Genotype-dependent behavioral sensitivity to mu vs. kappa opiate agonists. II. Antinociceptive tolerance and physical dependence.

Antinociceptive tolerance, cross-tolerance and an expression of physical dependence to morphine (MRP) and (+/-)-ethylketazocine (EKC) were quantitatively compared using two inbred strains of mice. The measure of analgesia was the area of a time-response curve (escape reaction, 52 degrees C heated plate). (-)-EKC was 1.5 to 1.8 times more potent than MRP in both C57B1/6J (C57) and DBA/2J (DBA) mice. The latter strain was significantly more sensitive to both analgesics. Paradoxically, after an identical dose, the MRP content in DBA plasma, brain and spinal cord was only 56 to 73% of that in C57 tissues. Mice rendered tolerant to MRP (32 mg/kg s.c./b.i.d./1 week) exhibited equivalent cross-tolerance to EKC. In contrast, mice made tolerant to EKC (32 mg/kg s.c./b.i.d./1 week) retained substantial sensitivity to MRP. Comparisons between drugs and strains indicate that analgesic tolerance and physical dependence did not develop in parallel.