Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112

Abstract

Chemical modifications of nociceptin/orphanin FQ (N/OFQ) peptide that result in increased potency and resistance to degradation have recently lead to the discovery of [(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-112), a novel N/OFQ peptide (NOP) receptor agonist. The aim of this study was to investigate the pharmacological profile of intrathecally administered UFP-112 in monkeys under different behavioral assays. Intrathecal UFP-112 (1-10 nmol) dose-dependently produced antinociception against an acute noxious stimulus (50 degrees C water) and capsaicin-induced thermal hyperalgesia. Intrathecal UFP-112-induced antinociception could be reversed by a NOP receptor antagonist, J-113397 (0.1mg/kg), but not by a classic opioid receptor antagonist, naltrexone (0.03 mg/kg). Like intrathecal morphine, UFP-112 produced antinociception in two primate pain models with a similar magnitude of effectiveness and a similar duration of action that last for 4-5h. Unlike intrathecal morphine, UFP-112 did not produce itch/scratching responses. In addition, intrathecal inactive doses of UFP-112 and morphine produced significant antinociceptive effects when given in combination without increasing scratching responses. These results demonstrated that intrathecal UFP-112 produced long-lasting morphine-comparable antinociceptive effects without potential itch side effect. This study is the first to provide functional evidence that selective NOP receptor agonists such as UFP-112 alone or in conjunction with morphine may improve the quality of spinal analgesia.

Fig. 1

Comparison of behavioral effects produced by intrathecal administration of UFP-112 and morphine. Abscissas: time in hours after intrathecal administration. Ordinates: latency to withdraw the tail in 50 °C water (top panels) and scratches per 15 min (bottom panels). Each value represents mean ± SEM (n = 6). Symbols represent different dosing conditions in the same monkeys. The asterisk represents a significant difference from the vehicle condition at corresponding time points (*p < 0.05).

Fig. 2

Effects of antagonists on intrathecal UFP-112 and morphine-induced antinociception in monkeys. The antagonist, either naltrexone (0.03 mg/kg) or J-113397 (0.1 mg/kg), was given subcutaneously 10 min after the 1-h time point. Abscissas: time in hours after intrathecal administration. Ordinates: latency to withdraw the tail in 50 °C water. Each value represents mean ± SEM (n = 6). Symbols represent effects with different post-injection conditions for the same monkeys. The asterisk represents a significant difference from the vehicle post-injection condition between time points 1.5 and 2.5 h (*p < 0.05).

Fig. 3

Antinociceptive effects of intrathecally administered UFP-112 and morphine against capsaicin-induced hyperalgesia in 46 °C water. The agonist was given intrathecally 1 h before administration of capsaicin (0.1 mg/tail). Each data point was determined 15 min after capsaicin administration and represents mean ± SEM (n = 6). Symbols represent effects with different dosing conditions in the same monkeys. The asterisk represents a significant difference from the vehicle condition (*p < 0.05).

Fig. 4

Comparison of durations of intrathecal UFP-112- and morphine-induced antihyperalgesia in 46 °C water. The antihyperalgesic effect of the agonist, either morphine (100 nmol) or UFP-112 (10 nmol), was determined by using a single dosing procedure. The agonist was given intrathecally at different time points before administration of capsaicin (0.1 mg/tail). Each data point was determined 15 min after capsaicin administration and represents mean ± SEM (n = 6). Symbols represent effects with different dosing conditions for the same monkeys. The asterisk represents a significant difference between morphine-treated condition and the vehicle condition (*p < 0.05). The symbol # represents a significant difference between UFP-112-treated condition and the vehicle condition (*p < 0.05).

Fig. 5

Behavioral responses of intrathecally administered UFP-112 in combination with morphine. Effects of intrathecal morphine (3 nmol) or UFP-112 (1 nmol) alone were determined separately. Then effects of intrathecal administration of a mixture, i.e., 3 nmol of morphine combined with 1 nmol of UFP-112, were tested in the same monkeys. Each value represents mean ± SEM (n = 6). The asterisk represents a significant difference from the vehicle condition (*p < 0.05).

Fig. 6

Effects of antagonists on antihyperalgesia by intrathecal combination of UFP-112 (1 nmol) and morphine (3 nmol) (i.e., a mixture). The antagonist, either naltrexone (0.03 mg/kg) or J-113397 (0.1 mg/kg), was given subcutaneously 30 min after intrathecal administration of a mixture. The symbol “+” indicates the corresponding compound was given. The symbol “−” indicates the corresponding was not given. Each value represents mean ± SEM (n = 6). The asterisk represents a significant difference from the vehicle condition (*p < 0.05).