Table 3. Development of tolerance and physical dependence to μ-δ bivalent ligands after chronic i.c.v. administration.
| ED50, nmol (95% C.I.)
|
||||
|---|---|---|---|---|
| Ligand | i.c.v. saline | i.c.v. ligand | Ligand ED50/saline ED50* | No. of jumps (S.E.M.) |
| Morphine | 4.54 (3.51–5.56) | 26.80 (20.82–32.78) | 6.0 | 100 (15) |
| 3 (MDAN-16) | 1.62 (1.35–1.89) | 4.72 (3.47–5.91) | 2.8 | 30 (23) |
| 4 (MDAN-17) | 1.54 (0.89–2.20) | 5.61 (4.39–6.83) | 3.6 | 0.9 (0.7) |
| 5 (MDAN-18) | 1.29 (0.97–1.61) | 4.75 (3.50–6.00) | 3.7 | 8.9 (3.0) |
| 6 (MDAN-19) | 0.42 (0.37–0.47) | 0.40 (0.33–0.47) | 1.0 | 3.6 (1.7) |
| 7 (MDAN-20) | 0.17 (0.15–0.20) | 0.17 (0.13–0.21) | 1.0 | 0.4 (0.4) |
| 8 (MDAN-21) | 0.10 (0.09–0.11) | 0.10 (0.09–0.11) | 1.0 | 3.5 (1.7) |
| 11 (MA-19) | 0.04 (0.03–0.05) | 0.22 (0.19–0.26) | 5.5 | 83 (13) |
| 11 and 15 (MA-19 and DN-20) | 0.04 (0.02–0.05) | 0.33 (0.28–0.37) | 8.9 | 29 (8) |
Saline or the indicated ligand were infused i.c.v. for 3 days via osmotic minipump. On day 4, naloxone (1 mg/kg, s.c.) was administered and the number of jumps was counted. The minipump was removed, and 4 h later, ligands were administered i.c.v. and antinociceptive ED50 values were determined.
*
Ligand ED50/saline ED50 ratio is an indicator of fold tolerance development