Functional Profile of Systemic and Intrathecal Cebranopadol in Nonhuman Primates

Abstract

Background: Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and μ receptors produces analgesia with reduced side effects in nonhuman primates.

Methods: The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of cebranopadol in adult rhesus monkeys (n = 22) were compared with μ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses.

Results: Subcutaneous cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] μg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] μg/kg). Pretreatment with antagonists selective for nociceptin and μ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose-response curve of cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal cebranopadol (1 μg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 μg; 3,009 ± 1,474 scratches).

Conclusions: In nonhuman primates, the μ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/μ receptor partial agonists, cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of cebranopadol.

Figure 1.

Effects of systemic administration of cebranopadol on thermal nociception and itch scratching responses in monkeys. (A, B) Time courses of cebranopadol (A)- and fentanyl (B)-induced antinociception against an acute noxious stimulus (50°C water). (C) Time courses of itch scratching responses elicited by cebranopadol (5.6 μg/kg) and fentanyl (30 μg/kg) at antinociceptive doses. (D) Effects of mu receptor antagonist naltrexone (0.03 mg/kg) and nociceptin receptor antagonist J-113397 (0.1 mg/kg) on cebranopadol-induced antinociception. (E) Effects of delta receptor antagonist naltrindole (1 mg/kg) and kappa receptor antagonist 5’-guanidinonaltrindole (1 mg/kg) on cebranopadol-induced antinociception. All drugs were delivered subcutaneously. Data represent the mean ± SD (n = 6 for A and C, and n = 4 for B, D, and E) and were analyzed by two-way repeated measures ANOVA followed by Dunnett’s multiple comparison test. *p < 0.05, significantly different from the vehicle condition.

Figure 2.

Reinforcing effects and strength of cebranopadol compared with fentanyl measured by intravenous drug self-administration in monkeys. (A) Number of injections received as a function of dose in monkeys responding to oxycodone (O, 3 μg/kg per injection, n = 6), saline (S, ~0.14 mL/kg per injection, n = 5), cebranopadol (0.01 [n = 6], 0.03 [n = 6], and 0.06 [n = 5] μg/kg per injection) or fentanyl (0.03 [n = 5], 0.1 [n = 6], and 0.3 [n = 5] μg/kg per injection) under a fixed ratio 30 schedule of reinforcement. (B) Number of injections received as a function of dose in monkeys responding to oxycodone (O, 3 μg/kg per injection, n = 5), saline (S, ~0.14 mL/kg per injection, n = 5), cebranopadol (0.03 [n = 5], 0.06 [n = 6], 0.1 [n = 6], and 0.3 [n = 5] μg/kg per injection) or fentanyl (0.1, 0.3, and 0.6 μg/kg per injection, n = 6) under a progressive ratio schedule of reinforcement. Data represent the mean ± SD and were analyzed by the mixed-effects model. *p < 0.05, significantly different from saline.

Figure 3.

Comparison of systemic cebranopadol- and fentanyl-induced changes of respiratory parameters in freely moving monkeys implanted with telemetric probes. (A, C) Respiration rate. (B, D) Minute volume. Data represent the mean ± SD (n = 4) from each individual data averaged from a 5-min time block. Both drugs were delivered intramuscularly. Open symbols represent the baseline data of the different dosing conditions from the same monkeys before drug administration. Data were analyzed by two-way repeated measures ANOVA followed by Dunnett’s multiple comparison test. *p < 0.05, significantly different from the vehicle condition.

Figure 4.

Effects of intrathecal administration of cebranopadol on thermal nociception and itch scratching responses in monkeys. (A) Time courses of cebranopadol-induced antinociception against an acute noxious stimulus (50°C water). (B) Time courses of itch scratching responses elicited by cebranopadol (1 μg) and morphine (30 μg) at antinociceptive doses. (C) Total number of scratches summed from the four time points shown in (B). Data represent the mean ± SD (n = 6) and were analyzed by two-way (A and B) or one-way (C) repeated measures ANOVA followed by Dunnett’s multiple comparison test. *p < 0.05, significantly different from the vehicle condition.