Jurnal FHR-Propofol Modulates Phasic and Tonic GABAergic Currents in Spinal Ventral Horn...

8/16/2019 Jurnal FHR-Propofol Modulates Phasic and Tonic GABAergic Currents in Spinal Ventral Horn Interneurones

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FAISAL RACHMAN

Propofol Modulates Phasic and Tonic

GABAergic Currentsin Spinal Ventral Horn Interneurones


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Background

Surgical interventions like skin incisions trigger withdrawal reflees which re!uire "otor neuronesand local circuit interneurones in the spinal ventral

horn#This region pla$s a ke$ role in "ediating

i""o%ili&ing properties of the GABAergicanaesthetic propofol#

However' it is unclear how propofol "odulatesGABA(A) receptors in the spinal ventral horn and

whether tonic or phasic inhi%ition is involved#


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Methods

*rganot$pic spinal cord tissue slices were preparedfro" "ice#

+hole,cell recordings were perfor"ed for

!uantif$ing effects of propofol on GABA(A)receptor"ediated phasic trans"ission and tonicconductance#


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-esults

Propofol increased GABAergic phasic trans"ission %$ a prolongation of the deca$ ti"e constant in aconcentration,dependent "anner#

The a"ount of the charge transferred per inhi%itor$post,s$naptic current' descri%ed %$ the area underthe curve' was significantl$ aug"ented %$ . /Mpropofol (P01#1.)#

A GABA(A) receptor,"ediated tonic current was notinduced %$ . /M propofol %ut at a concentration of 2/M (P01#12)#


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This conductance can %e !uantified as IPSCs %$ a whole,cell patch,cla"p techni!ue as displa$ed in3igure .#

3or this purpose' co""issural interneurones were visuall$ identified in la"ina VIII of the ventral hornand voltage cla"ped at ,41 "V as previousl$reported#

The "ean capacitance of these cells was 56#4 (7#5)p3 (n8..)#


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The effects of propofol on spontaneous IPSCs werestudied at two different anaesthetic concentrations#

At 9211 nM' propofol provides' on a %ehavioural

level' h$pnosis' whereas at . /M' nociceptive refleesare %locked#

The two concentrations are within the clinicall$relevant range of the anaesthetic#

Cu"ulative data revealed that propofol prolongedGABAergic IPSC deca$ ti"es in a concentration,dependent "anner (3ig# 6A)#


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:nder control conditions' the deca$ ti"e was 62#6 (2#;)"s (n8.5)' while at 211 nM propofol' the deca$ ti"eincreased a%out 65#2 (4#2#6 (;#6)"s' n82' P01#1.' t,test?' and prolonged at . /M propofol

a%out ;6#@ (.;#6)< co"pared with control =a%solute value75#6 (.5#@)"s'n84'P01#1.?#

Theaverage of the anal$sed eperi"ents showed that thea"plitude of GABAergic IPSCs was not significantl$

changed %$ application of propofol (3ig# 6B)#

:nder control conditions' the IPSC a"plitudes were 24(;#7) pA (n8.6)#


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Since IPSC a"plitudes were %asicall$ not altered andIPSC deca$ ti"es were well fitted with"onoeponentials' the prolongation of deca$ ti"es

was translated into an increase in the total a"ount ofcharge transferred per IPSC (P01#1.' 3ig# 6C)#

A%solute values were .#7. (1#;) pC under controlconditions (n8.6)' .#;; (1#;) pC (n82) for 211 nM

propofol' and 6#. (1#;) pC (n84) for . /M propofol# Additionall$' propofol reduced the IPSC event rate at

%oth tested concentrations (3ig# 63)#


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In recordings fro" whole,cell patch,cla"ped spinalinterneurones' holding currents re"ainedunchanged %$ application of . /M propofol as

de"onstrated ee"plaril$ in 3igure 5A and B#Su%se!uent application of the selective GABA(A)

receptor antagonist %icuculline (.11 /M) did not %asicall$ alter the holding current of the tested

neurones (3ig# 5)#


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In order to esti"ate the i"pact of propofol onetras$naptic GABAergic currents' we investigated ina further step a higher propofol concentration#

-e"arka%l$' at a high concentration (2 /M)'propofol significantl$ induced GABAergic toniccurrents (3ig# 5CD n82' P01#12)#


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In order to test this h$pothesis' we co"pared theeffects of propofol on spinal network activit$ incultured organot$pic slices fro" wild,t$pe and %5(E6;2M) knock,in "ice#

Spontaneous action potential activit$was "easured %$ etracellular recordings in the ventral horn area(3ig# 7)#


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iscussion

I#V# anaesthetics like propofol eert their anaestheticactions %$ "odulating inhi%itor$ neurotrans"ission viaGABA(A) receptors in different regions of the centralnervous s$ste"#

In the present stud$' the specific "odulation of GABAergictrans"ission %$ propofol was investigated in the spinal

ventral horn#

The "aFor findings of the present work indicate that

propofol "odulates %oth phasic GABA(A)receptor"ediated currents and tonic GABAergic currents'

%ut the latter at higher concentrations of the anaesthetic#


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The plas"a concentration of propofol causingsurgical i""o%ilit$ in 21< of the patients has %eenesti"ated to %e %etween .1 and .2#6 /g "l whichcorresponds to 9..#2 /M#

In contrast to the "oderate propofol concentrationsapplied in our eperi"ents' Bieda and MacIverperfor"ed eperi"ents in acute adult rat %rain slices

using concentrations of 2' .1' and 51 /M#


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Conclusions

Propofol depresses ventral horn interneuronespredo"inantl$ %$ phasic rather than %$ tonicGABA(A) receptor,"ediated inhi%ition#

However' the present results suggest that theinvolve"ent of a tonic inhi%ition "ight contri%ute tothe efficac$ of propofol to depress nociceptivereflees at high concentrations of the anaesthetic#


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Jurnal FHR-Propofol Modulates Phasic and Tonic GABAergic Currents in Spinal Ventral Horn...

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