Enhancement of homomeric glycine receptor function by long-chain alcohols and anaesthetics

Maria Paola Mascia, Tina K. Machu, R. Adron Harris

Research output: Contribution to journalArticle

187 Citations (Scopus)

Abstract

1. The effects of n-alcohols (ethanol to dodecanol) and anaesthetics on strychnine-sensitive glycine receptors were studied in Xenopus oocytes expressing homomeric α1 or α2 glycine receptor subunits, with the two electrode voltage-clamp recording technique. 2. The glycine-induced chloride conductance of homomeric a glycine receptors was potentiated by all the alcohols tested when an EC2 concentration of glycine was used. Homomeric α1 and α2 receptors were potentiated similarly by the n-alcohols, except that low concentrations of ethanol produced greater potentiation with α1, as previously reported. 3. Increasing the n-alcohol carbon number has been shown to increase the potency of the alcohols up to decanol at concentrations corresponding to EC50s for producing loss of righting reflex in tadpoles. However, dodecanol was no more potent than decanol, and only modest potentiation (30-60%) was obtained with dodecanol, in contrast to marked (150-200%) potentiation with the other alcohols. Thus, a 'cut-off' occurred at about dodecanol. 4. Propofol, alphaxalone, pentobarbitone, halothane and enflurane, reversibly potentiated the function of homomeric α1 glycine receptors at concentrations which represent approximately twice the EC50 for production of anaesthesia in mammals, but ketamine and etomidate were ineffective. 5. Two novel cyclobutane compounds were tested; the anaesthetic compound (1-chloro-1,2,2-trifluorocyclobutane) from 0.5 to 5 mM potentiated the action of glycine in a concentration-dependent manner; however, the non-anaesthetic analogue (1,2-dichloro-hexfluorocyclobutane) had no effect on glycine receptor function at concentrations (25 to 80 μM) predicted to be anaesthetic, based on the lipid solubility of this compound. 6. These results suggest that the a subunits of strychnine-sensitive glycine receptors contain sites of action for n-alcohols, propofol, alphaxalone, pentobarbitone and volatile anaesthetics, but not for ketamine and etomidate. Potentiation of glycine receptor function may contribute to the anaesthetic action of n-alcohols and volatile agents.

Original languageEnglish
Pages (from-to)1331-1336
Number of pages6
JournalBritish Journal of Pharmacology
Volume119
Issue number7
DOIs
StatePublished - 1 Jan 1996

Fingerprint

Glycine Receptors
Anesthetics
Dodecanol
Alcohols
Glycine
Etomidate
Strychnine
Ketamine
Propofol
Pentobarbital
Ethanol
Cyclobutanes
Righting Reflex
Enflurane
Patch-Clamp Techniques
Halothane
Xenopus
Solubility
Oocytes
Larva

Keywords

  • Anaesthetics
  • Strychnine-sensitive glycine receptors
  • n-alcohols
  • α subunits

Cite this

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abstract = "1. The effects of n-alcohols (ethanol to dodecanol) and anaesthetics on strychnine-sensitive glycine receptors were studied in Xenopus oocytes expressing homomeric α1 or α2 glycine receptor subunits, with the two electrode voltage-clamp recording technique. 2. The glycine-induced chloride conductance of homomeric a glycine receptors was potentiated by all the alcohols tested when an EC2 concentration of glycine was used. Homomeric α1 and α2 receptors were potentiated similarly by the n-alcohols, except that low concentrations of ethanol produced greater potentiation with α1, as previously reported. 3. Increasing the n-alcohol carbon number has been shown to increase the potency of the alcohols up to decanol at concentrations corresponding to EC50s for producing loss of righting reflex in tadpoles. However, dodecanol was no more potent than decanol, and only modest potentiation (30-60{\%}) was obtained with dodecanol, in contrast to marked (150-200{\%}) potentiation with the other alcohols. Thus, a 'cut-off' occurred at about dodecanol. 4. Propofol, alphaxalone, pentobarbitone, halothane and enflurane, reversibly potentiated the function of homomeric α1 glycine receptors at concentrations which represent approximately twice the EC50 for production of anaesthesia in mammals, but ketamine and etomidate were ineffective. 5. Two novel cyclobutane compounds were tested; the anaesthetic compound (1-chloro-1,2,2-trifluorocyclobutane) from 0.5 to 5 mM potentiated the action of glycine in a concentration-dependent manner; however, the non-anaesthetic analogue (1,2-dichloro-hexfluorocyclobutane) had no effect on glycine receptor function at concentrations (25 to 80 μM) predicted to be anaesthetic, based on the lipid solubility of this compound. 6. These results suggest that the a subunits of strychnine-sensitive glycine receptors contain sites of action for n-alcohols, propofol, alphaxalone, pentobarbitone and volatile anaesthetics, but not for ketamine and etomidate. Potentiation of glycine receptor function may contribute to the anaesthetic action of n-alcohols and volatile agents.",
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Enhancement of homomeric glycine receptor function by long-chain alcohols and anaesthetics. / Mascia, Maria Paola; Machu, Tina K.; Harris, R. Adron.

In: British Journal of Pharmacology, Vol. 119, No. 7, 01.01.1996, p. 1331-1336.

Research output: Contribution to journalArticle

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N2 - 1. The effects of n-alcohols (ethanol to dodecanol) and anaesthetics on strychnine-sensitive glycine receptors were studied in Xenopus oocytes expressing homomeric α1 or α2 glycine receptor subunits, with the two electrode voltage-clamp recording technique. 2. The glycine-induced chloride conductance of homomeric a glycine receptors was potentiated by all the alcohols tested when an EC2 concentration of glycine was used. Homomeric α1 and α2 receptors were potentiated similarly by the n-alcohols, except that low concentrations of ethanol produced greater potentiation with α1, as previously reported. 3. Increasing the n-alcohol carbon number has been shown to increase the potency of the alcohols up to decanol at concentrations corresponding to EC50s for producing loss of righting reflex in tadpoles. However, dodecanol was no more potent than decanol, and only modest potentiation (30-60%) was obtained with dodecanol, in contrast to marked (150-200%) potentiation with the other alcohols. Thus, a 'cut-off' occurred at about dodecanol. 4. Propofol, alphaxalone, pentobarbitone, halothane and enflurane, reversibly potentiated the function of homomeric α1 glycine receptors at concentrations which represent approximately twice the EC50 for production of anaesthesia in mammals, but ketamine and etomidate were ineffective. 5. Two novel cyclobutane compounds were tested; the anaesthetic compound (1-chloro-1,2,2-trifluorocyclobutane) from 0.5 to 5 mM potentiated the action of glycine in a concentration-dependent manner; however, the non-anaesthetic analogue (1,2-dichloro-hexfluorocyclobutane) had no effect on glycine receptor function at concentrations (25 to 80 μM) predicted to be anaesthetic, based on the lipid solubility of this compound. 6. These results suggest that the a subunits of strychnine-sensitive glycine receptors contain sites of action for n-alcohols, propofol, alphaxalone, pentobarbitone and volatile anaesthetics, but not for ketamine and etomidate. Potentiation of glycine receptor function may contribute to the anaesthetic action of n-alcohols and volatile agents.

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