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.

Introduction

Mu-opioid agonists are effective clinical analgesics, but their use is limited by untoward effects such as sedation, respiratory depression and constipation. Therefore, the development of candidate analgesics with improved therapeutic effects and decreased untoward effects is warranted. One strategy for achieving this goal may be to combine mu opioid agonists with adjuncts that improve effectiveness and/or safety. For example, numerous preclinical studies have shown that delta-opioid receptor agonists alone have antinociceptive effects in some nociceptive assays (Brandt et al., 2001, Do Carmo et al., 2008, Heyman et al., 1987, Stewart & Hammond, 1993). Moreover, combinations of mu and delta agonists have produced synergistic antinociceptive effects while producing additive, subadditive or mutually antagonistic effects in assays of other, undesirable drug effects (Adams et al., 1993, Heyman et al., 1989, Negus et al., 2009, O'Neill et al., 1997, Stevenson et al., 2003). These results suggest that delta agonists may have clinical value as adjuncts to mu agonists in the treatment of pain; however, clinical evaluation of this hypothesis cannot proceed until either selective delta agonists or mixed-action delta/mu agonists are approved for clinical use. An alternative strategy to gauging the potential value of delta/mu interactions is to conduct preclinical studies that directly compare delta/mu interactions with interactions between mu agonists and adjuncts that have been examined clinically. Toward that end, the present study compared interactions between the mu agonist fentanyl and either an intermediate-efficacy delta agonist (SNC162; Jutkiewicz et al., 2004, Negus et al., 1998) or the noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine.

Anatomical studies have demonstrated the presence of NMDA receptors at both spinal levels within the dorsal horn and at supraspinal levels involved in nociceptive transmission, such as brainstem, thalamus and cortex (Kalb & Fox, 1997, Mugnaini et al., 1996, Roth et al., 1996). Functional studies also suggest that NMDA receptors participate in the transmission of nociceptive signals (for review, see Dickenson et al., 1997, Furst, 1999, Mao, 1999). Although NMDA receptor function can be modulated by antagonists acting at glutamate- or glycine-binding sites (Brown and Krupp, 2006), the only clinically available NMDA receptor antagonists are noncompetitive channel blockers such as ketamine and dextromethorphan. Previous studies using these noncompetitive antagonists have provided some evidence to suggest that they can enhance the antinociceptive effects of mu agonists in rodents (Baker et al., 2002, Hoffmann et al., 2003, Holtman et al., 2008, Nadeson et al., 2002) and nonhuman primates (Allen et al., 2002). More importantly for the present study, an extensive clinical literature has investigated interactions between ketamine and mu agonists in humans (Bell et al., 2003, Carstensen & Moller, 2010, Schulte et al., 2003, Tucker et al., 2005). These studies generally agree that sedative and other untoward effects of ketamine complicate its use as an adjunct to mu agonists, but at least some studies have concluded that low-dose ketamine may be useful as a safe and effective adjunct under at least some conditions (Carstensen & Moller, 2010, Kollender et al., 2008, Subramaniam et al., 2004).

Fentanyl/ketamine and fentanyl/SNC162 interactions were compared in rhesus monkeys using procedures described previously to assess opioid interactions (Negus et al., 2008, Negus et al., 2009, Stevenson et al., 2003, Stevenson et al., 2005). Antinociceptive interactions were evaluated in a warm-water tail-withdrawal assay of thermal nociception. For two reasons, drug interactions were also evaluated in an assay of schedule-controlled behavior, in which operant responding was maintained by food reinforcement. First, fentanyl, ketamine and SNC162 administered alone each produce a dose-dependent and maximal effect in this procedure, and as a result, data from this procedure could be used to quantify relative potencies for determination of drug proportions in drug mixtures. Second, drug effects on schedule-controlled responding can provide one measure of non-selective behavioral depression that can confound measures of antinociception. Consequently, a comparison of drug (or drug mixture) effects in assays of thermal nociception and schedule-controlled responding can provide one useful index of antinociceptive selectivity.

Drug interactions within each procedure in the present study were analyzed using dose-addition analysis to compare experimental results with expected additivity (Stevenson et al., 2003, Tallarida, 2000). Drug interactions across procedures were analyzed using dose-ratio analysis to assess relative potencies to produce antinociception versus response-rate suppression (Negus et al., 2008, Negus et al., 2009). We hypothesized that SNC162, like other delta agonists studied previously, would selectively and synergistically enhance fentanyl-induced antinociception. In view of the findings with ketamine described above, we further hypothesized that SNC162 would produce a more selective enhancement of fentanyl-induced antinociception than ketamine.