Rev. bras. farmacogn. vol.27 número1

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w ww.e l s e v i e r . c o m / l o c a t e / b j p

Review

Natural

products

assessed

in

animal

models

for

orofacial

pain

–

a

systematic

review

Pollyana

S. Siqueira-Lima

a,b

_,

_Juliane

_C.

_Silva

a,c

_,

_Jullyana

_S.S.

_Quintans

a

_,

_Angelo

_R.

_Antoniolli

a

_,

Saravanan

Shanmugam

a

_,

_Rosana

_S.S.

_Barreto

a

_,

_Márcio

_R.V.

_Santos

a

_,

_Jackson

_R.G.S.

_Almeida

b,c

_,

Leonardo

R. Bonjardim

d

_,

_Irwin

_R.A.

_Menezes

e

_,

_Lucindo

_J.

_{Quintans-Júnior}

a,∗

a_Laboratório_de_{Neurociências}_e_Ensaios_{Farmacológicos,}_Universidade_Federal_de_Sergipe,_São_Cristóvão,_SE,_Brazil b_Departamento_de_Farmácia,_Universidade_Estadual_de_Feira_de_Santana,_Feira_de_Santana,_BA,_Brazil

c_Colegiado_de_Ciências_{Farmacêuticas,}_Universidade_Federal_do_Vale_do_São_Francisco,_Petrolina,_PE,_Brazil d_Faculdade_de_Odontologia_de_Baurú,_Universidade_de_São_Paulo,_Baurú,_SP,_Brazil

e_Departamento_de_{Quimica-Biologica,}_Federal_University_of_Cariri,_Crato,_CE,_Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received10February2016 Accepted27June2016

Keywords: Medicinalplants Naturalproducts Orofacialpain Pain Animalmodels

a

b

s

t

r

a

c

t

Orofacialpainisrelatedtotissuesofthehead,face,neckandalltheintraoralstructures;itisrather debil-itatingtothepatientandalsodifficulttotreat.Therearerelativelyfewstudiesdedicatedtotheuseof naturalproductstoalleviateorofacialpaininpreclinicalexperimentmodels(performedin experimen-talanimalswhichprovidesupportforclinicaltrials).Mainobjectivesofthepresentsystematicreview summarizethestudiesonnaturalproductsassessedinanimalmodelsfororofacialpainseekingtogive evidencetofuturedevelopmentofnewpharmaceuticalproductstomanagetheorofacialpain.Ourreview includesathoroughsearchofliteratureusingthetermsoforofacialpain,facialpain,medicinalplants andnaturalproducts.ThissearchwasperformedusingtoretrieveEnglishlanguagearticlesin Medline-PubMed,ScopusandWebofScience.Atotalofeighteenstudieswereincludedinoursurveyforthe inclu-sioncriteria.Firstly,thisreviewidentified210citationsfromelectronicsearch,afterremovalofduplicates andscreeningforrelevanttitlesandabstracts,atotalofeighteenarticleswereselectedtotheinclusion criteriaestablished.Ourfindingssuggestthatnaturalproductscanbeapromisingoratrumptoolforthe developmentofnewdrugstotreatorofacialpainconditions,buttheresearchersthatdealwith experi-mentalpreclinicaltrialsofnewdrugs(includingnaturalproductsorsyntheticdrugs)fororofacialpain conditionsurgentlyneedtoshowtranslationalevidence(withclinicalapproach)ofthesecompounds.

Introduction

Orofacialpainisrelatedtotissuesofthehead,face,neckand alltheintraoralstructuresdeterminedbytheAmericanAcademy ofOrofacialPain(AAOP).Thispainconditionrepresentsahighly prevalent spectrum of disorders with pain intensity involving anatomical,biochemicalandmolecularaspectswhichare associ-atedwithpsychosocialcomponents(Hargreaves,2011;Fanetal., 2012).Theorofacialregionisoneofthemostdenselyinnervated areasofthebody, andthetrigeminalnerve playsanimportant roleinthisprocess.Anorofacialpainencompassesawiderange ofconditionsincludingtemporomandibularjointdisorders, peri-odontalpain, trigeminalneuralgia, atypical facial pain, burning

∗ Correspondingauthor.

E-mail:lucindo@pq.cnpq.br(L.J.Quintans-Júnior).

mouthsyndrome,dentalsurgicalpain,headandneckcancerpain, painduetooralinfections,andotherneuropathicand inflamma-torypain(Gilbertetal.,2001).Itisalsothesiteoffrequentchronic post-herpetical neuralgia,migraine and referredpains(Pelissier etal.,2002;RaboissonandDallel,2004).Therefore,orofacialpainis oftenratherdebilitatingtothepatientandmanydifficultiesinthe managementofacuteandchronicorofacialpainconditionsstem fromalackofrecognitionandunderstandingofpainmechanisms (Mirandaetal.,2009;KrzyzanowskaandAvenda ˜no,2012).

Uptothepresentdate,severalanimalmodelshavebeenused tostudyorofacialpain.Theseincludeinfraorbitalnerveligationor axotomy,injectionofinflammatoryagentsintothevibrissalpads, temporomandibularjointormassetermuscle,aswellasintradental orduralapplicationofirritants(RenandDubner,1999).Clavelou etal.(1989)reportedthattheadaptationoftheformalinmodel ofpainfortheorofacialregionprovidesanimportant contribu-tiontothemechanismsoftrigeminalpainandanalgesicresponse

http://dx.doi.org/10.1016/j.bjp.2016.06.005

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(Mittal et al., 2009). Other orofacial pain animal models have beenmorerecentlyproposedandhavecontributedwithclinical studies,suchastheassessmentofneuropathicandinflammatory pain (Krzyzanowska and Avenda ˜no, 2012).Despite the impor-tanceoftheseanimalmodels,accordingtoKhanandHargreaves (2010),theyposesomelimitationsthatshouldalwaysbetakeninto accountinthechoiceofmodelsforthetestingofnewdrugs.Thus, theseanimalmodelshavegreatanimportancetothestudy,such asabetterunderstanding,developmentoftherapeuticproposals andadvancesinthetreatmentoforofacialpain.

The management of pain is still a major challenge to both the medical practitioners and the patients (Krzyzanowska and Avenda ˜no, 2012).Opioids,antidepressants, anticonvulsantsand non-steroidalanti-inflammatorydrugs(NSAID)remainasthemain agentsusedtorelieveacuteandchronicpain,includingorofacial pain(Paceetal.,2006),butthewiderangeofside-effectsaligned withlow adherencehasbeenastimulusintheconstantsearch fornewdrugstotreatorofacialpain(Quintans-Júnioretal.,2010). Anactualapproachistodevelopanewbiologicalcompoundthat inhibitspainfromnaturalproducts(NP),suchasmedicinalplants ortheirsecondarymetabolites,whichcouldenhanceefficacy, pro-duceminimalsideeffectsandoperateinunusualwayscompared tothesyntheticdrugs(Holanda-Pintoetal.,2008;Venâncioetal., 2011;Oliveiraetal.,2012).

The present systematic review was designed to summarize thecurrentstudiesonNPtestedinanimalmodelsfor attenuat-ingtheorofacialpain.Ourmainfocusaimedtomakethereader aware,throughasystematicway,ofwhichthemainaspectsofNP researchedtoorofacialpainare,inexperimentalprotocols.

Methods

Searchstrategy

Three internet sources were used to search for appropriate papersthatmetthestudypurpose.TheseincludedtheNational LibraryofMedicine,Washington,D.C.(Medline-PubMed),Scopus and,WebofScienceusingdifferentcombinationsofthe follow-ingkeywords:Orofacialpain,Facialpain,Medicinalplants,natural products.Thedatabasesweresearchedforstudiesconductedinthe perioduptoandincludingApril30,2015.Thestructuredsearch strategywasdesignedtoincludeallpublishedpapersthat evalu-atedtheuseofnaturalproductsinorofacialpain.Citationswere limitedtoanimalstudies.Additionalpaperswereincludedinour studyaftertheanalysesofallreferencesfromtheselectedarticles. Wedidnotcontactinvestigatorsanddidnotattempttoidentify unpublisheddata.

Studyselection

Allelectronicsearchtitles,selectedabstracts,andfull-text arti-cleswereindependentlyreviewedbyaminimumoftworeviewers (JSSQandPSSL).Disagreementsinstudyinclusion/exclusionwere resolved with a consensus meeting with more reviewers. The followinginclusioncriteria wereapplied:orofacialpainstudies, animalmodelsandtheuseofNPforreducingnociception. Stud-ieswereexcludedaccordingtothefollowingexclusion criteria: studiesinhumans,review articles,meta-analyses,abstractsand conferenceproceedings.

Dataextraction

Datawereextractedbyonereviewerusingstandardizedforms and were checked for completenessand accuracy by a second reviewer.Informationcollectedincludeddataregardingthestudy

Search pubmed (88), Scopus (68), Web of science (54) databases

210 original articles

53 articles deemed

potentially relevant 157 citations excluded:

not relevant by title

review

33 citations excluded:

not relevant by abstract

review _{20 articles deemed}

relevant by title and abstract or needed full

text to make

determination

18 articles included 4 citations excluded:

not relevant by full text

review

Inclusion of 2 articles

from reference list

Fig.1. Flowdiagramforliteraturesearchingandscreening.

substance(naturalproducts),animal,dose(route),model, recep-tors/mediators,antagonistsandresults.

Methodologicalqualityassessmentofstudies

Theriskofbiasandqualityofthestudydesignwereassessed using a 12-point checklist. The use of these questions has enabled theassessmentof importantaspectsthat contributeto the quality of the study, such as randomization of the treat-ment allocation, blinded drug administration, blindedoutcome assessment and outcome measurements. Studies that reported randomizationof animals,blindingandoutcomemeasurements were considered of higher methodological quality (Zeng et al., 2015).

Resultsanddiscussion

Thepreliminaryreviewofthepresentstudyidentified210 cita-tionsfromelectronicsearch,with88fromPubmed,68fromScopus, 54WebofScience.Afterremovalofduplicatesandscreeningfor rel-evanttitlesandabstracts,atotalofeighteenarticleswereselected totheinclusionandexclusioncriteriaestablished(Fig.1).

Curiously, fromeighteen final studiesselected, mostof that research,particularlyNP,wasconductedinBrazil(88%)(Table1) and 12% in India and USA. Detailsof theincluded studies are described inTable1.Thatcouldbebecausewelimitour inclu-sion criteria to orofacial pain animal models. However, if this surveysoughtclinicalstudiesand/orethnopharmacologicalsearch, it probably showed a wider range of countries (Tapsoba and Deschamps,2006;Taheri etal.,2011).Anotherfactormayhave contributedtothisfindingbecauseBrazilhastheextensiveethical, culturalandgreatestbiodiversityintheworld,whichhas histor-icallybeenasourceofexplorationandstudy(Macieletal.,2002; Oliveiraetal.,2012).TheresultshowsthescientificgrowthofBrazil in theareaofNP corroboratingwiththepotential ofbiological diversity(PeixotoandMorim,2003)thathasabout19%ofearth’s totaldiversity(Giuliettietal.,2005).Also,itisestimatedthat49,000 plantspecieshavealreadybeendescribed(Shepherd,2002).

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Table1

Characteristicsofstudiesinsertedinthereview.

Authors,year, country

Substance/chemical group/(natural product)

Animals (strain/sex)

Dose(route) Methodofinductionof orofacialpain

Parametersassessed R B

Behavior Biochemical/ molecular

Gilbertetal.,2001, USA

Epibatidine Rats(SD/M) 1–5␮g/kg 50␮lsubcutaneous injectionofformalin(5%) intoonevibrissalpad

Grooming, rubbingand/or scratchingface

– N Y

Mittaletal.,2009, India

Curcumin (Curcumalonga)

Rats(W/M) 1–600mg/kg (i.p.)

50␮lsubcutaneous injectionofformalin(5%) intoonevibrissalpad

Grooming, and/or scratchingface

– N N

Holanda-Pinto etal.,2008,Brazil

␣,␤-amyrin (Protium heptaphyllum)

Rats(W/M) 10–100mg/kg (i.p.)

20␮lsubcutaneous injectionofformalin (1.5%),capsaicin(1.5␮g) intoonevibrissalpad

Face-rubbing – N N

Siqueiraetal., 2010,Brazil

Atranorin (AT)/Liquen (Cladinakalbii Ahti)

Mice(S/M) 100–400mg/kg (i.p.)

20␮lsubcutaneous injectionofformalin (2%),capsaicin(2.5␮g) intotherightupperlip (perinasalarea)

Quintans-Júnior etal.,2010,Brazil

Citronellal (Cymbopogon genus)

20␮lsubcutaneous injectionofformalin (2%),capsaicin(2.5␮g), 40␮lglutamate(25␮M) intotherightupperlip (perinasalarea)

Face-rubbing Singlesucrosegap electrophysiologic assays

Y N

Bonjardimetal., 2011,Brazil

Ethanol, chloroform, methanolextract fractions(S. cordifolia)

Mice(S/M) 100–400mg/kg (p.o.)

20␮lsubcutaneous injectionofformalin (2%),40␮lglutamate (25␮M)intotheright upperlip(perinasalarea)

Venancioetal., 2011,Brazil

(Ocimum Basilicum)and (−)-linalool

Face-rubbing Fieldpotential recordings. electrophysiologic assays

N N

Santanaetal., 2011,Brazil

p-Cymene Mice(S/M) 25–100mg/kg (i.p.)

Britoetal.,2013, Brazil

Citronellol (Cymbopogon citrates,C. winterianus)

Face-rubbing Immunofluorescence Y N

Guimarãesetal., 2012,Brazil

Carvacrol Mice(S/M) 25–100mg/kg (i.p.)

Face-rubbing – Y N

Paixãoetal.,2013, Brazil

Aqueousextract (Hyptispectinata)

Face-rubbing TBARS DPPH

Y N

Limaetal.,2013b, Brazil

Hydroethanol extract(Hyptis fruticosa)

Face-rubbing TBARS Y N

Nomuraetal., 2013,Brazil

Ethanolicextract (Acmellaoleracea)

Mice(S/M) 10–100mg/kg (i.p)

20␮lsubcutaneous injectionofformalin (2%),capsaicin(2.5␮g), cinnamaldehyde (13.2␮g)intotheright upperlip(perinasalarea)

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Table1 (Continued)

Authors,year, country

Substance/chemical group/(natural product)

Animals (strain/sex)

Dose(route) Methodofinductionof orofacialpain

Parametersassessed R B

Behavior Biochemical/ molecular

Quintansetal., 2014a,Brazil

Ethanolicextract (Syzygiumcumini)

Mice(S/M) 100–400mg/kg (p.o)

20␮lsubcutaneous injectionofformalin (2%),40␮lglutamate (25␮M)intotheright upperlip(perinasalarea)

Face-rubbing – Y Y

Siqueira-Lima etal.,2014,Brazil

␤-Cyclodextrin complex containing essentialoil (Lippiagrata)

Face-rubbing Immunofluorescence Y Y

Quintansetal., 2014b,Brazil

Hexanicextract (Combretum duarteanum)and friedelin

Face-rubbing – Y Y

Damascenaetal., 2014,Brazil

Aqueousextract (Anadenanthera colubrina)

Face-rubbing DPPH,MDA,TBARS, AAPH,FeSO4

Y N

Nowackietal., 2015,Brazil

Hydroalcoholic extract (Hypericum perforatum, Valeriana officinalis,Piper methysticum)

Mice(S/M) NR 20␮lsubcutaneous injectionofformalin (2%)intotherightupper lip(perinasalarea)

Face-rubbing Hematologicaland hepaticmarkers

N N

Animals:SD,Sprague–Dawley;W,Wistar;S,Swiss.

Parameters assessed: DPPH, 2,2-diphenyl-1-picrylhydrazyl radical; MDA, malonaldehyde; TBARS, thiobarbituric acid-reactive substances; AAPH, 2,2′

-azobis(2-methylpropionamidine)dihydrochloride;FeSO4,ferroussulphate;R,reportingofrandomization;B,reportingofblinding;Y,yes;N,no.

thedrugsusedcommerciallyandarenowadaysaroundarederived fromnaturalsources(Braz-Filho,2010).

RegardingtheNPusedforthemanagement oforofacialpain tabulatedinthepresentstudy,(Table1)showsisolatedsubstance (47.25%),extracts(47.25%)and␤-cyclodextrin(␤-CD)complexes containing essential oil(5.5%). That interprets mostreviews of isolatedcompoundsasreflectingtheimportanceofthe pharma-ceuticalindustry,sincethedrugsare,almostentirely,asingleactive ingredient which is responsible for its pharmacological effect. Neverthless,theplantextractsconsistofmulticomponentactive mixtures, partially active and inactive substances, which often workindifferentpharmacologicaltargets(FerreiraandPinto,2010; Ulrich-Merzenichetal.,2010).

Moreover,our findingsdemonstrated that it is necessaryto increase thenumberof studieswithNP toorofacialpain mod-elsbecause100% oftheincludedstudies inthepresent review usemainlychemicalstimulitoinducepain(formalin,glutamate, capsaicinorcinnamaldehyde)intothevibrissalpad.These charac-teristicsofthestudiesfoundbecomeobviouslimitationsbecause orofacialpainis derivedfrommany uniquetargettissues, such asthemeninges,cornea,toothpulp,oral/nasalmucosaand tem-poromandibularjoint(Hargreaves,2011).Further,thereareother orofacialpain animal modelsalso established in theliterature, such as orofacial neurophatic pain or chronic pain model in temporomandibularjoint,whichhavenotbeenexploredin arti-clesinserted in this systematic review. AccordingtoRaboisson andDallel(2004),themechanismsunderlyingorofacialpainare still poorly understood, partly due to the relative scarcity of

investigationdevotedtothefaceandthemouth,whencompared withpaininbody.Inparticular,therearerelativelyfewbehavioral modelsinlaboratoryanimalsdedicatedtothestudypaininthe trigeminalregion.

Regardingtheanalysisof qualityof thestudiesinserted,we found that 50% of studies (9) mentioned randomization in the allocationofanimalsfortesting.However,theydidnotdescribe how theyperformedrandomization of animals.Moreover,only fourstudies(22%)wereperformedbydouble-blindmanner,asit canbeseeninFig.2.Thatlimitstheinterpretationoftheresults obtainedinourreview,whatshowsalowqualityinthestudies found.

To better describe and understand the results, we summa-rizedthemasisolatedcompounds,plantspecies,essentialoilsand extracts,whicharedescribedbelow.

Isolatedsubstance

Epibatidine(1)

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Is the hypothesis/aim/objective of the study clearly described?

Are the main outcomes to be measured clearly described in the Introduction/ Methods section?

Are the main findings of the study clearly described?

Were sample size calculations reported?

Was the allocation adequately concealed?

Were the caregivers and/or investigators blinded from knowledge which intervention each animal received during the experiment?

Were animals selected at random for outcome assessment?

Was the outcome assessor blinded?

Was the agent used to induce pain reported?

Was the dose to the algic agent reported?

Yes

14 9 18

18 18

No Unclear

Fig.2.Methodologicalqualityofincludedstudies.Darkgraybarsindicatetheproportionofarticlesthatmeteachcriterion;lightgraybarsindicatetheproportionofstudies thatdidnotandwhitebarsindicatetheproportionofstudieswithunclearanswers.

Curcumin(2)

Themajorbioactive constituentof theoleoresinof turmeric (Curcuma longa L., Zingiberaceae) demonstrated a significant reduction in grooming behavior induced with formalin in a dose-dependent manner in both phases. Curcumin has proven anti-inflammatoryeffectdemonstratingitsbeneficialroleforthis pain condition (Mittal et al., 2009). Kim et al. (2003) explains theanti-inflammatoryactivityofcurcuminduetoitsinhibitory actiononJanuskinase(JAK)– STATsignalingpathway inbrain microglialcells, whichcontributes totheattenuationof inflam-matoryresponse.Anti-inflammatoryactivityofcurcuminmayalso berelatedtoitsabilitytodirectlysuppressnuclearfactor-kappaB (NF-␬B),leadingtotheinhibitionofcellularCOX-2gene expres-sion.CurcuminalsocausesanindirectsuppressionoftheNF-␬Ban activitybyinhibitingthedegradationoftheinhibitoryunitI-␬B␣, whichhamperssubsequentnucleartranslocationofthe function-allyactivesubunitofNF-␬B(Surhetal.,2001).Also,ithasbeen showntooverturnthesynthesisofprostaglandinE2(PGE2),which isknowntobeinvolvedinmediating acuteinflammation(Goel etal., 2001).Thereare alsoevidencesof theinhibition of pro-inflammatorycytokineproduction(TNF-␣,IL-1␤,IL-8)bycurcumin (Xuetal., 1997–1998;Banerjeeetal.,2003; Jacobet al.,2007). Anotherstudyexplainsthattheoxygenradicalscavengingactivity ofcurcuminhasalsobeenimplicatedtoanti-inflammatoryeffects (KunchandyandRao,1990).Inadditiontotheanti-inflammatory profile,Sharmaetal.(2006, 2007)demonstratedtheefficacyof curcuminintheattenuationofdiabeticneuropathicpain. Accord-ingtoMittaletal.(2009),oneneedstoexplainthemechanism of curcumin in the first phase of formalin, which occurs as a directactivationofA-deltaandC-nociceptorsaswellas trigem-inaland spinalnociceptiveneurons,whereasanti-inflammatory actionoverthevariousmechanismsmentionedabovemightbe responsibleforreducingthegroomingbehaviorduringthetonic phase. Banafsheet al. (2014) explainsthat this antinociceptive effectmaybeduetotheactivationoftheopioidsystem.Based

onthesereports, the compoundcurcumin representsa natural sourceforthetreatmentoforofacialandattenuatingother pain-andinflammation-relateddisorders,whichallneedfutureclinical investigations.

˛,ˇ-Amyrin

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Atranorin(3₎

Siqueiraet al. (2010)evaluatedthe antinociceptiveeffect of atranorin onformalin- and capsaicin-induced orofacial pain in mice.Theirresultsshowedthatacuteadministrationofatranorin (400mg/kg,i.p.)informalin-inducedorofacialpainresultsina pro-nouncedanti-nociceptionasevidencedbydecreasedface-rubbing nociceptivebehaviorinthefirstandsecondphasesoftheformalin test.Alldosesofatranorinsignificantlyinhibitedtheface-rubbing behavioratthesecondphaseof theformalintest justasinthe capsaicintest.Therefore,thestudysuggestedapossible antinoci-ceptiveeffectofthisimportantlichenmetaboliteextractedfrom CladinakalbiiAhti,inunspecifictests(Meloetal.,2008).Thiseffect mayhaveresultedfromtheinhibitionoftheSubstancePreleaseor duetoadirectblockingactiononitsneurokinin-1receptor(NK-1) (Holanda-Pintoetal.,2008).Meloetal.(2008)suggesteda pos-sibleantinociceptiveeffectofatranorintoactperipherallyonthe inflammatorymediators,especiallyonprostaglandins.Bugnietal. (2009)showedthatapartoftheantinociceptiveeffectobtained withatranorinmaybeduetotheCOXinhibition.Additionally,it wasdemonstratedthatatranorineffectivelyinhibitedthe biosyn-thesisofleukotrieneB4inbovinepolymorphonuclearleukocytes, whichcouldalsoleadtoananti-inflammatoryeffect(Kumarand Muller,1999).Theprecisemechanismsthroughwhichatranorin exertsitsactionarecurrentlyunderinvestigation,buttheycould possiblyberelatedtothearachidonicacidcascadeand/or mod-ulationofpro-inflammatorymoleculeproduction(Siqueiraetal., 2010).

Citronella

ReportsfromQuintans-Júnioretal.,2010,revealedtheeffects ofcitronellal,amonoterpenefromtheoilsofCorymbiacitriodora (Hook.)K.D.Hill&L.A.S.Johnson,Myrtaceae,Cymbopogonnardus (L.)Rendle,C.citratus(DC.)StapfandC.winterianusJowittexBor, Poaceae,inthepossibleanti-nociceptiveactivitybyusingorofacial nociceptive tests (formalin-, capsaicin-, and glutamate-induced orofacialnociception)andinvestigatedwhethersucheffectsmight causea changetoneuralexcitability.Theirresultsshowedthat an acute administration of citronellal caused pronounced anti-nociceptionasevidencedbydecreasedface-rubbingbehaviorin thefirstandsecondphasesoftheformalintest,suggestingthat citronellalhasacentralanalgesiceffect.Toconfirmsuchaneffect, theblockingeffectofnaloxone,aspecificantagonistof morphi-nomimeticreceptors,wastestedonbothphasesoftheformalin test(Belvisietal.,1998).Itsantagonisteffectssuggestedthe par-ticipationoftheopioidsysteminthemodulationofnociception inducedbycitronellal.Citronellalalsoinhibitednociceptive behav-ior inducedby the capsaicininjection intothe right upperlip. Theinhibitoryeffectobservedwithcitronellaloncapsaicin-and formalin-inducedface-rubbingbehaviorseemssimilarlyactto␣,␤ -amyrin,whichcaninvolvetheinhibitionoftheSubstancePrelease ortheactiononreceptorneurokinin-1(NK-1)(Holanda-Pintoetal., 2008).Theresultsalsoshowedthattheintraperitoneal adminis-trationofthecitronellalproduceda significantinhibitionofthe nociceptiveresponseinducedbytherightupperinjectionof glu-tamateintomice.Thatnociceptiveresponseinducedbyglutamate seemstoinvolveperipheral,spinalandsupraspinal sitesandits action ismediated byNMDAand non-NMDA receptors(Beirith

etal.,2002).Thus,thesuppressionofglutamate-induced nocicep-tionbycitronellaltreatmentcanbeassociatedwiththeinteraction ofcitronellalwiththeglutamatergicsystem(Ferreiraetal.,1999). Thepresent studyusedthesinglesucrosegapmethodtoshow that citronellal couldreduce the excitability of isolated nerves throughadiminutionofamplitudeofcompoundactionpotential (CAP).It is possible thatthe antinociceptiveeffects of citronel-lalintheexperimentalmodelsofnociceptioncouldbeinvolved in voltage-gatedNa+ _channel _blocking,_and _may_also_have _CNS effects(Quintans-Júnioretal.,2010).Quintans-Júnioretal.(2010, 2011) alsoproposed thatthe orofacialantinociceptive effectof citronellalcouldberelatedtotheantioxidantprofilesincethese monoterpenesexhibitedasignificantantioxidantactivityasseen inTRAP/TARassays,andscavengeNOandsuperoxidemolecules whicharewidelyacceptedmethodstoreliablyestablishthe abil-ity of isolatedmolecules toact as generalantioxidantsinvitro (Salveminietal.,2006;Guimarãesetal.,2010).Thus,citronellal whenclinicallytestedcouldformapromisingsourceofdrugfor treatingorofacialpaindisorders.

p-Cymene

Santanaetal.(2011)investigated theantinociceptive poten-tialofp-cymene,amonoterpenebiologicalprecursorofcarvacrol and one of themain constituentsof theessential oil obtained fromspeciesofProtium.p-Cymenesignificantlyreducedthe noci-ceptive behavior in the first and second phases of orofacial nociceptioninallmodelsinducedbyformalin,capsaicinand glu-tamate,suggestinganactioninbothneurogenicandinflammatory pain.Recently,Santanaetal.(2015)demonstratethatp-cymene anti-hyperalgesic shows an effect against carrageenan, TNF-␣, dopamineandPGE2tests.Theanti-hyperalgesiceffectseemsto berelatedtothecapacityofp-cymenetodecreasetotalleukocyte migration,TNF-␣levels,actinopioidreceptorsandincreased num-berofc-Fos-immunoreactiveneuronsinperiaqueductalgray(PAG) area.Quintansetal.(2013)suggestedthatp-cymenecouldhaveits analgesicandanti-inflammatoryeffectenhancedbycomplexation withcyclodextrinsprobablybyincreasingthebioavailabilityofthe terpenoid.

Citronellol

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ofperipheralmediators,aswellastheactivation,directorindirect, ofCNSregions.

Carvacrol

Thismonoterpeneispredominantinmanyessentialoilsfrom thefamilyLamiaceae,includingtheOriganumandSaturejaspecies. Guimarãesetal.(2012)reportedthatacutetreatmentwith car-vacrolplaysaprotective roleinreducing behavioralpain when screenedfor formalin-, capsaicin-,and glutamate-induced orof-acialnociceptioninmice.Accordingtotheauthors,carvacrolseems toproduceanti-nociceptionintheorofacialformalin-, capsaicin-andglutamate-testsduetoitseffectsinthereductionofthe neu-ronalexcitabilityandvoltage-gatedNa+_channel_(NaV)_inhibition inperipheralneurons(Jocaetal.,2015)ortoproduceanalgesicand anti-inflammationeffectsbythemodulationofcytokines,suchas IL-10,IL-1␤orTNF-␣(Guimarãesetal.,2014,2015).Additionally, thecarvacrol effects ontheCNSwere assessedthrough immu-nofluorescencefor Fosprotein. Furthermore,moleculardocking studieswereperformedtoevaluateintermolecularinteractionsof thecarvacrolandmuscimol,asligandsofIL-10andGABAA recep-tors,whichshowedtheneuromodulatorypropertiesofcarvacrol inthebrainareasthatcomprisethedescending-painpathway con-trol,suchasPAG,nucleusraphemagnus(NRM)andlocusceruleus (LC).Inaddition,carvacrolcomplexedin␤-cyclodextrin(␤-CD)had prolongedanalgesiceffectandactedondescending-paininhibitory pathwaywithoutshowingtoleranceandina smallerdosethan thecarvacrolisolatedastheywererenderedhighlybioavailable (Barretoetal.,2014;Guimarãesetal.,2014,2015).

Additionally, Lima et al. (2013a) evaluated the contribution of thecytokine modulation tothe anti-inflammatoryeffects of carvacrol in complete Freund’s adjuvant (CFA) model. Hence, theadministrationofthissubstanceproducedanti-inflammatory effectsandattenuatedthepawedemaandreducedtheIL-1␤and PGE2,butnotTNF-␣,locallevels.Thateffectsuggestedthat car-vacrolcausedanti-inflammatoryeffectsbyreducingtheproduction ofinflammatorymediators,suchasIL-1␤andprostanoids, possi-blythroughtheinductionoftheIL-10release.Banjietal.(2014) usedthesamemodel,CFA,asLimaetal.(2013a),butBanjietal. usedacombinationofcarvacrolwithmethotrexateobservingthat thisassociationenrichesthetherapeuticbenefitenhancingits anti-arthriticactionandminimizingitstoxicity.

Plantspecies,essentialoilsandextracts

SidacordifoliaL.,Malvaceae

ThisplantisanativespeciesofNortheasternBrazil,popularly knownas“malva-branca”.Pharmacologicalactivityoftheextracts and fractions from S. cordifolia in two animal models of orof-acialnociceptionhasbeenpreviouslyreported(Bonjardimetal., 2011).Administrationofethanolextract(EE),chloroform(CF)and methanol(MF)fractionsfromS.cordifoliaproducedareductionin thefacerubbingbehaviorinducedbyformalin.Alldosestested sig-nificantlyincreasedanti-nociceptionbothinthefirstandsecond phasecomparedwiththecontrol(vehicle).Morphine(MOR)was abletoreducenociceptivebehaviorinbothphases.TheeffectsofEE, CF,MFandMORwereantagonizedbynaloxone.Thetreatmentwith CFandMFsignificantlyreducedthenociceptivebehaviorinduced byglutamateinrelationtothecontrolgroup.Thus,itissuggested thattheconstituentsofthisfractioncouldinterfereinthe gluta-matergicsystem,throughtheactivationofNMDAreceptors,which wouldlimittheproductionofNOandotherinflammatory media-tors(Ribasetal.,2008).Henceforth,theantinociceptiveeffectofthe ethanolextractfromS.cordifoliaanditschloroformandmethanol fractionsisprobablyduetothepresenceofalkaloidsandflavones. Additionally,itseemsatleastinpartthatthisantinociceptiveaction

ofEE,CFandMFinvolvestheopioidandtheglutamatergicsystems (Bonjardimetal.,2011).

Hyptispectinata(L.)Poit.,Lamiaceae

Paixãoetal.(2013,2015)investigatedtheeffectofthe aque-ousextractfromH.pectinata(AEPH)ontheorofacialnociceptive modelsandits antioxidantpotential.Theresultsofthepresent studyshowedthatAEPHisactiveagainstneurogenicand inflam-matorypain sinceit inhibitsthemice face-rubbingnociceptive behavior in both phases. In addition, when the mechanism of AEPHactionwasinvestigatedusingnaloxone,itseffectwasnot reversed,suggestingthatitsanalgesicactivitydoesnotinvolve opi-oidreceptors.Bispo etal.(2001)foundthatnaloxone(5mg/kg, i.p.)markedlyreversedtheantinociceptiveeffectoftheaqueous extract(200mg/kg)andofmorphine(10mg/kg)inthehot-plate test.Inordertobetterassessthisaspect,Lisboaetal.(2006) eval-uatedthenon-selectiveopioidantagonistnaloxone(5mg/kg,i.p.), whichwasco-administratedwithchloroform(200mg/kg),ethyl acetate(100mg/kg)andhexaneextracts(100mg/kg),since nalox-onereversedtheantinociceptiveeffect.Thismechanismissimilar tothatfoundinthevolatileoilofH.pectinata,inwhichthe admin-istration(i.p.)of theopioid agonistnaxolone(5mg/kgbodywt) completelyreversedtheantinociceptiveeffectofthevolatileoils ofallgenotypesonthehot-platetest,suggestingthatopioid recep-torsareinvolvedinitsantinociceptiveaction(Arrigoni-Blanketal., 2008;Raymundoetal.,2011).Othermechanismsofvolatileoilof H.pectinatawerealsoinvestigated.l_-NAME_{significantly}_reversed theeffectsoftheEOintheaceticacid-inducedcontortionsand hot-platemodelsand atropine completelyreversed in all mod-els.Besides,theEOinhibitedtheinflammatoryprocessinduced bysubcutaneouscarrageenaninjectionbyreducingcellmigration, exudatevolume,proteinconcentrationandinflammatory media-tors(nitricoxide,PGE2,IL-6,andTNF-␣)(Raymundoetal.,2011).

To further investigate the mechanism through which AEPH actsagainstorofacialpain,capsaicinwasused,and therewasa reductioninthecapsaicinnociceptiveeffectinadose-dependent manner,whichindicatesAEPHisactingasanantagonistof vanil-loidreceptors,possiblybyinhibitingtheinitialreleaseofsubstance Porboundingintoitsneurokinin1receptor.AEPHexhibited signif-icantantinociceptiveactivitywhentheglutamatemodelwasused. Therefore,itcanbesuggestedthatitinterfereswiththe glutamater-gicsystem.InvitrostudiesofthisstudyshowedthatAEPHhasan importantneurogenicandinflammatoryorofacialantinociceptive effect,withoutinterferenceinthemotorperformance(Paixãoetal., 2013).

Recently,theliteraturehasshownthattheanalgesicand anti-inflammatory effects of H.pectinata can be improvedwiththe incorporationintocomplexingsystems(ascyclodextrins)or vec-torizationofdrugs,whichcanbringbenefitstophysicochemical orpharmacologicalaspectsofpharmaceuticalpreparations con-tainingextractsoressentialoilsofmedicinalplants(Oliveiraetal., 2015;Britoetal.,2015;Paixãoetal.,2015;Menezesetal.,2015; Quintans-Júnioretal.,2016).

HyptisfruticosaSalzm.exBenth.,Lamiaceae

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duetothevarietyofvolatilecompoundsfoundintheleavessuch as,␣-pinene,␤-pinene,1,8-cineoleandlimonene.

TheresultsofLimaetal.(2013b)showedthatthehydroethanol extractoftheH.fruticosaleaves(CHEE)inhibitedthenociception causedbyglutamatewithsignificantresultsforthehighest concen-trationused(200mg/kg),suggestingthattheextractcanbeactive ininhibitingthepainfulstimulusinducedbythisaminoacid.CHEE at100and200mg/kgwasabletoreducethecapsaicinnociceptive effect,suggestingthatvanilloidreceptorscanbeinvolvedinthe CHEEaction.

OcimumbasilicumL.,Lamiaceae,andlinalool

Venâncioetal.(2011)evaluatedearliertheeffectofO.basilicum. Lamiaceae.Theleafessential oilfromO.basilicum (LEO)andits majorchemicalconstituentlinalool(LIN)informalin-, glutamate-and capsaicin-induced orofacial nociception in mice and were investigatedforwhetherthesesubstancescouldalsointerferewith thehippocampalneuronalexcitability.Intheformalintest,there was a reduction in face rubbing after intraperitoneal injection of LEOor linalool(LIN). Every doseof linalooltested produced significantantinociceptive action in the first and second phase comparedtocontrolgroup.LEOmanifesteditseffectonlyinthe highdose, whilemorphinedecreased thepainbehavior inboth phases.Incapsaicintest,LINorLEOdiminishedthenociception evidencedbythesuppressionoftheface-rubbingbehavior.When assessedtoglutamatetest,LEOandLINproducedmarked analge-sia,but onlyinhigherdoses.Batistaetal.(2008)demonstrated that the antinociceptive effect of LIN may have a relationship withglutamatereceptors,namely␣ -amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA), NMDA and kainate. These resultsconfirmedthishypothesis,sincepretreatmentwithLIN sig-nificantlyprotectedagainsttheorofacialformalintest.Asimilar resultwasobtainedbyacuteadministrationofLEO.Itissuggestthat LEOandLINcanbeconsideredasnon-NMDAglutamateantagonists (AMPAorKainateblockers).Hence,thesebehavioralexperiments suggestthatmostoftheanalgesiceffectsofLEOcouldbeattributed toLIN,itsmajorcomponent.Thestimulationofthehylarregion of thedentategyrus(antidromic stimulation)generated a field potentialresponsein thegranularlayer,which is characterized byamajornegativecomponent(populationspike)followedbya smallpositivephase.Sincethisresponseisaconsequenceof acti-vationofvoltage-dependentsodiumchannelsintheaxonsofthe granularcells(Andersenetal.,1971),antagonistsofthesechannels wereexpectedtoblocktheresponse.Similareffectswereseenfor LEOandLIN,whichinhibitedthefieldpotentialsactivatedbythe antidromicstimulationofthehylus.

Acmellaoleracea(L.)R.K.Jansen,Asteraceae

Nomuraet al.(2013) examinedtheantinociceptive effectof theethanolicextractobtainedfromtheflowersofAcmella oler-acea (EEAO) and their results revealed that EEAO (10, 30 and 100mg/kg)reducedbothphasesoftheformalin-inducedorofacial nociception.Besides,theresultsdecreasedthepainin capsaicin-andcinnamaldehyde-inducedorofacialnociception.Furthermore, thestudyalsosuggestedthattheanalgesiceffectofEEAOonthe orofacialnociceptionmediatedbycapsaicinandcinammaldehyde couldberelatedtoTRPV1andTRPA1receptormodulationand/or blockade.

Syzygiumcumini(L.)Skeels,Myrtaceae

Quintansetal.(2014a)evaluatedtheantinociceptiveeffectof theethanolextract(EE)fromS.cuminileavesonorofacial nocicep-tionthatproducedsignificantanti-nociceptionintheinflammatory phase of theformalin and glutamate test. Whenglibenclamide andl-NOARGwereadministrated,theantinociceptioncausedby EEwasreversed. However,pretreatmentwithnaloxonedidnot

change theantinociceptive action. Muruganandanet al. (2001) investigatedtheethanolicextractofthebarkofS.cuminiforits anti-inflammatoryactivityandtheirresultsshowthatthisextract hasapowerfulanti-inflammatoryactionagainstdistinctphases of inflammationwithoutanyside effectonthegastricmucosa. Theanti-inflammatoryactivityofthis specieswaseven studied byMachadoetal.(2013),whoinvestigatedtheanti-inflammatory andapoptoticactivityoftheessentialoilofS.cuminishowing rel-evantanti-inflammatoryactivityinvivo,possiblyduetothehigh percentageof␤-caryophylleneidentified.

LippiagrataSchauer,Verbenaceae

Siqueira-Limaetal.(2014)investigatedthepossible antinoci-ceptiveactivityof␤-cyclodextrincomplexcontainingLippiagrata leafessentialoil(␤-CD/EO) inanimalmodelsespeciallyin orof-acial pain.The resultsdemonstrated that ␤-CD/EO wascapable ofreducingthenociceptiveface-rubbingbehaviorinbothphases oftheformalin,glutamateandcapsaicininduction,possiblydue totherelationshipwithvanilloid,opioidandcannabinoid recep-tors.␤-CD/EOappearstobeveryeffectiveinactivateddescending pain-inhibitory mechanisms without untoward effects already described for morphine-like drugs (Siqueira-Lima et al., 2014, 2016).Additionally,this studywasthefirsttoshowthe chemi-calandpharmacologicalbenefitscausedbythecomplexationin cyclodextrins,which seemstobean advantageousapproach to essentialoilsandnon-polarcompounds(Oliveiraetal.,2015;Brito et al.,2015).The cyclodextrins(CD)uses toenhance biological andchemicalcharacteristicsofterpenesandrelatedcompounds, such asessential oils,have beenwidely explored in the study ofnewdrugstotreatpain,inflammationandcancerbecauseCD maypromoteincreasedbioavailabilityandpharmacological effi-cacy(Siqueira-Limaetal.,2016).

CombretumduarteanumCambess.,Combretaceae

Quintansetal.(2014b)demonstratedthatthehexanicextract andfriedelinmainbeacompoundfromtheCombretumduartenum -reducednociceptionofformalin(inbothphases).Glutamateand capsaicin-induced orofacialnociceptiontests suggest a possible interactionwiththeglutamatergicsystemandapossibleinhibition ofthesubstancePreleaseorduetoadirectblockofits neurokinin-1receptor(NK-1).Theseresultsaresupportedbypreviousfindings ofAntonisamyetal.(2011)regardingfriedelin,whoattributedthe analgesicprofileduetothecentralandperipheraleffects.However, noneofthestudiesprovidemolecularevaluationsasfriedelincan actbycentralandperipheralways.

Anadenantheracolubrina(Vell.)Brenan,Fabaceae

A.colubrina,popularlyknownas‘angico-branco’,isnativetothe BrazilianCaatingabiomeandusedbythepeopletotreatrespiratory conditions(asthma,bronchitis,coughandflu),asaskin-healing agent,analgesicandagainstinflammatoryprocesses(Damascena et al., 2014)due to its biological properties, Damascena et al. (2014)soughttoassesswhethertheA.colubrinastembarkaqueous extractcaninhibitorofacialpaininducedbychemicalagents (for-malin,capsaicinandglutamate)andinvestigatedtheantioxidant potential.Thus,theA.colubrinastembarkaqueousextractreduced orofacialpaininallanimalmodelsassessedandthiseffectappears tobeassociatedwithitsredox-activeradicalscavengingactivities.

HypericumperforatumL.Hypericaceae,ValerianaofficinalisL., Caprifoliceae,andPipermethysticumG.Forst.,Piperaceae

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hepatic,hematologicandbiochemicalalterationsinducedby reg-ularadministrationoftheseextracts.Theauthorsfoundthatthe compositionofthesethreemedicinalplantsproducedsignificant analgesicprofileinformalin-inducedorofacialpaininrodents,and alsoproducedanoutstandinghepatoprotectiveeffect.

Animalmodelsoforofacialpain

Theimportanceinthefieldof orofacialpain assessmentcan besuggestedbythesharpincreaseinpublicationsovertherecent decades(Hargreaves,2011).Thisfacthasalsobeenaccompaniedby theincreasednumberofstudiesusingorofacialpainanimal mod-els,whichhavesoughttobetterunderstandthepathophysiology oforofacialpainandtoassessnewdrugstotreatit(Raboissonand Dallel,2004).Therearerelativelyfewbehavioralmodelsin labora-toryanimalsdedicatedtothestudyofnociceptioninthetrigeminal region(RaboissonandDallel,2004).Thus,theanimalmodelsof orofacialpainhadsoughttomimicsymptomsorthediseaseperse (KhanandHargreaves,2010).However,theorofacialpainis mul-tifactorialandtoocomplexfor asinglemodeltoincorporateall thenuances,sothereisanincreasingnumberofdifferenttypesof animalmodels.

Asinoursurveymoststudieshavesoughtaccesstoorofacial painbychemicalstimuli,wemadehereabriefcommentonthe orofacialpainanimalmodelsinducedbychemicalstimuli,suchas formalin,capsaicinandglutamate(animalmodelsarebasedonthe inductionofpainbyadministrationofalgogenintothevibrissal padofrodents).

AsdescribedbyHargreaves(2011),thistypeofanimalmodel canbringlimitationsfortheanalysisoftheresultsbecausethe orof-acialpainconditionisnotderivedfromauniquetargettissue,but fromavarietyofsensitivetissuessuchasthemeninges,cornea, toothpulp,oral/nasalmucosaandtemporomandibularjoint.Thus, thechoiceoftheappropriatemethodforinvestigatingthe phys-iologicalorpharmacologicaleventisextremelyimportantinthe studydesignbytheresearcher.

Fortheformalintest,probablythebestestablishedandmost reliableexperimentalprotocoltoassessquicklyorofacialpain con-dition(itisknowntobethesubcutaneous,s.c.,injectionofdilute formalin),whichcausesindeedtissueinjuriesandgenerates behav-ioralaswellaselectrophysiologicalresponsesthatlastfromseveral minutesuptomorethan1h(RaboissonandDallel,2004). Simi-larly,asithappenswiththeadministrationofformalinintothe rodentspaw,theinjectionofformalininthevibrissapad(intothe upperlip)producesabiphasicpainstage(Luccarinietal.,2006).It isamodelthatevaluatesdrugsthatactcentrallyorbyperipheral mechanismsmediatedbylocalinflammationinducedbyformalin (RaboissonandDallel,2004;HunskaarandHole,1987).However,it isnotthebestanimalmodeltoevaluatepainfuloranalgesicroutes. Recently,twootheranimalmodelshavebeenwidelyusedto assessdrugswithpotentialanalgesicprofiletoorofacialpain: cap-saicinandglutamate-inducedorofacialpaintests.Theapplication ofcapsaicin,theprototypicaltransientreceptorpotentialvanilloid 1(TRPV1)agonist,evokesneuropeptidereleaseandinduces pri-maryandsecondaryhyperalgesia(KhanandHargreaves,2010).The administrationofcapsaicinintothevibrissapadofmiceinduces significantnociceptivebehaviorsexpressedasheadflinchingand rubbingoftheorofacialtissuesduringatleast1h(Holanda-Pinto et al.,2008).On the otherhand, glutamate is one of themost important excitatory neurotransmitters in the production and managementofpain(Mogil,2009).Moreover,glutamateispresent inbothcentralandperipheralterminalsoftrigeminalanddorsal rootganglionneurons(KeastandStephensen,2000).Accordingto Quintans-Júnioretal.(2010),theinjectionofglutamate(volume of20␮l)intotherightupperlip(perinasalarea),usinga27-gauge needle,causedapersistentnociceptivebehaviorcharacterizedby

strongrubbingoftheorofacialfaceandheadflinching.Therefore, drugsthatinhibitthesebehaviors,afteradministrationofcapsaicin orglutamate,arepotentiallyusefulasanalgesics(Quintans-Júnior etal.,2010).

Nowwebrieflymentionthemostcommonanimalmodelsto assessorofacialpaininducedbychemicalstimuli.More informa-tionaboutanimalmodelstostudyorofacialpaincanbeassessedin theexcellencereviewspublishedbyRaboissonandDallel(2004), Mogil(2009),KhanandHargreaves(2010)andHargreaves(2011).

Conclusion

Thissystematicreview suggeststhatthenaturalcompounds haveapotentialforthetreatmentofpainconditionsinorofacial region,hopingtodiscovernewbiologicallyactivesubstancesthat mayofferanewpossibilityforthemostappropriatetreatmentof orofacialpain,sincethereisnopharmacologicaltreatmentswhich mayresultinclinicalimprovementwithoutsignificantsideeffects inthesepathologicalconditions.Paradoxically,thestudiesfound inoursurveyareverylead-off(basicallyscreenings),whicharenot directlyrelatedtothepossibleclinicalapplicability.Therefore,it couldbebelievedthatpharmacokineticstudies,incorporationinto modernpharmaceuticalformulationsandbiotechnological prod-uctdevelopmentseemtobeadistanthorizonineventheselected studies.Thus,ouropinionisthattheevidencefoundinthestudies showedapossibleuseoftheseNPinthemanagementoforofacial painconditions.However,newstudiesareneededtoprovetheir underlyingmechanismsandeffectsonthemolecularlevelandin clinicalresearchinanearfuture.

Authors’contributions

PSSL,JCS,JSSQ,RSSBandJRGSAcontributedwithboththesurvey ofthearticlesandthepreparationofthemanuscript.SS,MRVS,LRB, JSSQ,ARA,IRAMandLJQJparticipatedinthedrafting,correction andwiththeirexpertiseinthediscussionandfinalizationofthe manuscript.

Conflictsofinterest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

ThisworkwassupportedbygrantsfromFAPITEC-SE, CAPES andCNPq(allfromBrazil).WethankteacherAbilioBorghiforthe grammarreviewofthemanuscript.

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