Stereoselective modulatory actions of oleamide on GABAA receptors and voltage‐gated Na+ channels in vitro: a putative endogenous ligand for depressant drug sites in CNS

British Journal of Pharmacology - Tập 129 Số 2 - Trang 283-290 - 2000
Bernard Verdon1, Jian Zheng2, Russell A. Nicholson2, C Robin Ganelli3, George Lees1
1Institute of Pharmacy and Chemistry, School of Sciences, University of Sunderland, Wharncliffe Street, Sunderland SR2 3SD
2Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada
3Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London

Tóm tắt

cis‐9,10‐octadecenoamide (‘oleamide’) accumulates in CSF on sleep deprivation. It induces sleep in animals (the trans form is inactive) but its cellular actions are poorly characterized. We have used electrophysiology in cultures from embryonic rat cortex and biochemical studies in mouse nerve preparations to address these issues.

Twenty μM cis‐oleamide (but not trans) reversibly enhanced GABAA currents and depressed the frequency of spontaneous excitatory and inhibitory synaptic activity in cultured networks.

cis‐oleamide stereoselectively blocked veratridine‐induced (but not K+‐induced) depolarisation of mouse synaptoneurosomes (IC50, 13.9 μM).

The cis isomer stereoselectively blocked veratridine‐induced (but not K+‐induced) [3H]‐GABA release from mouse synaptosomes (IC50, 4.6 μM).

At 20 μM cis‐oleamide, but not trans, produced a marked inhibition of Na+ channel‐dependent rises in intrasynaptosomal Ca2+.

The physiological significance of these observations was examined by isolating Na+ spikes in cultured pyramidal neurones. Sixty‐four μM cis‐oleamide did not significantly alter the amplitude, rate of rise or duration of unitary action potentials (1 Hz).

cis‐Oleamide stereoselectively suppressed sustained repetitive firing (SRF) in these cells with an EC50 of 4.1 μM suggesting a frequency‐ or state‐dependent block of voltage‐gated Na+ channels.

Oleamide is a stereoselective modulator of both postsynaptic GABAA receptors and presynaptic or somatic voltage‐gated Na+ channels which are crucial for synaptic inhibition and conduction. The modulatory actions are strikingly similar to those displayed by sedative or anticonvulsant barbiturates and a variety of general anaesthetics.

Oleamide may represent an endogenous modulator for drug receptors and an important regulator of arousal.

British Journal of Pharmacology (2000) 129, 283–290; doi:10.1038/sj.bjp.0703051

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British Journal of Pharmacology

Tập 129 Số 2

283-290

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