral procedures, an assay of schedulecontrolled responding for food reinforcement and an assay of thermal nociception. Results were analyzed using dose-addition analysis. In the assay of schedule-controlled responding, the; the agonists methadone, fentanyl, morphine, and nalbuphine; and the agonists (5␣,7␣,8)-(Ϫ)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide (U69,593) and bremazocine all dose dependently decreased rates of food-maintained responding when administered alone. Fixed ratio mixtures of SNC80 ϩ agonists produced additive or subadditive effects, whereas SNC80 ϩ agonist mixtures produced only additive effects. In the assay of thermal nociception, SNC80 produced no measurable effects when administered alone, whereas and agonists produced dose-dependent antinociception. SNC80 ϩ agonist mixtures produced superadditive effects manifested as leftward shifts in agonist dose-effect curves. This synergism was antagonized by the ␦-selective antagonist naltrindole, suggesting that SNC80-induced enhancement of agonist antinociception was ␦ receptor-mediated. SNC80 did not enhance the antinociceptive effects of the highly selective agonist U69,593, and it produced only a marginal enhancement of antinociception produced by the less selective agonist bremazocine. These results suggest that ␦ agonists may selectively enhance the antinociceptive effects of agonists in rhesus monkeys. These results also confirm that opioid agonist interactions may depend on the receptor selectivity and relative doses of the agonists and on the experimental endpoint.Biochemical and behavioral evidence indicates the existence of three opioid receptor types, the ␦, , and receptors (Martin et al., 1976;Lord et al., 1977;Evans et al., 1992;Thompson et al., 1993;Yasuda et al., 1993). Agonists selective for ␦, , and receptors produce distinct profiles of physiological and behavioral effects (Gutstein, 2001). In addition, selective ␦, , and agonists may also produce interacting effects. Studies of opioid receptor interactions have been conducted primarily with ␦ and agonists in rodents using assays of antinociception, and results from these studies suggest that the nature of the interaction depends on such variables as the particular agonists used, the relative doses tested, and the behavioral endpoint (Heyman et al., 1989;Jiang et al., 1990;Adams et al., 1993). For example, the peptidic ␦ agonists [D-Pen 2 ,D-Pen 5 ]-enkephalin (DPDPE) and deltorphin II enhanced the effects of some intermediate-efficacy agonists (morphine, normorphine, and codeine), but not of higher efficacy -agonists (PL017, fentanyl, or sufentanil), in an assay of thermal nociception in mice (Heyman et al., 1989;Jiang et al., 1990). In a subsequent study, DPDPE enhanced ...