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γ-Hydroxybutyrate (GHB)-induced respiratory depression: combined receptor-transporter inhibition therapy for treatment in GHB overdose - PubMed

γ-Hydroxybutyrate (GHB)-induced respiratory depression: combined receptor-transporter inhibition therapy for treatment in GHB overdose

Bridget L Morse et al. Mol Pharmacol. 2012 Aug.

Abstract

Overdose of γ-hydroxybutyrate (GHB) frequently causes respiratory depression, occasionally resulting in death; however, little is known about the dose-response relationship or effects of potential overdose treatment strategies on GHB-induced respiratory depression. In these studies, the parameters of respiratory rate, tidal volume, and minute volume were measured using whole-body plethysmography in rats administered GHB. Intravenous doses of 200, 600, and 1500 mg/kg were administered to assess the dose-dependent effects of GHB on respiration. To determine the receptors involved in GHB-induced respiratory depression, a specific GABA(B) receptor antagonist, (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911), and a specific GABA(A) receptor antagonist, bicuculline, were administered before GHB. The potential therapeutic strategies of receptor inhibition and monocarboxylate transporter (MCT) inhibition were assessed by inhibitor administration 5 min after GHB. The primary effect of GHB on respiration was a dose-dependent decrease in respiratory rate, accompanied by an increase in tidal volume, resulting in little change in minute volume. Pretreatment with 150 mg/kg SCH50911 completely prevented the decrease in respiratory rate, indicating agonism at GABA(B) receptors to be primarily responsible for GHB-induced respiratory depression. Administration of 50 mg/kg SCH50911 after GHB completely reversed the decrease in respiratory rate; lower doses had partial effects. Administration of the MCT inhibitor l-lactate increased GHB renal and total clearance, also improving respiratory rate. Administration of 5 mg/kg SCH50911 plus l-lactate further improved respiratory rate compared with the same dose of either agent alone, indicating that GABA(B) and MCT inhibitors, alone and in combination, represent potential treatment options for GHB-induced respiratory depression.

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Figures

Fig. 1.
Fig. 1.

Dose-dependent effects of GHB on measures of respiration. GHB was administered intravenously at time 0. Data are presented as mean ± S.D.; n = 4 to 6.

Fig. 2.
Fig. 2.

Effect of GHB administration on respiratory pattern. Displayed are sample 10-s interval plethysmography traces obtained at baseline (A) and 30 min after administration of GHB 1500 mg/kg i.v. (B).

Fig. 3.
Fig. 3.

Effect of specific receptor inhibitors on GHB-induced respiratory depression. GHB (1500 mg/kg) was administered intravenously, alone and after pretreatment with the GABAB receptor antagonist SCH50911 (150 mg/kg) and the GABAA receptor antagonist bicuculline methiodide (5 mg/kg). Inhibitors were administered intravenously 5 min before GHB. Data are presented as mean ± S.D.; n = 3 to 5.

Fig. 4.
Fig. 4.

Effect of potential treatment strategies on respiratory rate after GHB administration. A, dose-dependent effects of SCH50911. B, effects of

l

-lactate and

l

-lactate and SCH50911 combination therapy. All treatments were administered intravenously 5 min after GHB (1500 mg/kg i.v.). Data are presented as mean ± S.D.; n = 3 to 5.

Fig. 5.
Fig. 5.

Plasma lactate concentrations after administration of

l

-lactate alone and with GHB. Data are presented as mean ± S.D.; n = 4 to 5.

l

-Lactate low-dose (LD) = 66 mg/kg + 302.5 mg/kg/h.

l

-Lactate high-dose (HD) = 66 mg/kg + 605 mg/kg/h.

l

-Lactate LD and HD were administered alone at time 0.

l

-Lactate LD was administered 5 min after GHB when administered concomitantly.

Fig. 6.
Fig. 6.

Effect of

l

-lactate on respiration. Data are presented as mean ± S.D.; n = 4.

l

-Lactate high dose (HD) = 66 mg/kg + 605 mg/kg/h, administered at time 0.

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