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CONTRIBUTORS
SeenaK.Ajit
DepartmentofPharmacologyandPhysiology,DrexelUniversityCollegeofMedicine,
Philadelphia,Pennsylvania,USA
JamesE.Barrett
DepartmentofPharmacologyandPhysiology,DrexelUniversityCollegeofMedicine,
Philadelphia,Pennsylvania,USA
GeoffreyBurnstock
AutonomicNeuroscienceCentre,RoyalFreeandUniversityCollegeMedicalSchool,
London,UnitedKingdom;DepartmentofPharmacologyandTherapeutics,TheUniversity
ofMelbourne,Melbourne,Australia
SantinaChiechio
DepartmentofDrugSciences,UniversityofCatania,Catania,Italy
HuipingDing
DepartmentofPhysiologyandPharmacology,WakeForestUniversitySchoolofMedicine,
Winston-Salem,NorthCarolina,USA
Guan-huaDu
StateKeyLaboratoryofBioactiveSubstancesandFunctionsofNaturalMedicines;Beijing
KeyLaboratoryofDrugTargetsIdentificationandDrugScreening,InstituteofMateria
Medica,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,
PRChina
Li-daDu
SchoolofBiomedicalSciences,ChineseUniversityofHongKong,HongKong,PRChina
DerickA.Haas
DepartmentofPharmacologyandPhysiology,DrexelUniversityCollegeofMedicine,
Philadelphia,Pennsylvania,USA
HuijuanHu
DepartmentofPharmacologyandPhysiology,DrexelUniversityCollegeofMedicine,
Philadelphia,Pennsylvania,USA
AnthonyC.Johnson
OklahomaCenterforNeuroscience,UniversityofOklahomaHealthSciencesCenter,
OklahomaCity,Oklahoma,USA
JeffreyD.Kennedy
JKAssociatesBioPharmaConsulting,LLC,Carmel,Indiana,USA
BradleyJ.Kerr
NeuroscienceandMentalHealthInstitute;DepartmentofPharmacology;Departmentof
AnesthesiologyandPainMedicine,UniversityofAlberta,Edmonton,Alberta,Canada
NorikazuKiguchi
DepartmentofPhysiologyandPharmacology,WakeForestUniversitySchoolofMedicine,
Winston-Salem,NorthCarolina,USA
ix
x Contributors
Mei-ChuanKo
DepartmentofPhysiologyandPharmacology,WakeForestUniversitySchoolofMedicine,
Winston-Salem,NorthCarolina,USA
AnaPaulaLuiz
MolecularNociceptionGroup,WolfsonInstituteforBiomedicalResearch,University
CollegeLondon,London,UnitedKingdom
BeverleyGreenwood-VanMeerveld
OklahomaCenterforNeuroscience;VeteransAffairsMedicalCenter;Departmentof
Physiology,UniversityofOklahomaHealthSciencesCenter,OklahomaCity,Oklahoma,
USA
ManuelMerlos
DrugDiscoveryandPreclinicalDevelopment,ESTEVE,ParcCient´ıficdeBarcelona,Baldiri
Reixac4-8,Barcelona,Spain
FrancesMunoz
DepartmentofPharmacologyandPhysiology,DrexelUniversityCollegeofMedicine,
Philadelphia,Pennsylvania,USA
JamesD.Pomonis
AmericanPreclinicalServices,LLC,Minneapolis,Minnesota,USA
SujayRamanathan
DepartmentofPharmacologyandPhysiology,DrexelUniversityCollegeofMedicine,
Philadelphia,Pennsylvania,USA
LuzRomero
DrugDiscoveryandPreclinicalDevelopment,ESTEVE,ParcCient´ıficdeBarcelona,Baldiri
Reixac4-8,Barcelona,Spain
Jose´ MiguelVela
DrugDiscoveryandPreclinicalDevelopment,ESTEVE,ParcCient´ıficdeBarcelona,Baldiri
Reixac4-8,Barcelona,Spain
GarthT.Whiteside
DiscoveryResearch,PurduePharmaL.P.,Cranbury,NewJersey,USA
JohnN.Wood
MolecularNociceptionGroup,WolfsonInstituteforBiomedicalResearch,University
CollegeLondon,London,UnitedKingdom
MuhammadSaadYousuf
NeuroscienceandMentalHealthInstitute,UniversityofAlberta,Edmonton,Alberta,
Canada
Tian-yiYuan
StateKeyLaboratoryofBioactiveSubstancesandFunctionsofNaturalMedicines;Beijing
KeyLaboratoryofDrugTargetsIdentificationandDrugScreening,InstituteofMateria
Medica,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,
PRChina
Yong-xiangZhang
DepartmentofNeuroimmunopharmacology,BeijingInstituteofPharmacologyand
Toxicology;StateKeyLaboratoryofToxicologyandMedicalCountermeasures,Beijing,
PRChina
PREFACE
Despiteourlong-standingintimacywiththeexperienceofpain,itcontinues
to be a significant health burden, often disabling, frequently intrusive, and
with restrictive treatment options. Associated with many psychiatric and
neurologicalconditions,themanydifferentfacetsofpainarepoorlyunder-
stood,veryheterogeneous,etiologicallydiverse,andoftenprogressivewith
the link between acute and chronic pain remaining enigmatic. Current
treatmentsarealltoofrequentlyineffectiveorareassociatedwithconsider-
able side effects and, in the case of opioids, significant abuse liability. The
challenges of addressing these complex issues are widely acknowledged,
andanumberofnewapproachesarebeingtakentoaddressperceivedshort-
comings that have thwarted the development of new therapeutics. One of
the major shortcomings is the lack of understanding of the molecular
and cellular bases of pain pathophysiology which are needed to reveal
newvalidatedtargetsforpharmacologicalintervention.Ourunderstanding
ofpainrequiresapproachesfrommanydifferentperspectives,amuchbetter
knowledge of the genetic, epigenetic, and systems-level approaches, and
includes the need for new tools for more insightful clinical diagnosis and,
eventually, adoption of stratified treatment interventions. The chapters in
this volume cover many of these areas and provide a rich overview of
interestingpharmacologicaltargetsthatincludevoltage-gatedsodiumchan-
nels, purinergic receptors, store-operated calcium channels, metabotropic
glutamate receptors, Sigma-1 inhibitors, transporter systems, and the
nociceptin/orphaninFQ–NOPreceptorsystem.Thesetargetsareinvolved
in a wide variety of pain conditions that include cancer, neuropathic, and
inflammatory pain. The focus on the pharmacological modulation of pain
is complemented by chapters on visceral pain and stress, an overview of
animal models of pain, and their translational alignment with the clinic,
and a chapter on the development of miRNA-based biomarkers for pain.
Finally, wehaveattemptedto provideaninitial perspectiveofsometrends
xi
xii Preface
in pain research to set a foundation for subsequent opportunities in the
areaofcomorbiddisordersassociatedwithpain,substanceabuse,andmodel
systems.
JAMES E. BARRETT
Department of Pharmacology and Physiology,
Drexel University College of Medicine, Philadelphia,
Pennsylvania, USA
S. J. ENNA
Department of Molecular and Integrative Physiology,
Department of Pharmacology, Toxicology and Therapeutics,
University of Kansas Medical Center, Kansas City,
Kansas, USA
CHAPTER ONE
Perspectives and Trends in
Pharmacological Approaches to
the Modulation of Pain
James E. Barrett1, Derick A. Haas
DepartmentofPharmacologyandPhysiology,DrexelUniversityCollegeofMedicine,Philadelphia,
Pennsylvania,USA
1Correspondingauthor:e-mailaddress:[email protected]
Contents
1. Introduction 2
1.1 EpidemiologyandIncidenceofPain 2
1.2 UnmetNeedandChallenges 3
2. AnimalModelsandTranslationalPainResearch 5
2.1 TransgenicAnimalsinPainResearch 5
2.2 DrugSelf-administrationintheContextofPainandAnalgesia 11
3. ComorbiditieswithPainorMultisymptomDisorders 15
3.1 ClinicalStudies 16
3.2 PreclinicalStudiesofCoexistingMorbidities 17
3.3 PainandPosttraumaticStressDisorder 20
3.4 PainandCognition 21
4. RecentTrendsinPainResearchandNewApproachestoDrugDiscovery 22
4.1 EpigeneticsandmiRNAs 22
4.2 StemCellApproaches 24
4.3 Organs-on-a-Chip 25
5. Conclusion 26
ConflictofInterest 27
References 27
Abstract
Pharmacologicalapproachestoourunderstandingandtreatmentofpainhavehada
longhistoryandhavetraditionallyreliedonveryfewdrugsthateitherhavesignificant
sideeffectsandabuseliability,suchasthenonsteroidalanti-inflammatorydrugsorthe
opioids,respectively,orthosethathavebeendevelopedforotherconditionssuchas
the tricyclic antidepressants. The pathophysiology of pain is undoubtedly complex,
complicated in part by the fact that it is not a singular condition, and has a variety
ofetiologiesandanumberofassociatedcomorbiditiesthatmaketreatmentinterven-
tionschallenging. Moreover,therearechangesin thecentralnervoussystemduring
the course of the development of chronic pain that, in a manner parallel to
AdvancesinPharmacology,Volume75 #2016ElsevierInc. 1
ISSN1054-3589 Allrightsreserved.
http://dx.doi.org/10.1016/bs.apha.2015.12.004
2 JamesE.BarrettandDerickA.Haas
neurodegenerativedisorders,likelyrequiredifferentpharmacologicalapproachesinthe
earlystagesofacutepaincomparedtothosethatwouldbeeffectivewhenpainhas
becomechronic.Thischapterreviewsthecurrentstatusofthefieldofpainresearch
focusingonsomerelativelyunderdevelopedareas,suchaspainanditsassociatedcom-
orbidities,andtheuseoftransgenicanimalsanddrugself-administrationproceduresin
thecontextofanalgesicassessment.Thischapteralsoincorporatesmorerecentdevel-
opmentsandemergingtrendsintheareaofepigenetics,biomarkers,andtheuseof
induced pluripotent stem cells for pharmacological evaluation, target identification,
andvalidation.Recentprogressinthestudyof“organs-on-a-chip”willalsobeincluded
inthisoverview,settingexpectationsforfutureprogressthatintegratestheseadvances
fordeeperinsightsintomechanisms,noveltreatments,andfacilitatedeffortsindrug
discovery.
1. INTRODUCTION
1.1 Epidemiology and Incidence of Pain
Effortstounderstandthecomplexandmultifacetednatureofpainhavechal-
lenged researchers for decades. Estimates of the prevalence and severity of
pain vary considerably depending on several factors such as the manner in
whichpainhasbeendefined,whetherthefocusisonacuteorchronicpain,
whether it is associated with other pathologies, and how it is measured or
defined in terms of onset, duration and/or relief (Nahin, 2015). There
arealsonoteworthydifferencesintheinfluenceofgender,age,andethnic-
ities that have not been clearly addressed. It is increasingly acknowledged
that pain has several other effects that impact the well-being and quality
of life issues for individuals that, when not effectively managed, lead to
the development of other, often incapacitating, conditions such as depres-
sionandanxiety.Thetransitionfromacutetochronicpainresultsincom-
plexprogressivechangesinandreorganizationofthecentralnervoussystem,
therebyposingsignificantchallengesforpharmacologicalinterventionasthe
potentialtargetsfortreatmentmaywelldependonthestageinwhichthese
transitionstakeplace(Henry,Chiodo,&Yang,2011;Mifflin&Kerr,2014).
Inthissense,painsharessomefeatureswithanumberofneurodegenerative
disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, and
Parkinson’s disease where the progression of the disorder results in signifi-
cant changes in the central nervous system and where the quest for new
drugsiscurrentlydirectedatdelayingorstoppingtheprogressionofthedis-
ease.Withtheseconditions,itmaywellbetoolateintheprocesstorestore
the progressive destruction and neuronal loss, whereas in pain, it is not
PerspectivesandTrendsinPharmacologicalApproachestoPainModulation 3
currently know whether it is possible to restore normal homeostatic pro-
cesses once chronic pain has been established. With the many variations
in the assessment and characterization of pain and its associated com-
orbidities, and with the findings that the development and chronicity of
pain is not static, it is perhaps not surprising that pain remains poorly
managed and that the identification of pathophysiological mechanisms
that precede the introduction of new drugs to treat pain has been so prob-
lematic (Woolf, 2010).
Whatisclear,however,isthatpainrepresentsasignificanthealthburden
that, byany estimate,affectsa significantnumberof individualsworldwide
and at an economic cost in the hundreds of billions of dollars. These costs
exceed the combined costs of cancer, heart disease, and diabetes
(Gaskin & Richard, 2012; Institute of Medicine Report, 2011). Gereau
et al. (2014), in characterizing the status of pain research together with
the development of an agenda for the twenty-first century in America,
referred to “the desperate status of pain research in America” which is a
poignant and forthright acknowledgment of the challenges as well as the
opportunities for basic research and for the development and introduction
of new therapeutics. Despite these alarming facts on the impact of chronic
painonbothindividualsandsociety,NIHexpendituresperaffectedperson
in the United States are the lowest of those listed as major chronic condi-
tions,witha10-to250-foldseparationinexpendituresforthoseconditions
relative to pain (Gereau et al., 2014; see also Max & Stewart, 2008).
1.2 Unmet Need and Challenges
Fordecades,thedevelopmentofnovelandeffectiveanalgesicshasremained
largely stagnant. Most analgesic development efforts have concentrated on
variousreformulationsofexistingopioids,withtheseformulationsincorpo-
rated into existing treatments that, for decades, have involved anticonvul-
sants, amine reuptake inhibitors, nonsteroidal anti-inflammatory drugs
(NSAIDs),andcyclooxygenaseinhibitors.Ithasbeenalltoocommonover
thepastfewyearstolamentthelackofprogressindevelopingdrugsforthe
treatmentofawidevarietyofcentralnervoussystemdisordersaswellasfor
pain.Kissin(2010),forexample,hascommentedthatmorphineandaspirin,
bothintroducedmorethanacenturyago(morphinein1827byMerckand
aspirinin1897byBayer),continuetodominatebiomedicalpublicationson
pain despite their serious side effects and limited efficacy for a number of
painful conditions. Kissin also points out that between 1960 and 2009,
4 JamesE.BarrettandDerickA.Haas
59 drugs were identified as analgesics that remain in use today. However,
only seven of these were considered to be drugs directed against novel
moleculartargets,andonlyoneclass,thetriptans,wasviewedashavingsuf-
ficientefficacytospawnthedevelopmentofsimilardrugsactingatthesame
target.Clearly,despiteconsiderableeffortsandsignificantadvancesinawide
varietyofareas,agreatdealremainstobeaccomplishedtobetterunderstand
thepathophysiologyandheterogeneityunderlyingchronicpain,alongwith
the nature of the variability in response by different individuals to pain
treatments.
A number of relatively novel pharmacological mechanisms have been
evaluatedinrecentyearsbut,forthemostpart,withlittlesuccessinyielding
new medications (Hayes, Arendt-Nielsen, & Tate, 2014). The challenges
are unquestionably considerable. Suggestions for increasing the probability
of success have ranged from the need to better understand the underlying
pathophysiology of acute and chronic pain, to the need to develop better
diagnostic tools. Other proposals have included the need to pursue human
genome-wideassociationstudiesforidentifyingnovelanalgesictargetsalong
withtheveryfrequentcallfordevelopingmorepredictiveandtranslational
animal as well as human experimental pain models. Additional suggestions
haveincludedtheneedtoexpandepidemiologicalstudies,improveclinical
trial design, and expand epigenetic studies addressing the mechanisms of
chronic pain, proof of target engagement, and the development of
genetic- and imaging-based biomarkers (Crow, Denk, & McMahon,
2013; Descalzi et al., 2015; Hayes et al., 2014; Max & Stewart, 2008; Seo
et al., 2013; Woolf, 2010). Individually, these are significant challenges
and, collectively, these proposals amount to a considerable undertaking.
Theobjectiveofthischapteristocoversomeemergingareasthatmayhelp
toshednewlightontheabilitytobetterdifferentiatepainconditions,iden-
tifyameansfordevelopingmoreappropriateanimalmodelsorinvivoassay
systems,andfocusontheissuesofcomorbiditywherepainisassociatedwith
arangeofotherconditionsanddisorders.Inaddition,someattentionwillbe
given to the issue of substance abuse assessment in the context of pain and
analgesic drug development. We will then summarize current efforts to
identifyappropriatebiomarkers,highlightingtheneedtobetterunderstand
epigenetic mechanisms in pain, and will conclude with an overview of
recent developments in the use of in vitro approaches that include the use
ofstemcellsandorgans-on-chipstoaidintheidentificationofnewtargets
andtoprovideothermeansofunderstandsignalingpathwaysandpotentially
toxicities.
PerspectivesandTrendsinPharmacologicalApproachestoPainModulation 5
2. ANIMAL MODELS AND TRANSLATIONAL PAIN
RESEARCH
There are several accounts and descriptions of the various animal
models that have been used in pain research along with extensive analyses
of their use and limitations (e.g., Barrett, 2015; Berge, 2014; Gregory et al.,
2013; King & Porreca, 2014; Yaksh, Woller, Ramachandran, & Sorkin,
2015).Thechapter“PreclinicalPharmacologicalApproachesinDrugDiscov-
ery for Chronic Pain” by Whiteside, Pomonis, and Kennedy supplements
thesearticlesbyfocusingontheuseofanimalmodelsofpaininthepharma-
ceutical industry. Although a few new approaches have been developed to
examinepaininpreclinicalprocedures,itisstrikingthatoneofthemorefre-
quently used procedures continues to be the method first introduced by von
Frey(1896).Thisprocedure,usedextensivelyinrodentpainassays,measures
reflexive withdrawal responses ofthe hind paw following variousprocedures
that induce pain (e.g., spinal nerve ligation). A measure of mechanical
allodynia, the von Frey method,uses fibers or filaments ofdifferent strengths
to determine sensory withdrawal thresholds to the application of different
forcesappliedtothesensitiveregionsofthehindpaw.TheHargreavesmethod
isanotherprocedurebasedonreflexiveresponsestoheat.Despitetheirrelative
easeandwidespreaduse,theseprocedureshavenotreliablypredictedclinical
utility nor have they translated well to clinical assessments where the assess-
ments of analgesia are typically not measured as reflexive responses but rely
moreonspontaneousbehaviorandsubjectiveassessments.Wewillnotreview
thesevariousmodelshere(refertoreferencesaboveformoredetailonanimal
models and alternative approaches) but will instead concentrate on selected
procedures using animals that warrant particular emphasis in this context
andwherethereappeartobefurtheropportunitiesforadvancingpainresearch.
2.1 Transgenic Animals in Pain Research
Insights into genetic factors associated with pain and pain syndromes have
emerged from both human genetic studies as well as from animal models.
These developments have provided new tools and targets as well as
approaches to validate those targets and yield potentially novel pain thera-
peutics.Over15yearsago,MogilandGrisel(1998)providedoneofthefirst
reviews of the use of transgenic animals for the study of pain. Advances in
molecularbiologyforthestudyofpainatthegeneticlevelwereheraldedasa
significant improvement, providing another tool to complement the
