GABA Analgesic Flashcards
(23 cards)
Lipid membrane theory
The more lipid soluble a GA the better it is at exerting unconsciousness (right reflex) - GAs were acting via the membrane
Isomers have identical lipid solubility (same effect on achiral stuff) so should have same abilities but isomers (e.g. S vs R etomidate) had different enhancement of GABA
Belelli 2003
IV anaesthetic with cleanest profile
etomidate
Glutamate —-> GABA needs
GAD
GABA ——> glutamate
GABA transaminase
where are a2 GABAARs densely expressed
lamina II/III of Rexed in dorsal horn neurons AND primary afferent dorsal root ganglion neurons
benzo binding site
alpha gamma
benzo sensitive
a1,2,3,5
what makes alpha subunits sensitive
histidine residue
in rats BZD-like L838417 suppresses neuropathic and inflammatory pain without sedation or tolerance
Knabl et al., 2008
etomidate selective for b2/3 subunits
Hill-Venning et al., 1997
B2/3 have asparagine instead of serine
Belelli et al., 2003
b2 N265S mice etomidate as no sedative effect
Reynolds et al., 2003
b3 N265M suppresses immobility
Jurd et al., 2003
delta -/- attenuated THIP effects on currents (THIP is selective for extrasyn Rs)
Herd et al., 2013
a5 Rs mainly extrasynaptic - knockout reduces tonic inhibition
Caraiscos et al., 2004
at hospital discharge, >30% pts have cognitive impairment, 12% of >60yo still suffer after 3 months
Monk et al., 2011
a5 -/- performed better in memory tasks spatial learning
Collinson et al., 2002
etomidate caused decreased LTP and impaired hippocampal dependent memory tasks in WT but not a5-/- mice
Cheng et al., 2006
suppression of a5GABARs enhanced hippo LTP
Atack et al., 2010
IL-1B increases cell-surface expression of GABARs and enhances their activity
Serantes et al., 2006
IL-1B causes memory deficits in WT but not a5-/- mice. These deficits in WT were reversed with an a5 inverse agonist
Wang et al., 2012
a5 antag for cognitive enhancement? has improved LTP and cog deficits in mice in studies
Glacsayi et al., 2017, Etherington et al., 2017
