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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM070726-05
Application #
7578342
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2005-03-01
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2009
Total Cost
$263,528
Indirect Cost
Name
University of Virginia
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Eckle, Veit-Simon; Digruccio, Michael R; Uebele, Victor N et al. (2012) Inhibition of T-type calcium current in rat thalamocortical neurons by isoflurane. Neuropharmacology 63:266-73
Orestes, Peihan; Bojadzic, Damir; Lee, Jeonghan et al. (2011) Free radical signalling underlies inhibition of CaV3.2 T-type calcium channels by nitrous oxide in the pain pathway. J Physiol 589:135-48
Sanchez, Victoria; Feinstein, Shawn D; Lunardi, Nadia et al. (2011) General Anesthesia Causes Long-term Impairment of Mitochondrial Morphogenesis and Synaptic Transmission in Developing Rat Brain. Anesthesiology 115:992-1002
Eckle, Veit-Simon; Todorovic, Slobodan M (2010) Mechanisms of inhibition of CaV3.1 T-type calcium current by aliphatic alcohols. Neuropharmacology 59:58-69
Joksovic, Pavle M; Choe, Won Joo; Nelson, Michael T et al. (2010) Mechanisms of inhibition of T-type calcium current in the reticular thalamic neurons by 1-octanol: implication of the protein kinase C pathway. Mol Pharmacol 77:87-94
Orestes, Peihan; Todorovic, Slobodan M (2010) Are neuronal voltage-gated calcium channels valid cellular targets for general anesthetics? Channels (Austin) 4:518-22
Joksovic, Pavle M; Todorovic, Slobodan M (2010) Isoflurane modulates neuronal excitability of the nucleus reticularis thalami in vitro. Ann N Y Acad Sci 1199:36-42
Orestes, Peihan; Bojadzic, Damir; Chow, Robert M et al. (2009) Mechanisms and functional significance of inhibition of neuronal T-type calcium channels by isoflurane. Mol Pharmacol 75:542-54
Joksovic, Pavle M; Weiergräber, Marco; Lee, WooYong et al. (2009) Isoflurane-sensitive presynaptic R-type calcium channels contribute to inhibitory synaptic transmission in the rat thalamus. J Neurosci 29:1434-45
Eckle, V-S; Hucklenbruch, C; Todorovic, S M (2009) [What do we know about anesthetic mechanisms?: hypnosis, unresponsiveness to surgical incision and amnesia]. Anaesthesist 58:1144-9

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