Modulation of neuronal nicotinic acetylcholine receptors by halothane in rat cortical neurons

T. Mori*, G. L. Aistrup, K. Nishikawa, W. Marszalec, J. Z. Yeh, T. Narahashi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Inhalational general anesthetics have recently been shown to inhibit neuronal nicotinic receptors (nnAChRs) expressed in Xenopus oocytes and in molluscan neurons. However, drug actions on these systems are not necessarily the same as those seen on native mammalian neurons. Thus we analyzed the detailed mechanisms of action of halothane on nnAChRs using rat cortical neurons in long-term primary culture. Currents induced by applications of ACh via a U-tube system were recorded by the whole-cell patch clamp technique. ACh evoked two types of currents, α-bungarotoxin (α-BuTX)-sensitive, fast desensitizing (α7-type) currents and α-BuTX-insensitive, slowly desensitizing (α4β2-type) currents. Halothane suppressed α4β2-type currents more than α7-type currents with IC50s of 105 μM and 552 μM, respectively. Halothane inhibited the activated and resting α4β2-type receptors with similar onset rates, with respective time constants of 295 and 218 msec. The rate of recovery after washout from halothane block in the activated receptors was faster than that in the resting receptors, with respective time constants of 285 and 499 msec. The halothane block was not due to desensitization because the recovery from ACh desensitization occurred slowly with a time constant of 5.65 sec. Chlorisondamine, an irreversible open channel blocker for nnAChRs, caused a time-dependent block, which was attenuated by halothane. This result is consistent with the mechanism in which halothane causes flickering of open channels as seen in muscle nAChRs. In conclusion, halothane blocks α4β2-type nnAChRs more potently than α7-type receptors, the activated and resting receptors are blocked similarly, and the block is not due to receptor desensitization. Halothane binding site may be related to the chlorisondamine binding site for open channel block. Halothane block of nnAChRs is deemed to play an important role in anesthesia via a direct action on the receptor and an indirect action to suppress transmitter release.

Original languageEnglish (US)
Pages (from-to)163-164
Number of pages2
JournalAnesthesia and Resuscitation
Volume36
Issue number4
StatePublished - 2000

Keywords

  • Cortical neuron
  • Halothane
  • Ion channel
  • Nicotinic acetylcholine receptor

ASJC Scopus subject areas

  • Emergency Medicine
  • Anesthesiology and Pain Medicine

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