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.
Rahman
A F
AF
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Nagasaki University, Japan.
Takahashi
M
M
Kaneto
H
H
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D003975:Diazepam / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004361:Drug Tolerance; D005442:Flumazenil / Q000494:pharmacology; D005557:Formaldehyde / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000494:pharmacology*; D009118:Muscimol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects; D018079:Receptors, GABA / Q000187:drug effects*
D000701:Analgesics, Opioid; D018755:GABA Agonists; D018756:GABA Antagonists; D018079:Receptors, GABA; D005557:Formaldehyde; D009118:Muscimol; D005442:Flumazenil; D009020:Morphine; D001418:Baclofen; D003975:Diazepam; D001640:Bicuculline