Roles of μ-opioid receptors and nociceptin/orphanin FQ peptide receptors in buprenorphine-induced physiological responses in primates

Abstract

Buprenorphine is known as a μ-opioid peptide (MOP) receptor agonist, but its antinociception is compromised by the activation of nociceptin/orphanin FQ peptide (NOP) receptors in rodents. The aim of this study was to investigate the roles of MOP and NOP receptors in regulating buprenorphine-induced physiological responses in primates (rhesus monkeys). The effects of MOP antagonist (naltrexone), NOP antagonist [(±)-1-[(3R*,4R*)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397)], and NOP agonists [(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5] decan-4-one (Ro 64-6198) and 3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510)] on buprenorphine were studied in three functional assays for measuring analgesia, respiratory depression, and itch in primates. Over the dose range of 0.01 to 0.1 mg/kg, buprenorphine dose-dependently produced antinociception, respiratory depression, and itch/scratching responses, and there was a ceiling effect at higher doses (0.1-1 mg/kg). Naltrexone (0.03 mg/kg) produced similar degrees of rightward shifts of buprenorphine's dose-response curves for all three endpoints. Mean pK(B) values of naltrexone (8.1-8.3) confirmed that MOP receptors mediated mainly buprenorphine-induced antinociception, respiratory depression, and itch/scratching. In contrast, J-113397 (0.1 mg/kg) did not change buprenorphine-induced physiological responses, indicating that there were no functional NOP receptors in buprenorphine-induced effects. More importantly, both NOP agonists, Ro 64-6198 and SCH 221510, enhanced buprenorphine-induced antinociception without respiratory depression and itch/ scratching. The dose-addition analysis revealed that buprenorphine in combination with the NOP agonist synergistically produced antinociceptive effects. These findings provided functional evidence that the activation of NOP receptors did not attenuate buprenorphine-induced antinociception in primates; instead, the coactivation of MOP and NOP receptors produced synergistic antinociception without other side effects. This study strongly supports the therapeutic potential of mixed MOP/NOP agonists as innovative analgesics.

Fig. 1.

Antinociceptive effects of subcutaneously administered buprenorphine over a wide dose range against an acute noxious stimulus (50°C water) in primates. A, low doses. B, high doses. Each data point represents a mean ± S.E.M. (n = 6). *, a significant difference from the vehicle condition from the time point 30 min to the corresponding time point for each dose (p < 0.05). The same data of buprenorphine (0.1 mg/kg) are presented in A (●) and B (▼) for comparison with other doses.

Fig. 2.

Respiratory depressant effects of intramuscularly administered buprenorphine over a wide dose range in primates breathing air mixed with 5% CO₂. A and C, f values for low doses (A) and high doses (C) of buprenorphine. B and D, V_e values for low doses (B) and high doses (D) of buprenorphine. Each data point represents a mean ± S.E.M. (n = 6). *, a significant difference from the vehicle condition for all time points (p < 0.05). The same data of buprenorphine (0.1 mg/kg) are presented in A and B (●) and C and D ▼) for comparison with other doses.

Fig. 3.

Itch/scratching eliciting effects of intramuscularly administered buprenorphine over a wide dose range in primates. Each data point represents a mean ± S.E.M. (n = 6). *, a significant difference from the vehicle condition from the time point 30 min to the corresponding time point for each dose (p < 0.05).

Fig. 4.

Effects of MOP and NOP antagonists on buprenorphine-induced antinociception in primates. The MOP antagonist naltrexone (0.03 mg/kg) or the NOP antagonist J-113397 (0.1 mg/kg) was administered subcutaneously 15 min before determination of buprenorphine's dose-response curve. Each data point represents a mean ± S.E.M. (n = 6).

Fig. 5.

Effects of MOP and NOP antagonists on buprenorphine-induced respiratory depression in primates. A single dose of the MOP antagonist naltrexone (0.03 mg/kg) or the NOP antagonist J-113397 (0.1 mg/kg) was administered intramuscularly 30 min before administration of the first dose of buprenorphine. Data represent the changes of both parameters, ƒ (A) and V_E (B), in primates breathing air mixed with 5% CO₂. Each data point represents a mean ± S.E.M. (n = 6).

Fig. 6.

Effects of MOP and NOP antagonists on buprenorphine-induced itch/scratching activity in primates. A single dose of the MOP antagonist naltrexone (0.03 mg/kg) or the NOP antagonist J-113397 (0.1 mg/kg) was administered intramuscularly 15 min before determination of buprenorphine's dose-response curve. Each data point represents a mean ± S.E.M. (n = 6).

Fig. 7.

Effects of the NOP agonists Ro 64-6198 and SCH 221510 in combination with buprenorphine on antinociception, respiratory depression, and itch/scratching responses. A and B, dose-response curves for antinociception produced by buprenorphine alone and in mixtures with either Ro 64-6198 (A) or SCH 221510 (B). C and D, dose-response curves for respiratory depression produced by buprenorphine alone and in the same dose combination, as presented in A and B, with either Ro 64-6198 (C) or SCH 221510 (D). E and F, dose-response curves for itch/scratching responses elicited by buprenorphine alone or in the same dose combination, as presented in A and B, with either Ro 64-6198 (E) or SCH 221510 (F). All drugs were administered intramuscularly in the same subjects. Each data point represents a mean ± S.E.M. (n = 6). *, a significant difference from the dosing condition of buprenorphine (0.003 mg/kg) alone (p < 0.05).

Fig. 8.

Effects of the NOP agonists Ro 64-6198 and SCH 221510 in combination with buprenorphine on antinociceptive effects against 50°C water. Isobolograms for the mixture of buprenorphine with either Ro 64-6198-induced antinociception (A) or SCH 221510-induced antinociception (B) are displayed. . Each data point represents a mean ± S.E.M. (n = 6). See Tables 2 and 3 and Data Analysis for other details.