Sevoflurane depresses glutamatergic neurotransmission to brainstem inspiratory premotor neurons but not postsynaptic receptor function in a decerebrate dog model.
BACKGROUND
Inspiratory bulbospinal neurons in the caudal ventral medulla are premotor neurons that drive motoneurons, which innervate pump muscles such as the diaphragm and external intercostals. Excitatory drive to these neurons is mediated by N-methyl-d-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors and is modulated by an inhibitory gamma-aminobutyric acid type A (GABAA)ergic input. The authors investigated the effect of sevoflurane on these synaptic mechanisms in decerebrate dogs.


METHODS
Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration sevoflurane on extracellularly recorded activity of single neurons was measured during localized picoejection of the GABAA receptor blocker bicuculline and the glutamate agonists AMPA and NMDA. Complete blockade of the GABAAergic mechanism by bicuculline allowed differentiation between the effects of sevoflurane on overall GABAAergic inhibition and on overall glutamatergic excitation. The neuronal responses to exogenous AMPA and NMDA were used to estimate the anesthetic effect on postsynaptic glutamatergic neurotransmission.


RESULTS
One minimum alveolar concentration sevoflurane depressed the spontaneous activity of 23 inspiratory premotor neurons by (mean +/- SD) 30.0 +/- 21.0% (P < 0.001). Overall glutamatergic excitation was depressed 19.2 +/- 18.5% (P < 0.001), whereas overall GABAAergic inhibition was enhanced by 11.9 +/- 25.1% (P < 0.05). The postsynaptic responses to exogenous AMPA and NMDA did not change.


CONCLUSIONS
One minimum alveolar concentration depressed the activity of inspiratory premotor neurons by a reduction of glutamatergic excitation and an increase in overall inhibition. The postsynaptic AMPA and NMDA receptor response was unchanged. These findings contrast with studies in inspiratory premotor neurons where halothane did not change overall inhibition but significantly reduced the postsynaptic glutamate receptor response.
Department of Anesthesiology, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, USA.
Astrid G
AG
Stucke
Edward J
EJ
Zuperku
Viseslav
V
Tonkovic-Capin
Mirko
M
Krolo
Francis A
FA
Hopp
John P
JP
Kampine
Eckehard A E
EA
Stuth
D000818:Animals; D001933:Brain Stem / Q000187:drug effects* / Q000502:physiology; D003655:Decerebrate State / Q000503:physiopathology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D001239:Inhalation / Q000187:drug effects* / Q000502:physiology; D008738:Methyl Ethers / Q000494:pharmacology*; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017470:Receptors, Glutamate / Q000502:physiology*; D000077149:Sevoflurane; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D008738:Methyl Ethers; D017470:Receptors, Glutamate; D000077149:Sevoflurane; D016202:N-Methylaspartate