GABA Analgesic

Question 1

Lipid membrane theory

Answer 1

The more lipid soluble a GA the better it is at exerting unconsciousness (right reflex) - GAs were acting via the membrane

Question 2

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

Answer 2

Belelli 2003

Question 3

IV anaesthetic with cleanest profile

Answer 3

etomidate

Question 4

Glutamate —-> GABA needs

Answer 4

GAD

Question 5

GABA ——> glutamate

Answer 5

GABA transaminase

Question 6

where are a2 GABAARs densely expressed

Answer 6

lamina II/III of Rexed in dorsal horn neurons AND primary afferent dorsal root ganglion neurons

Question 7

benzo binding site

Answer 7

alpha gamma

Question 8

benzo sensitive

Answer 8

a1,2,3,5

Question 9

what makes alpha subunits sensitive

Answer 9

histidine residue

Question 10

in rats BZD-like L838417 suppresses neuropathic and inflammatory pain without sedation or tolerance

Answer 10

Knabl et al., 2008

Question 11

etomidate selective for b2/3 subunits

Answer 11

Hill-Venning et al., 1997

Question 12

B2/3 have asparagine instead of serine

Answer 12

Belelli et al., 2003

Question 13

b2 N265S mice etomidate as no sedative effect

Answer 13

Reynolds et al., 2003

Question 14

b3 N265M suppresses immobility

Answer 14

Jurd et al., 2003

Question 15

delta -/- attenuated THIP effects on currents (THIP is selective for extrasyn Rs)

Answer 15

Herd et al., 2013

Question 16

a5 Rs mainly extrasynaptic - knockout reduces tonic inhibition

Answer 16

Caraiscos et al., 2004

Question 17

at hospital discharge, >30% pts have cognitive impairment, 12% of >60yo still suffer after 3 months

Answer 17

Monk et al., 2011

Question 18

a5 -/- performed better in memory tasks spatial learning

Answer 18

Collinson et al., 2002

Question 19

etomidate caused decreased LTP and impaired hippocampal dependent memory tasks in WT but not a5-/- mice

Answer 19

Cheng et al., 2006

Question 20

suppression of a5GABARs enhanced hippo LTP

Answer 20

Atack et al., 2010

Question 21

IL-1B increases cell-surface expression of GABARs and enhances their activity

Answer 21

Serantes et al., 2006

Question 22

IL-1B causes memory deficits in WT but not a5-/- mice. These deficits in WT were reversed with an a5 inverse agonist

Answer 22

Wang et al., 2012

Question 23

a5 antag for cognitive enhancement? has improved LTP and cog deficits in mice in studies

Answer 23

Glacsayi et al., 2017, Etherington et al., 2017