In Vitro and In Vivo Profile of PPL-101 and PPL-103: Mixed Opioid Partial Agonist Analgesics with Low Abuse Potential

Abstract

Opiates are still the most effective and widely used treatments for acute and chronic pain. However, the problems associated with morphine and other standard opioid analgesics severely limit their effectiveness in the clinic. PPL-101 and PPL-103 derived from morphine and morphinan ring systems contain a chiral N-substituent, which confers it with a unique combination of high-binding affinities and partial agonist activities at mu, delta, and kappa opioid receptors, leading to unique in vivo pharmacology compared to other conventional opioids. Acute antinociceptive and reward acquisition of PPL-101 and PPL-103 were assessed in mice using the tail flick assay and conditioned place preference (CPP) paradigm, respectively. The reinforcing effects of these compounds were assessed in rats using the self-administration paradigm. In mice, PPL-101 and PPL-103 produced antinociception reaching maximal effects that were equivalent to morphine at approximately 1/3 and 1/10 of morphine's dose, respectively. PPL-101-induced antinociception was attenuated following pretreatment with the kappa antagonist JDTic, but not the mu opioid antagonist beta-FNA. In mice, PPL-101 and PPL-103 produced dose-dependent decreases in activity, similar to other kappa agonists; however, they did not produce conditioned place aversion, and in fact elicited a trend toward CPP. In rats, neither PPL-101 nor PPL-103 were self-administered when substituted for morphine and PPL-101 attenuated morphine self-administration, when administered systemically prior to the self-administration session. Collectively, these results indicate that mixed opioid receptor partial agonists can produce potent antinociceptive activity with a lack of aversion in mice and without being self-administered in rats. Compounds with this profile could be superior analgesics with greatly reduced addiction liability and fewer side-effects compared to traditional opiates.

Keywords: analgesic; conditioned place preference; kappa opiate; non-addicting; self-administration.

Figure 1

Structures of PPL-103 and PPL-101.

Figure 2

Acute thermal antinociceptive effects of PPL-101 (A) and PPL-103 (B) alone using the tail flick assay in mice. Data are mean % maximum potential effect (%MPE) (± SEM) 60-min post-injection. *, significant difference from vehicle control group (P < 0.05).

Figure 3

Time course for acute thermal antinociceptive effect of PPL-101 (0.3–10 mg/kg, subcutaneous) alone in the tail flick assay in mice. Data are mean % maximum potential effect (%MPE) (± SEM). *, significant difference from vehicle control group (P < 0.05). ^†, significant difference from first test-point, 0.5 h (P < 0.05).

Figure 4

The effect of kappa antagonist, JDTic [10 mg/kg, subcutaneous (s.c.)], and mu antagonist, beta-FNA (40 mg/kg, s.c.) on PPL-101-induced antinociception 0.5-h (A), 1-h (B), 2-h (C), and 4-h (D) post-PPL-101 injection in mice. Data are mean % maximum potential effect (%MPE) (± SEM). *, significant difference from respective vehicle control groups (P < 0.05). ^†, significant difference from PPL-101 alone (P < 0.05).

Figure 5

The effect of PPL-101 [1–3 mg/kg, subcutaneous (s.c.)] and PPL-103 (0.3–3 mg/kg, s.c.) on conditioned place preference (CPP) (A,B) and on global activity (C,D) following the first (open bars) and third (black bars) drug injections in mice. CPP data are mean (± SEM) difference score calculated as time spent in the drug-paired compartment minus time spent in the vehicle-paired compartment, whereas global activity data are activity (centimeters) following first and last drug injection. *, significant difference from vehicle control group (P < 0.05). ^†, significant difference from first drug injection (P < 0.05).

Figure 6

Self-administration of PPL-101 (30 and 100 µg/kg/infusion) and PPL-103 (30 and 100 µg/kg/infusion) under fixed ratio 1 (FR-1) (A,B) and progressive ratio (PR) (C,D) schedules of reinforcement in rats. For the PPL-101 experiment (A,C), a between-subject design was used with four groups of n = 6. For the PPL-103 experiment (B,D), a Latin Square within-subject design was used (n = 8). In both procedures, initial self-administration (baseline) was established with morphine (100 µg/kg/infusion). Data are mean (± SEM) number of infusions under both FR-1 and PR schedules. *P < 0.05, **P < 0.01, and ***P < 0.001 significant difference from morphine. B, baseline; MR, morphine re-acquisition.

Figure 7

Effect of PPL-101 [0.3–3.0 mg/kg, intraperitoneal (i.p.)] pretreatment on morphine (100 µg/kg/infusion) self-administration under an FR1TO20 schedule in rats. Data are mean (± SEM) number of infusions during 120 min session. *P < 0.05 difference from vehicle treated group (PPL-101, 0.0 mg/kg).

Figure 8

Effect of kappa antagonist JDTic [10 mg/kg, intraperitoneal (i.p.)] on morphine (100 μg/kg/infusion) (A) and PPL-101 (100 μg/kg/infusion) (B) self-administration under an FR1TO20 schedule in rats. JDTic was given 24 h prior to the first self-administration session. Data are the mean (± SEM) of the last 3 days of morphine SA prior to JDTic treatment compared to average lever pressing of the same rats treated with JDTic and self-administering morphine across the following seven sessions (A), and baseline lever pressing for PPL-101 of the last three sessions versus the average lever pressing of JDTic-treated rats self-administering PPL-101 across 7 days (B). **P < 0.01 difference from rats JDTic-treated and self-administering PPL-101.

Figure 9

U-69,593-induced antinociception using the plantar test in rats. The kappa agonist U-69,593 (0.3 mg/kg) produced analgesia, an effect abolished by pretreatment with the kappa antagonist JDTic. Data are mean (± SEM) paw-withdrawal latency (seconds). **P < 0.01 difference from control group (VEH/VEH), ^#P < 0.05 difference from U-69,593 treated group (VEH/U-69,593).