The Anaesthetic Steroid Alphaxalone Positively Modulates α₁-Glycine Receptor Function

Abstract

Inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the processing of nociceptive signals, and mainly involves glycine. We have studied the effects of alphaxalone on α₁ homomeric glycine receptors expressed in a mammalian expression system (HEK 293 cells) using the whole-cell patch-clamp technique. Our experiments showed a coactivating effect of alphaxalone with a concentration for half-maximum activation (EC₅₀) of the effect of a low glycine concentration (EC₂₀) of 70.9 ± 21.5 µmol/l. Taking into account the results of other groups, our study suggests that neuroactive steroids might be an interesting class of compounds to probe subunit-specific effects of glycine receptors.

Activation and Regulation of Purinergic P2X Receptor Channels

“…The effect of neurosteroids on the GABA A receptor channel is well established (Harrison and Simmonds, 1984). There are also reports of allosteric actions of neurosteroids on nicotinic ␣4␤2, N-methyl-D-aspartate, and glycine receptors (Paradiso et al, 2001;Ahrens et al, 2008;Johansson et al, 2008). Sex and adrenal steroid hormones influence P2XR expression by activating cytosolic receptors, leading to changes in transcriptional regulation Fan et al, 2009;Urabe et al, 2009).…”

The safety, efficacy and neuromotor effects of the neurosteroid anaesthetic alfaxalone in rats

“…However, previous studies have shown that the ability of alfaxalone to potentiate GlyR activity was minimal and the concentration of alfaxalone necessary to potentiate α 1 GlyR in HEK 293 cells was outside the clinically relevant dose ranges (Ahrens et al, 2008). By contrast, the inhibition of α 1 glycinergic transmission causes exaggerated startle responses, as seen with hyperekplexia and strychnine poisoning (Zhou et al, 2002) and we hypothesised alfaxalone might produce similar suppressive effects on glycinergic transmission.…”

“…The potentiation of α1 GlyRs was much less pronounced for alfaxalone than that of ORG20599 and minaxolone, suggesting that GlyR modulation does not play a critical role for the anaesthetic action of neurosteroids (Weir et al, 2004). Similarly, the concentration of alfaxalone necessary to potentiate the α1 GlyR subunits, transiently transfected into transformed human embryonic kidney (HEK 293) cells, was much higher than that required for GABA A R modulation, suggesting that GlyR potentiation by neurosteroids would fall outside a clinically relevant range (Ahrens et al, 2008).…”

“…Glycinergic neurotransmission is involved in the coordination of reflex responses, sensory signal processing and nociception in the adult CNS . Strychnine-sensitive GlyRs are involved in the modulation of spinal sensory input, nociceptive signals and pain processing, and enhancement of inhibitory GlyR activity could lead to suppression of nociceptive signals (Ahrens et al, 2008, Betz and Laube, 2006.…”

“…The enhancement of GlyR activity has the potential to suppress nociceptive signals and many studies have focussed on whether alfaxalone possesses this property (Ahrens et al, 2008, Betz and Laube, 2006.…”