Hyperalgesic effect induced by barbiturates, midazolam and ethanol: pharmacological evidence for GABA-A receptor involvement.
The involvement of GABA-A receptors in the control of nociception was studied using the tail-flick test in rats. Non-hypnotic doses of the barbiturates phenobarbital (5-50 mg/kg), pentobarbital (17-33 mg/kg), and thiopental (7.5-30 mg/kg), of the benzodiazepine midazolam (10 mg/kg) or of ethanol (0.4-1.6 g/kg) administered by the systemic route reduced the latency for the tail-flick response, thus inducing a 'hyperalgesic' state in the animals. In contrast, non-convulsant doses of the GABA-A antagonist picrotoxin (0.12-1.0 mg/kg) administered systemically induced an increase in the latency for the tail-flick response, therefore characterizing an 'antinociceptive' state. Previous picrotoxin (0.12 mg/kg) treatment abolished the hyperalgesic state induced by effective doses of the barbiturates, midazolam or ethanol. Since phenobarbital, midazolam and ethanol reproduced the described hyperalgesic effect of GABA-A-specific agonists (muscimol, THIP), which is specifically antagonized by the GABA-A antagonist picrotoxin, our results suggest that GABA-A receptors are tonically involved in the modulation of nociception in the rat central nervous system.
Tatsuo
M A
MA
Departamento de Farmacologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brasil.
Yokoro
C M
CM
Salgado
J V
JV
Pesquero
S M
SM
Santana
M A
MA
Francischi
J N
JN
D000818:Animals; D001463:Barbiturates / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D006930:Hyperalgesia / Q000139:chemically induced*; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D010424:Pentobarbital / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D013874:Thiopental / Q000494:pharmacology
D001463:Barbiturates; D002492:Central Nervous System Depressants; D000431:Ethanol; D018756:GABA Antagonists; D018757:GABA Modulators; D008874:Midazolam; D010424:Pentobarbital; D010634:Phenobarbital; D010852:Picrotoxin; D011963:Receptors, GABA-A; D013874:Thiopental