The goal is to understand the molecular and cellular mechanisms by which volatile anesthetics alter nervous system function. These drugs, which are administered to an estimated 20 million Americans annually, have many serious side effects, but a lack of knowledge about their basic mechanism of action hinders the development of improved agents. The specific hypothesis addressed by this proposal is that the multiple actions of volatile anesthetics in the nervous system occur principally through normal cellular regulatory mechanisms common to diverse ion channels. Studies to test this hypothesis will be carried out in rat hippocampal brain slices and dissociated guinea pig hippocampal neurons. Experiments will focus on three ion currents that are known to be altered by volatile anesthetics and that are modulated by second messenger/protein kinases and phosphatases; 1) calcium activated potassium current; 2) voltage activated calcium currents; and 3) GABA/a chloride current. Three specific mechanisms of ion channel regulation will be tested for their roles in volatile anesthetic action: 1) phosphorylation of ion channels, both as a general mechanism and via specific protein kinases and phosphatases; 2) free radical mediated channel modulation participates in producing the clinical state of anesthesia. If so, it raises the possibility that improved anesthetics with more specific actions and desirable properties, and fewer adverse effects, can be developed by targeting specific regulatory pathways.
| Banks, M I; Li, T B; Pearce, R A (1998) The synaptic basis of GABAA,slow. J Neurosci 18:1305-17 |
| Pearce, R A (1996) Volatile anaesthetic enhancement of paired-pulse depression investigated in the rat hippocampus in vitro. J Physiol 492 ( Pt 3):823-40 |
| Pearce, R A; Grunder, S D; Faucher, L D (1995) Different mechanisms for use-dependent depression of two GABAA-mediated IPSCs in rat hippocampus. J Physiol 484 ( Pt 2):425-35 |
| Pearce, R A (1993) Physiological evidence for two distinct GABAA responses in rat hippocampus. Neuron 10:189-200 |
| Banks, M I; Pearce, R A; Smith, P H (1993) Hyperpolarization-activated cation current (Ih) in neurons of the medial nucleus of the trapezoid body: voltage-clamp analysis and enhancement by norepinephrine and cAMP suggest a modulatory mechanism in the auditory brain stem. J Neurophysiol 70:1420-32 |
