Nerve Injury Induced Pain and Spinal Cord Stimulation

10/12/2015
NerveInjuryInducedPainandSpinalCordStimulation
NerveInjuryInducedPainandSpinalCord
Stimulation
Author:Ultenius,Camilla
Date:20101126
Location:Fakultetsklubben,CMM,HusL1,ingngRolfLuftsCentrum,Karolinska
Universitetssjukhuset,Solna.
Time:09.00
Department:Instfrkliniskneurovetenskap/DeptofClinicalNeuroscience
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Abstract
Chronicneuropathicpaincausedbyinjurytoordiseaseinthenervoussystemisrelativelycommon
andresultsinmajorsuffering,poorqualityoflifeandincapacity.Suchpainisatherapeuticchallenge
because a considerable portion of the patients fails to benefit from pharmacotherapy. Therefore,
there is a need for alternative treatment modalities. Spinal cord stimulation (SCS) has proven to be
effective in the management of some forms of neuropathic pain. The experimental studies
constitutingthisthesisaddressvariousaspectsofneuropathicpainofperipheraloriginandthemode
of action of SCS. Neuropathic pain is generally associated with abnormal responsiveness of the
somatosensory system sometimes presenting as increased sensitivity to mechanical stimuli. Animal
experimental models supposedly representing neuropathic pain, especially evoked pain, typically
exhibit signs of neuropathy in the form of local cutaneous hypersensitivity. In the present thesis a
model of neuropathy (rat) according to Seltzer et. al. (1990) was used. In behavioral tests the
withdrawalthresholdsinresponsetovonFreyfilaments,coldsprayandradiantheatwereassessed.
Possibly attenuating effects of SCS on hypersensitivity were examined in the awake and freely
movinganimal.Immunohistochemistry,WesternBlot,ELISA,microdialysisandHPLCwereemployed
for the analysis of some transmitters and receptors related to neuropathic pain and/or SCS effects.
Variousagonists/antagonistswereadministeredintrathecallyfortheevaluationofthesignificanceof
the corresponding spinal receptors in mechanisms underlying SCS effects. Activation of the
glutamatergicNMDAreceptorinthespinaldorsalhorn(DH)isessentialforcentralsensitizationand
plays an important role in the generation and maintenance of neuropathic pain. Quantification of
dorsal horn NMDA receptor subunit expression was based on comparisons between the DHs ipsi
andcontralateraltothenervelesion.ThephosphorylationoftheNR1subunitoftheNMDAreceptor
wassignificantlyincreasedintheipsilateralDHinhypersensitive,butnotinnonhypersensitivenerve
injured rats. The nonphosphorylated NR1, NR2A, NR2B, NR2C or the NR2D subtypes were
unaffectedbythenerveinjuryascomparedtocontrols.AdysfunctionalspinalGABAergicsystemis
considered to be an important feature of neuropathic pain and this might imply also a reduced
synthesis of GABA. The DH levels of the GABA synthesizing enzymes, glutamic acid decarboxylase
(GAD)65and67,wereanalyzedafternerveinjuryandfollowingapplicationofSCS.Theexpression
of both enzymes appeared to be increased in SCS responding rats subjected to SCS immediately
prior to tissue collection as compared to responders without stimulation. In nonresponding rats
subjectedtoSCS,asimilarincreaseinGAD67wasalsopresent.Withoutstimulation,nerveinjuryper
se was not associated with any changes in enzyme expressions regardless of whether or not
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hypersensitivitywaspresent.Onthebasisofprecedingobservationthatclonidinemayenhancethe
SCS effect, experiments with microdialysis of the DH of nerve injured rats and quantitative
assessmentofextracellularacetylcholine(ACh)releasewereperformed.ThebasalAChreleasewas
significantly lower in nerve injured than in normal rats. In SCS responding, but not in SCS non
responding rats, application of SCS produced an increased release of ACh. In behavioral
experiments, the muscarinic M4 receptor was identified as the principle one being involved in
cholinergicSCSmechanisms.Thenicotinicreceptorappearedtobeofnosignificanceinthisstudy.
ThereisevidencethattheSCSeffectispartlyexertedviaaspinalsupraspinalspinalloopandmost
probablycomprisesdescendingserotonergicpathways.WhenSCSwasappliedinnerveinjuredrats
immediatelypriortosacrifice,the5HTcontentinthedorsalquadrantofthespinalcordipsilateralto
theinjurywasincreasedinSCSrespondingrats.Therewasintheseratsalsoahighdensityof5HT
immunoreactive terminals in the DH superficial laminae (III) as demonstrated
immunohistochemically. The potency to attenuate mechanical hypersensitivity of SCS could be
significantlyenhancedbyalowdoseofintrathecalserotonin,andthiseffectwaspartiallyblockedbya
GABAB,butnotbyamuscarinicM4receptorantagonist.Thereareconflictingresultsregardingthe
predictive value of certain neurological symptoms, e.g. cutaneous sensory abnormalities, for the
outcomeofSCStreatment.Inanimalmodelsofneuropathicpain,theincidence,extentandseverity
ofhypersensitivityisquitevariable.Aseriesofratsexhibitingsignsofneuropathyweresubdividedin
groups according to the severity of mechanical hypersensitivity and then subjected to SCS. It
appeared that SCS produces a faster and more effective attenuation of hypersensitivity in rats with
mildascomparedtothosewithmoreseveresensorydisturbance.Inconclusion,thecurrentstudies
have shown that in the DH of a rodent model of neuropathy, the expression of nonphosphorylated
NMDAreceptorsubtypesaswellasofGABAsynthesizingenzymesisnotaffectedbyanerveinjury,
irrespectiveofthepresenceofneuropathicsigns.SCSappearstoproduceamoderateaugmentation
oftheGABAsynthesizingenzymes.ThereisevidenceindicatingthatSCSmayactivateseveralpain
modulatorysystems,andhereithasbeenshownthatbothcholinergicandserotonergicmechanisms
are involved in the SCS effect. The latter may relate to a stimulationinduced restoration of a
dysfunctional descending inhibitory and/or facilitatory supraspinal endogenous control. The different
SCS mechanisms may operate independently, in parallel or in concert. Finally, the relationship
betweentheoutcomeofSCSanddegreeofhypersensitivitydemonstratedinananimalmodelmay
haveclinicalimplications.
Listofpapers:
UlteniusC.,LinderothB.,MeyersonBA.,WallinJ.SpinalNMDAreceptorphosphorylationcorrelates
with the presence of neuropathic signs following peripheral nerve injury in the rat. Neuroscience
Letters399(2006)8590
Fulltext(DOI)(http://dx.doi.org/10.1016/j.neulet.2006.01.018)
Pubmed(http://www.ncbi.nlm.nih.gov/pubmed/16469445)
View record in Web of Science (http://ws.isiknowledge.com/cps/openurl/service?url_ver=Z39.88
2004&rft.genre=article&rft_id=info:ut/000237526700017)
UlteniusC.,SongZ.,MeyersonBA.,LinderothB.GABAsynthesisinthedorsalspinalcordfollowing
peripheralnerveinjuryandeffectsofspinalcordstimulation.SubmittedtoBrainResearch
SchechtmannG.,SongZ.,UlteniusC.,MeyersonBA.,LinderothB.Cholinergicmechanismsinvolved
inthepainrelievingeffectofspinalcordstimulationinamodelofneuropathy.Pain139(2008)136
145
Fulltext(DOI)(http://dx.doi.org/10.1016/j.pain.2008.03.023)
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Song Z., Ultenius C., Meyerson BA., Linderoth B. Pain relief by spinal cord stimulation involves
serotonergicmechanisms:Anexperimentalstudyinaratmodelofmononeuropathy.Pain147(2009)
241248
Fulltext(DOI)(http://dx.doi.org/10.1016/j.pain.2009.09.020)
SmitsH.,UlteniusC.,DeumensR.,KoopmansGC.,HonigWM.,vanKleefM.,LinderothB.,Joosten
EA., Effect of spinal cord stimulation in an animal model of neuropathic pain relates to degree of
tactileallodynia.Neuroscience143(2006)541546
Fulltext(DOI)(http://dx.doi.org/10.1016/j.neuroscience.2006.08.007)
URI:http://hdl.handle.net/10616/40269(http://hdl.handle.net/10616/40269)
Institution:KarolinskaInstitutet
Issuedate:20101102
Publicationyear:2010
ISBN:9789174571394
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