Background: Dexmedetomidine (DEX) is a highly selective α2 agonist with marked sedative and analgesic properties thought to be mediated via reduction of central noradrenergic transmission. Because an anticonvulsant effect is associated with increased noradrenergic activity, we investigated the possible proconvulsant effects of DEX in an experimental model of generalized seizures. Methods: Male rats (n = 82) were administered 0.9% saline as placebo (n = 18) or pretreatment drug(s) before initiation of an infusion of pentylenetetrazol (PTZ) at 5.5 mg · kg-1 · min-1. The total dose of PTZ required to elicit electroencephalographic (EEG) and behavioral seizure activity was assessed. Blood samples were obtained 15 min after initiation of infusion (82.5 mg/kg) for determination of serum PTZ concentrations by gas chromatography. Pretreatment drug groups included DEX (20 μg/kg [n = 11], 100 μg/kg [n = 14], and 500 μg/kg [n = 10]); L-medetomidine (500 μg/kg [n = 7]); the α2 antagonist atipamezole (500 μg/kg [n = 9]); and atipamezole (500 μg/kg) before DEX (100 μg/kg [n = 7] and 500 μg/kg [n = 6]). Results: In control animals, PTZ 25-35 mg/kg induced EEG evidence of epileptiform activity. The mean dose to EEG epileptiform activity and clonic convulsions was 30 ± 5.8 (SE) and 59 ± 3.2 mg/kg, respectively. Infusion of DEX at 100 and 500 μg/kg resulted in a marked sedative response and reduced the EEG seizure threshold of PTZ to 18 ± 1.5 and 7 ± 1.8 mg/kg, respectively (P < 0.05 at both doses). The clonic convulsant threshold also was significantly decreased in both groups, to 37 ± 3.2 and 28 ± 2.3 mg/kg (P < 0.01 at each dose). Before clonic convulsion, a significantly greater number of motor seizure manifestations were scored in the DEX-treated animals at all three dose levels compared with the number scored in control animals. The proconvulsant action of DEX was not a result of alteration of PTZ kinetics, because serum concentrations did not differ between control and DEX-treated animals. Animals treated with L-medetomidine demonstrated more paroxysmal motor phenomena before clonic seizures than controls (P < 0.01) although the clonic seizure threshold was not altered. Atipamezole alone did not alter background EEG, nor did it affect the clonic convulsant threshold. Atipamezole did, however, block the proconvulsant behavioral action at both doses of DEX, raising clonic seizure threshold from 37 ± 3.2 to 59 ± 5.8 mg/kg (100 μg/kg DEX, P < 0.05) and from 28 ± 2.3 to 59 ± 6.9 mg/kg (500 μg/kg DEX, P < 0.01). Conclusions: DEX exerted a significant proconvulsant action in the PTZ experimental seizure model. The pharmacodynamic effect was dose-dependent and stereospecific and was blocked by the selective α2- receptor antagonist atipamezole. These data are consistent with previous data demonstrating that inhibition of central noradrenergic transmission facilitates seizure expression. Further evaluation of DEX for possible clinical proconvulsant effects may be warranted.
ASJC Scopus subject areas
- Anesthesiology and Pain Medicine