TABLE 2

PKC and GRK inhibitors and ED50 and potency ratio values

Mice were either repeatedly administered opioid over 8 h and then administered vehicle intracerebroventricularly immediately before being challenged with the opioid (opioid + vehicle) or repeatedly administered opioid over 8 h and then administered the PKC inhibitor Gö6976 (4 nmol/mouse i.c.v.; A), the GRK inhibitor β-ARK 1 inhibitor (20 nmol/mouse i.c.v.; B), or the GRK inhibitor Ro 32-0432 (2 nmol/mouse i.c.v.; C) immediately before being challenged with the opioid (opioid + inhibitor). Meperidine (40 mg/kg s.c.; A and B), morphine (10 mg/kg s.c.; A–C), and fentanyl (0.2 mg/kg s.c.; A and B) were administered every 2 h for a total of four injections, with inhibitor or vehicle and then test doses of the opioid administered 2 h after the last injection. DAMGO (25.7 ng/kg i.c.v.; A–C) was administered every 1 h for a total of eight injections, with inhibitor or vehicle and then test doses of DAMGO administered 1 h after the last injection. Thirty minutes (20 min for DAMGO) after test doses were administered, tail immersion latencies were determined for construction of dose-response curves as well as calculation of ED50 values and potency ratios.

TreatmentED50 Value (95% CL)Potency Ratio (95% CL)
A. PKC inhibitor Gö6976
    Meperidine + vehicle41.9 mg/kg (37.1, 47.3)
    Meperidine + Gö697615.0 mg/kg (12.9, 17.5)vs. meperidine + vehicle2.76 (2.41, 3.16)
    Fentanyl + vehicle 60.292 mg/kg (0.26, 0.33)
    Fentanyl + Gö6970.07 mg/kg (0.06, 0.07)vs. fentanyl + vehicle4.65 (4.12, 5.26)
    Morphine + vehicle16.3 mg/kg (13.4, 19.8)
    Morphine + Gö69763.6 mg/kg (2.6, 4.8)vs. morphine + vehicle4.33 (3.30, 5.20)
    DAMGO + vehicle28.3 ng/kg (25.7, 36.0)
    DAMGO + Gö697626.2 ng/kg (25.7, 30.8)vs. DAMGO + vehicle1.07 (0.89, 1.30)
B. GRK inhibitor β-ARK 1 inhibitor
    Meperidine + vehicle51.4 mg/kg (46.4, 56.9)
    Meperidine + β-ARK 146.3 mg/kg (42.5, 50.5)vs. meperidine + vehicle1.10 (1.00, 1.21)
    Fentanyl + vehicle0.392 mg/kg (0.35, 0.44)
    Fentanyl + β-ARK 10.395 mg/kg (0.35, 0.45)vs. fentanyl + vehicle1.01 (0.90, 1.13)
    Morphine + vehicle22.4 mg/kg (19.3, 26.1)
    Morphine + β-ARK 120.3 mg/kg (17.6, 23.3)vs. morphine + vehicle1.10 (0.92, 1.32)
    DAMGO + vehicle30.3 ng/kg (25.7, 36.0)
    DAMGO + β-ARK 111.3 ng/kg (10.3, 15.4)vs. DAMGO + vehicle2.57 (2.28, 2.88)
C. GRK inhibitor Ro 32-0432
    Morphine + vehicle23.2 mg/kg (20.0, 26.8)
    Morphine + Ro 32-043225.9 mg/kg (22.6, 29.8)vs. morphine + vehicle1.11 (0.93, 1.33)
    DAMGO + vehicle27.7 ng/kg (25.7, 30.8)
    DAMGO + Ro 32-043211.8 ng/kg (10.3, 15.4)vs. DAMGO + vehicle2.34 (2.04, 2.65)