ROLE OF GABAERGIC SYSTEMS IN THE DEVELOPMENT OF MORPHINE-TOLERANCE INFORMALIN-TREATED MICE

Since the development of tolerance to morphine antinociception in form alin-treated mice was delayed and diazepam normalized the delay, the i nvolvement of GABAergic systems in the process was investigated. Gamma amino-n-butyric acid (GABA) at 10 mg/kg and the GABA(A)-receptor agon ist muscimol at 0.05 mg/kg, i.p., 30 min before daily morphine injecti on at 10 mg/kg, s.c. completely reversed the delay in the development of morphine tolerance in the formalin-treated mice. The GABA(A) antago nist bicuculline at 1 mg/kg and the Cl--channel blocker picrotoxin at 1 mg/kg extinguished the reverse effect of muscimol and GABA(A) respec tively. In contrast, the GABA, antagonist CGP 35348 (3-aminopropane-di ethoxymethyl-phosphinic acid) up to 100 mg/kg, i.p. failed to abolish the GABA effect; and baclofen, a GABA(A)-receptor agonist, at 0.5 and 2 mg/kg, i.p., 30 min before morphine was without effect on the delay. On the other hand, bicuculline was incapable of abolishing the revers e effects of diazepam on the delay of tolerance development; and likew ise, the reverse effect of muscimol was not affected by flumazenil. No appreciable influence of these GABA-related compounds was seen on mor phine antinociception itself nor the development of tolerance in norma l mice. These results suggest that the benzodiazepine-GABA(A)-Cl- chan nel complex is involved in the mechanism underlying the delay of the d evelopment of morphine tolerance in formalin-treated mice; however, it is deduced that benzodiazepine-receptor and GABAergic systems are not always functionally coupled to each other in the mechanisms.