Hyperalgesic effect induced by barbiturates, midazolam and ethanol: pharmacological evidence for GABA-A receptor involvement

Abstract

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.

Pretreatment with Dexmedetomidine or Thiopental Decreases Myoclonus after Etomidate: A Randomized, Double-Blind Controlled Trial

“…However, thiopental is a short-acting barbiturate and is not analgesic. Since phenobarbital has a hyperalgesic effect on GABA-A-specific agonists [21], a low dose of this drug, as used in the current study, causes hyperalgesia (antanalgesia). This study confirms a previous report of hyperalgesia in association with small doses of thiopental [22].…”

Prevention by celecoxib of secondary hyperalgesia induced by formalin in rats

“…This modification has been published elsewhere (Tatsuo et al, 1997). In brief, hyperalgesia was defined as a decrease in the latency for rats to withdraw their tails from a noxious radiant heat source (TF latency).…”

Ethanol Increases Mechanical Pain Sensitivity in Rats via Activation of GABAA Receptors in Medial Prefrontal Cortex

“…The antinociception induced by acute doses of ethanol is fully suppressed by intrathecal administration of flumazenil, a GABA A receptor antagonist [20], and increased by benzodiazepines (diazepam and midazolam) [43,44], implicating the participation of the spinal dorsal horn in the ethanol-induced analgesia. However, it has also been reported that systemic administration of non-hypnotic doses of ethanol and barbiturates to rats results in reduction of tail-flick latency and this is abolished by non-convulsant doses of the GABA A receptor channel blocker picrotoxin, indicating involvement of GABAergic mechanisms in the mediation of ethanol-induced hyperalgesia [22]. Other studies have demonstrated that intracerebroventricular, but not intrathecal administration of these drugs induces a similar hyperalgesic state that is also reversed by a GABA A receptor blocker [45,46].…”

“…On one hand, ethanol has been shown to have an analgesic effect by systemic (intraperitoneal, i.p.) administration [18][19][20][21], but on the other hand, a hyperalgesic effect can also be induced by systemic or intracerebroventricular administration [22]. Human and animal studies have respectively demonstrated that cerebral blood flow [23][24][25] and c-Fos immunoreactivity [26,27] in the PFC are significantly increased after acute alcohol administration.…”