Selective enhancement of fentanyl-induced antinociception by the delta agonist SNC162 but not by ketamine in rhesus monkeys: Further evidence supportive of delta agonists as candidate adjuncts to mu opioid analgesics

Abstract

Mu-opioid receptor agonists such as fentanyl are effective analgesics, but their clinical use is limited by untoward effects. Adjunct medications may improve the effectiveness and/or safety of opioid analgesics. This study compared interactions between fentanyl and either the noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine or the delta-opioid receptor agonist SNC162 [(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-phenyl)methyl]-N,N-diethylbenzamide] in two behavioral assays in rhesus monkeys. An assay of thermal nociception evaluated tail-withdrawal latencies from water heated to 50 and 54°C. An assay of schedule-controlled responding evaluated response rates maintained under a fixed-ratio 30 schedule of food presentation. Effects of each drug alone and of three mixtures of ketamine+fentanyl (22:1, 65:1, 195:1 ketamine/fentanyl) or SNC162+fentanyl (59:1, 176:1, 528:1 SNC162/fentanyl) were evaluated in each assay. All drugs and mixtures dose-dependently decreased rates of food-maintained responding, and drug proportions in the mixtures were based on relative potencies in this assay. Ketamine and SNC162 were inactive in the assay of thermal antinociception, but fentanyl and all mixtures produced dose-dependent antinociception. Drug interactions were evaluated using dose-addition and dose-ratio analysis. Dose-addition analysis revealed that interactions for all ketamine/fentanyl mixtures were additive in both assays. SNC162/fentanyl interactions were usually additive, but one mixture (176:1) produced synergistic antinociception at 50°C. Dose-ratio analysis indicated that ketamine failed to improve the relative potency of fentanyl to produce antinociception vs. rate suppression, whereas two SNC162/fentanyl mixtures (59:1 and 176:1) increased the relative potency of fentanyl to produce antinociception. These results suggest that delta agonists may produce more selective enhancement than ketamine of mu agonist-induced antinociception.

Figure 1

Effects of the mu-opioid agonist fentanyl alone or in combination with the noncompetitive NMDA antagonist ketamine (top panels) or in combination with the delta-opioid agonist SNC162 (bottom panels) on rates of schedule-controlled responding (left panels) and thermal nociception at 50°C (center panels) and 54°C (right panels). All panels show isobolograms for each behavioral endpoint at the ED50 effect level for fentanyl, ketamine, or SNC162 alone or as part of a mixture. Abscissae: ED50 values for fentanyl alone or in a mixture in mg/kg (linear scale). Ordinates (top panels): ED50 values for ketamine alone or in a mixture in mg/kg (linear scale). Ordinates (bottom panels) ED50 values for SNC162 alone or in a mixture in mg/kg (linear scale). Each point represents mean ± SEM of 3–5 monkeys. * Asterisk indicates that the 176:1 SNC162/fentanyl mixture produced a synergistic antinociceptive effect as determined by dose-addition analysis (see Table 4).

Figure 2

Effects of ketamine and SNC162 on the relative potency of fentanyl to produce rate suppression vs. thermal nociception. Abscissae: Proportions of ketamine + fentanyl (left panel) or SNC162 + fentanyl (right panel) in the mixtures. Ordinates: Percent of the dose ratio for fentanyl alone. Dose ratios were calculated as the potency in the assay of schedule-controlled responding (SCR) ÷ potency in the assay of thermal nociception at stimulus intensities of 50°C (open bars) or 54°C (gray bars). In the groups used to assess the fentanyl/ketamine interactions, the dose ratios for fentanyl alone were 2.64 (SCR/50°C) and 0.55 (SCR/54°C). In the groups used to assess SNC162/fentanyl interactions, the dose ratios for fentanyl alone were 0.43 (SCR/50°C) and 0.20 (SCR/54°C).

Figure 3

Time courses of equieffective doses of fentanyl (0.021 mg/kg), ketamine (1.4 mg/kg) and SNC162 (3.7 mg/kg) in the assay of schedule-controlled responding. Abscissae: time in min. post administration. Ordinate: Percent control rate of responding. Each point represents mean±SEM of four rhesus monkeys. Two-way repeated-measures analysis of variance revealed a significant main effect of time F(3,9) = 22.4, p < 0.05, drug F(3,9) = 6.5, p < 0.05 and a significant time × drug interaction F(9,27) = 2.3, p < 0.05. Post-hoc analysis using the Bonferroni method for multiple comparisons demonstrated that all three drugs were significantly different (p < 0.05) from vehicle at 10 min, and fentanyl and SNC162 were significantly different from vehicle at 30 min. However, there were no significant differences at any time point between fentanyl, ketamine and SNC162. Open symbols represent points significantly different (p < 0.05) from vehicle.