title: γ-Hydroxybutyrate (GHB)-induced respiratory depression: combined receptor-transporter inhibition therapy for treatment in GHB overdose.
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.
authors.affiliation: University at Buffalo, 352 Kapoor Hall, Buffalo, NY 14214, USA.
authors.forename: Bridget L
authors.initials: BL
authors.lastname: Morse
authors.forename: Nisha
authors.initials: N
authors.lastname: Vijay
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Morris
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose; D008297:Male; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000502:physiology; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D012978:Sodium Oxybate / Q000378:metabolism / Q000633:toxicity*; D016896:Treatment Outcome
chemical_list: C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; C039403:4-hydroxybutyric acid receptor; D009025:Morpholines; D011956:Receptors, Cell Surface; D012978:Sodium Oxybate; D001640:Bicuculline