Anesthetics block neuronal voltage-gated Ca2+ currents

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DESCRIPTION (provided by applicant): The mechanisms by which general anesthetics produce anesthesia are not completely understood but it is likely that they involve specific effects on multiple classes of ion channels that control excitability of nerve cells. Neuronal high voltage-activated (HVA) and low voltage-activated (LVA) or transient (T-type) Ca2+ channels play a key role in control of neuronal excitability and transmitter release, and are implicated in pain perception, memory and control of arousal. To address the potential role of T-type Ca2+ current inhibition in the action of anesthetics, we will examine the effects of general anesthetics in vitro in the neurons of thalamic reticular nucleus (nRT) in slices from young rats. Our preliminary results indicate that the volatile general anesthetics (VA) isoflurane and nitrous oxide (N2O; laughing gas) block slowly inactivating T-type Ca2+ currents and underlying burst of action potentials in nRT neurons in clinically relevant concentrations. This is important since thalamic neurons play a central role in generation of rhythmic oscillations, which in turn control the level of consciousness, sensory cognitive and pain pathways, as well as abnormal excitability that can contribute to seizures. Therefore, these experiments will help in better understanding of the contribution of actions of VAs on specific subtypes of Ca2+ channels to hypnotic-sedative, amnesic, anticonvulsant and analgesic components of anesthetic state. It is hoped that these studies will contribute to better and safer practice of clinical anesthesia and analgesia. The applicant proposes to follow up the initial findings with investigations of the anesthetic mechanisms of blockade of T currents in the somata, as well as dendrites of intact nRT neurons in slices. Additionally, the molecular identity of somatic and dendritic T channels in nRT neurons will be investigated. These experiments will set the stage for functional studies in thalamic slices where the roles of T type Ca2+ current in neuronal excitability, synaptic integration and synaptic transmission will be addressed. This potential role of VAs in disrupting synaptic transmission and synaptic integration mediated by T -type calcium currents in the thalamus, may underlie an important but unappreciated mechanism by which VAs depress excitation in CNS and contribute to the clinical effects of general anesthesia.