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Anaesthetic effects in thalamocortical neurons

University of British Columbia

The perturbation that is responsible for the anaesthetic-induced unconscious state remains undefined because of an incomplete understanding of awareness and the non-specific nature of anaesthetic actions. Recent investigations into sleep mechanisms show that thalamocortical neurons prevent throughput-gating of sensory information to the cerebral cortex, yet orchestrate oscillating cortical activity as part of consciousness. Extrinsic neuromodulation of membrane potential and intrinsic voltage-dependent firing patterns regulate this gating during wakefulness and sleep. The objective was to determine the effects of inhalational anaesthetics on intrinsic firing activities of thalamocortical neurons. Investigations were carried out on ventrobasal neurons from thalamic brain slices of juvenile rats. The whole-cell patch-clamp method was used with current-clamp and voltage-clamp recording techniques. Aqueous applications of the inhalational anaesthetic, isoflurane (IFL), were studied in detail at 22°C to determine concentration-response relations, to approximate in vivo potencies at 31°C, to compare effects of IFL with halothane and enflurane, and to assess the universality of anaesthetic action in thalamic neurons. IFL inhibited evoked tonic firing of action potentials (wakefulness mode) by increasing membrane conductance and inducing hyperpolarization in a reversible and concentrationdependent manner. IFL, halothane and enflurane were equipotent in producing similar effects, whereas IFL concentrations, that were proportionate to in vivo concentrations, increased conductance by 15-30%. Despite the hyperpolarization, IFL also suppressed burst firing (sleep mode). The inhibition of firing was mainly due to a shunt, as the increased conductance "shortcircuited" the effectiveness of DC current injections which thereby reduced the spatial distribution of voltage responses. The increased conductance was direct (postsynaptic) and voltage-independent, reversing near the calculated equilibrium potential for K⁺. The IFL-induced conductance increase was dependent on the external [K⁺] and was suppressed by either external Ba2⁺ or internal Cs⁺ applications. In summary, IFL inhibited thalamic relay neuron excitabilities by increasing a K⁺ leak conductance. Together with the thalamic roles in consciousness of cortical gateway and orchestrator, suppression of the activities of thalamocortical neurons may be critically important to the production of in vivo anaesthesia.

Thesis/Dissertation

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2009-04-03

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http://hdl.handle.net/2429/6795

Pharmacology

University of British Columbia

UBCV

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