Role of GABAergic systems in the development of morphine tolerance in formalin-treated mice.

Since the development of tolerance to morphine antinociception in formalin-treated mice was delayed and diazepam normalized the delay, the involvement of GABAergic systems in the process was investigated. Gamma amino-n-butyric acid (GABA) at 10 mg/kg and the GABAA-receptor agonist muscimol at 0.05 mg/kg, i.p., 30 min before daily morphine injection at 10 mg/kg, s.c. completely reversed the delay in the development of morphine tolerance in the formalin-treated mice. The GABAA antagonist bicuculline at 1 mg/kg and the Cl(-)-channel blocker picrotoxin at 1 mg/kg extinguished the reverse effect of muscimol and GABA, respectively. In contrast, the GABAB antagonist CGP 35348 (3-aminopropane-diethoxymethyl-phosphinic acid) up to 100 mg/kg, i.p. failed to abolish the GABA effect; and baclofen, a GABAB-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 reverse effects of diazepam on the delay of tolerance development; and likewise, the reverse effect of muscimol was not affected by flumazenil. No appreciable influence of these GABA-related compounds was seen on morphine antinociception itself nor the development of tolerance in normal mice. These results suggest that the benzodiazepine-GABAA-Cl- channel complex is involved in the mechanism underlying the delay of the development 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.