Subanesthetic concentrations of volatile anesthetics potently depress upper airway defense mechanisms. In particular, hypoglossal motor control of the tongue that maintains airway patency during inspiration is severely compromised. The overall goal of this proposal is to characterize the actions of volatile anesthetics on specific synaptic mechanisms and neuronal excitability within spontaneously active mammalian inspiratory hypoglossal motoneurons (IHMNs) in vivo. While in vitro studies have identified potential mechanisms for anesthetic-induced depression, this proposal is unique because we focus on functionally identified IHMNs in an intact neuronal network under in vivo conditions, where neurotransmitters are released at physiologically relevant levels. Our overall hypothesis is 1) that the activity of IHMNs is dependent on synaptic inputs mediated by ligand-gated glutamatergic, GABAergic, and glycinergic and G-protein coupled serotonergic and adrenergic receptors, and 2) the effects of volatile anesthetics on neuronal activity are due to depression of excitatory and enhancement of inhibitory synaptic neurotransmission, rather than non-synaptically mediated intrinsic membrane mechanisms such as changes in K+conductance. Recordings of action potentials from IHMNs in conjunction with localized pressure microejection of neurotransmitter agonists and antagonists will be used to examine the relative importance of anesthetic-induced alterations on excitatory and inhibitory neurotransmission and intrinsic neuronal excitability.
Three specific aims have been developed to test our hypothesis in a decerebrate canine model.
In specific aim 1, we will identify the key contributing neurotransmitters in IHMNs and determine their physiological receptor activity.
In specific aim 2, we will determine the effect of subanesthetic concentrations of volatile anesthetics on overall synaptic transmission of the key neurotransmitter systems in IHMNs.
In specific aim 3, we will determine the effects of volatile anesthetics on the postsynaptic receptor responses for the key contributing neurotransmitters in IHMNs. The insights that will be gained from our proposed studies will contribute to our understanding of the effects of volatile anesthetics on upper airway function in the perioperative period and may suggest rational mechanism-based therapeutic interventions to mitigate these effects in the postoperative setting when patients are at high risk of airway- related morbidity. ? ?
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