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.
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D004361:Drug Tolerance; D016314:Ethylketocyclazocine; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009020:Morphine / Q000378:metabolism / Q000494:pharmacology; D009293:Opioid-Related Disorders; D010146:Pain / Q000503:physiopathology*; D011957:Receptors, Opioid / Q000187:drug effects* / Q000502:physiology; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013045:Species Specificity
D000700:Analgesics; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D016314:Ethylketocyclazocine; D009020:Morphine; D003496:Cyclazocine