Dr Robert Dickinson

Mechanisms of Anaesthesia & Neuroprotection

I am a lecturer in the Department of Anaesthetics, Pain Medicine & Intensive Care. My research interests are in molecular mechanisms of general anaesthesia and neuroprotection.  Despite the fact that general anaesthetics have been in clinical use for over 150 years, it is only relatively recently that specific molecular targets for general anaesthetics have started to be identified.  Attention has focused on a small number of ion-channels that are sensitive to anaesthetics at clinically relevant concentrations: inhibitory GABA _A & glycine receptors, excitatory NMDA receptors and background 2P domain potassium channels.  In my lab we use a variety of biophysical approaches to study the molecular actions of general anaesthetics; these include patch-clamp electrophysiology, site-directed mutagenesis, transient transfection and cell culture techniques.

 Enquiries from prospective PhD,  BSc, MRes or Erasmus students are always welcome

Projects have included thermodynamic studies of anaesthetic/receptor interactions, the effects of general anaesthetics on synaptic transmission in cultured hippocampal neurons and the effects of general anaesthetics on gamma (40Hz) oscillations. Recently our investigations have focussed on molecular targets of the neuroprotectant anaesthetic inert gas xenon.

That xenon is an anaesthetic has been known since the 1950s. However, it's mechanism of action was unknown.   Electrophysiological studies in our laboratory were the first to show that xenon inhibits the NMDA subtype of glutamate receptor.  NMDA receptors are membrane proteins with an integral cation-selective ion-channel.  NMDA receptors play novel roles in synaptic transmission and synaptic plasticity; they also play a key roles in pathological conditions such as ischemia, stroke and traumatic brain injury.  Our identification of xenon as an NMDA antagonist triggered interest in xenon's potential use as a neuroprotectant.  Xenon has now been shown to be neuroprotectant in models of stroke and traumatic brain injury and is currently in the early stages of clinical trials for use in neonatal asphyxia and cardiopulmonary bypass.

We  recently identified how xenon inhibits the NMDA receptor. Using a combination of molecular modelling and electrophysiology, we showed that xenon (and the volatile anaesthetic isoflurane) act at the glycine-binding site of the NMDA receptor.  The figure on the right shows  xenon atoms (red spheres) binding in the glycine site of the NR1 subunit of the NMDA receptor. This mode of inhibition of the NMDA receptor may explain why xenon is an effective neuroprotectant, apparently devoid deleterious clinical side-effects common with other NMDA receptor antagonists.

Our most recent work focuses on understanding the mechanism of xenon neuroprotection in models of  brain injury.  Currently there are no effective clinical treatments aimed at preventing neuronal damage following stroke, neonatal asphyxia and traumatic brain injury. Xenon is highly effective at preventing neuronal damage in in-vitro and in-vivo models and is beginning clinical trials.  Until very recently there was little information on the mechanism by which xenon causes neuroprotection.  We have shown that xenon neuroprotection against hypoxia-ischemia is mediated by inhibition of the NMDA-receptor at its glycine site.  In addition to explaining the mechanism of xenon neuroprotection, this finding identifies, for the first time, the NMDA-receptor as a target underlying xenon neuroprotection. 

Selected Publications:

1) Dickinson, R, Banks, Franks, N.P. Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia.  Anesthesiology, 112, p 614-622 (2010)

2) Dickinson, R, Peterson, B.K., Banks, P, Simillis, C, Sacristan-Martin, J.C, Valenzuela, C.A, Maze, M, Franks, N.P. Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon and isoflurane: Evidence from molecular modelling and electrophysiology.  Anesthesiology, 107, p 756-767 (2007)

3) Andres-Enguix, I, Caley, A, Yustos, R, Schumacher, M A, Spanu, P D, Dickinson, R, Maze, M, Franks, N. P. Determinants of the anaesthetic sensitivity of TASK channels: molecular cloning of an anaesthetic-activated potassium channel from Lymnaea stagnalis. Journal of Biological Chemistry,  282, p. 20977-90 (2007). 

4) White, I.L., Franks, N.P., Dickinson R. Effects of isoflurane and xenon on Ba2+ currents mediated by N-type calcium channels. British Journal of Anaesthesia, 94: p. 784-790 (2005).

5) Dickinson, R., Awaiz, S., Whittington, M.A., Lieb, W.R., and Franks, N.P., The effects of general anaesthetics on carbachol-evoked gamma oscillations in the rat hippocampus in vitro. Neuropharmacology, 44: p. 864-872 (2003). 

6) de Sousa, S.L., Dickinson, R., Lieb, W.R., and Franks, N.P., Contrasting synaptic actions of the inhalational general anesthetics isoflurane and xenon.  Anesthesiology, 92: p. 1055-1066 (2000).

7) Franks, N.P., Dickinson, R., de Sousa, S.L., Hall, A.C. and Lieb, W.R., How does xenon produce anaesthesia? Nature, 396: p. 324 (1998).