Self-injurious behaviour in intellectual disability syndromes: evidence for aberrant pain signalling as a contributing factor

Self-injurious behaviour in intellectual disabilitysyndromes: evidence for aberrant pain signalling as acontributing factorjir_1484 441..452

K.A. Peebles & T. J. Price

Department of Pharmacology, University of Arizona,Tucson, Arizona, USA

Abstract

Background In most individuals, injury results inactivation of peripheral nociceptors (pain-sensingneurons of the peripheral nervous system) andamplification of central nervous system (CNS) painpathways that serve as a disincentive to continueharmful behaviour; however, this may not be thecase in some developmental disorders that causeintellectual disability (ID). Moreover, individualsaffected by ID disorders may initiate self-injuriousbehaviour to address irritating or painful sensations.In normal individuals, a negative feedback loopdecreases sensation of pain, which involves descend-ing inhibitory neurons in the CNS that attenuatespinal nociceptive processing. If spinal nociceptivesignalling is impaired in these developmental disor-ders, an exaggerated painful stimulus may berequired in order to engage descending anti-nociceptive signals.Methods Using electronic databases, we conducteda review of publications regarding the incidence ofchronic pain or altered pain sensation in IDpatients or corresponding preclinical models.Results There is a body of evidence indicating thatindividuals with fragile X mental retardation and/orRett syndrome have altered pain sensation. These

findings in humans are supported by mechanisticstudies using genetically modified mice harbouringmutations consistent with the human disease. Thus,once self-injurious behaviour is initiated, the signalto stop may be missing. Several developmental dis-orders that cause ID are associated with increasedincidence of gastroesophageal reflux disease(GERD), which can cause severe visceral pain. Indi-viduals affected by these disorders who also haveGERD may self-injure as a mechanism to engagedescending inhibitory circuits to quell visceral pain.In keeping with this hypothesis, pharmacologicaltreatment of GERD has been shown to be effectivefor reducing self-injurious behaviour in somepatients. Hence, multiple lines of evidence suggestaberrant nociceptive processing in developmentaldisorders that cause ID.Conclusions There is evidence that pain pathwaysand pain amplification mechanisms are altered inseveral preclinical models of developmental disor-ders that cause ID. We present hypotheses regardinghow impaired pain pathways or chronic pain mightcontribute to self-injurious behaviour. Studiesevaluating the relationship between pain and self-injurious behaviour will provide better understand-ing of the mechanisms underlying self-injuriousbehaviour in the ID population and may lead tomore effective treatments.

Keywords central sensitisation, diffuse noxiousinhibitory control, fragile X, pain, Rett syndrome,self-injury

Correspondence: Professor Theodore J. Price, Department ofPharmacology, University of Arizona, 1501 N. Campbell Avenue,Life Sciences North, Room 660, Tucson, AZ 85724, USA (e-mail:[email protected]).

Journal of Intellectual Disability Research doi: 10.1111/j.1365-2788.2011.01484.x

volume 56 part 5 pp 441–452 may 2012441

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© 2011 The Authors. Journal of Intellectual Disability Research © 2011 Blackwell Publishing Ltd

Despite the prevalence of self-injurious behaviour(SIB) in many genetic developmental disordersassociated with severe intellectual impairment, verylittle is known about the neurobiological underpin-nings of this comorbidity. SIB occurs in differentsectors of the normal population, but its frequencyis much higher among individuals with develop-mental disorders that negatively influence brainfunction. Several recent advances in preclinicalmodels of such disorders have led to a greaterunderstanding of how mutations in genes that causethese diseases lead to changes in the structure andfunction of the central nervous system (CNS). Atthe same time, a greater appreciation of plasticity inthe CNS as it pertains to chronic pain conditionshas led to the recognition that molecular mecha-nisms of pain amplification are remarkably similarto those of learning and memory (Ji et al. 2003).Here we will summarise recent evidence for aber-rant pain processing in humans affected by develop-mental disorders that cause intellectual disability(ID) and in preclinical models of these diseases. Wewill place these findings into the context of what iscurrently known about the initiation and persistenceof SIB and discuss possible molecular mechanismsand anatomic pathways that may be disrupted inthese diseases. We will outline an experimentalframework for further work in this area to test therole of defective pain amplification in SIB that canpotentially point to new therapeutic avenues. Wewill also discuss chronic pain as a potential contrib-uting factor in SIB, which is a complex behaviour.Understanding the role of the nociceptive system inSIB may improve therapeutic outcomes.

Amplification is a key feature ofpain pathways

Pain is a cortically dependent sensory experiencewith an affective component arising from activationof peripheral pain-sensing neurons (nociceptors). Ina healthy individual, experiencing pain is importantfor survival. In the acute setting, activation of noci-ceptors and CNS neurons that receive input fromthese peripheral neurons elicits a withdrawal reflexfrom noxious insults to avoid further tissue damage.Nociceptors signal to supraspinal CNS structuresinvolved in fear, emotion, and other components of

avoidance in order to reduce the likelihood of sub-sequent dangerous encounters. Inflammation of awound sensitises the surrounding area and encour-ages guarding of the affected tissue to allow healing.This last example involves pain amplification inwhich pain thresholds are decreased through mul-tiple mechanisms. Pain amplification is part of thehealthy self-protective response to noxious insult,but can be dysregulated in multiple pathologies(Woolf 2010).

Ronald Melzack and Patrick Wall were amongthe first to recognise that transmission of paininformation from primary nociceptor to higherCNS structures was not always faithful and that anetwork of neurons in the spinal dorsal horn wasresponsible for gating pain information (Melzack& Wall 1965). We now have a much moreadvanced understanding of the anatomy and physi-ology underlying transmission of pain signals tothe CNS and factors that influence the severity ofperceived pain. The primary nociceptor is a singlecell with an axon that extends from a target tissueto the dorsal horn of the spinal cord where itforms a synapse with a second-order neuron. Thepain signal can then be transmitted directly fromthe second-order neuron to higher centres or befiltered by additional spinal neurons before pro-jecting to the brainstem and brain (Melzack &Wall 1965). The pain signal is transmitted to mul-tiple CNS structures that exert pronouncedcontrol over pain signalling by sending descendingprojections that inhibit or amplify the excitabilityof neurons at earlier stages in the pathway(Ossipov et al. 2010). Thus, cellular feedback loopsfilter pain signalling. Pain amplification can occurat multiple stages in this pathway: nociceptorfiring threshold can be decreased, synaptic effi-ciency increased (Woolf & Salter 2000), or activityof inhibitory or amplifying descending neuronsmodified (Ossipov et al. 2010). While an exhaustivedescription of mechanisms responsible for painamplification is beyond the scope of this review,we will explain two mechanisms that are dysregu-lated in mouse models of ID: wind-up and long-term potentiation (LTP), which represent two welldefined neurophysiological events involved in sen-sitisation of CNS pain pathways – collectivelycalled central sensitisation (Latremoliere & Woolf2009; Woolf 2010).

442Journal of Intellectual Disability Research volume 56 part 5 may 2012

K. A. Peebles & T. J. Price • Pain and self-injurious behaviour


Wind-up

When a noxious stimulus, such as tissue damage, isapplied, it causes an initial stinging or sharp painwith a short latency (called ‘first pain’) and is fol-lowed by a more persistent pain that commonlypossesses a burning quality. This so-called ‘secondpain’ has a longer latency and is thought to be asso-ciated with wind-up of dorsal horn neurons (Price1972; Price et al. 1977). Wind-up involves a progres-sive increase in action potential frequency insecond-order spinal dorsal horn neurons withrepetitive firing of peripheral nociceptors. This takesless than 1 s to begin and can be observed in mostdorsal horn neurons that receive a nociceptiveinput. While the molecular mechanisms of wind-up are complex, its basic mechanisms involveglutamatergic neurotransmission and postsynapticglutamate receptors of the N-methyl-D-asparticacid (NMDA) type. Existing evidence points to pro-gressive depolarisation through NMDA channels asa primary means through which frequency-dependent amplification of dorsal horn neuronfiring is augmented (Dickenson & Sullivan 1987).In addition to increased input–output firing ofdorsal horn neurons, wind-up can also lead to after-discharge in these neurons (continued firing despitethe absence of continued input). Wind-up is com-monly viewed as a primary mechanism for short-term plasticity in the nociceptive system because ittakes place over such a short time-course (Herreroet al. 2000).

Long-term potentiation

Unlike wind-up, LTP involves an increase in synap-tic efficacy that has a longer latency to onset andcan persist for days to weeks and may even be per-manent. As such, most work on LTP has focusedon LTP as a mechanism of learning and memory.Several lines of evidence suggest that LTP occursduring learning and memory (Whitlock et al. 2006)and inhibition of molecular maintenance mecha-nisms of LTP reverse established memories(Pastalkova et al. 2006; Shema et al. 2007). More-over, LTP is impaired in preclinical models of Rett(Moretti et al. 2006) and Fragile X mental retarda-tion (FxS) (Zhao et al. 2005; Wilson & Cox 2007)syndromes. In terms of pain signalling, LTP hasrecently been recognised as an important synaptic

amplifier mechanism in the dorsal horn (Ikeda et al.2006; Sandkuhler 2007). While LTP can be inducedin dorsal horn neurons by artificial high-frequencystimulation of nociceptors, it can also be observedafter natural stimulation that mimics persistentinflammation and/or injury to the peripheralnervous system (Ikeda et al. 2006) pointing to thephysiological importance of this type of plasticity inchronic pain states. While the ability of LTP toexplain the full sequelae of chronic pain symptomsis still controversial (Latremoliere & Woolf 2010;Sandkuhler 2010), it is, nevertheless, a criticalamplification mechanism for pain pathways thatleads to enhanced pain perception in human sub-jects (Klein et al. 2004; Lang et al. 2007).

The significance of these mechanisms for organ-ism fitness is reflected in their evolutionary conser-vation. Several studies have demonstrated thatwind-up can be observed across divergent verte-brate species (Herrero et al. 2000), indicating that itis an evolutionarily conserved mechanism for ampli-fying incoming pain signals. Similarly, an LTP-likemechanism, termed long-term facilitation, can beobserved in sea snails and shares molecular mecha-nisms with mammalian LTP (Martin et al. 1997).While this neurophysiological event has been exten-sively studied as a primitive learning and memorymechanism, it is evoked by a painful stimulus andits behavioural endpoint is a facilitation of a with-drawal reflex. Hence, pain amplification mecha-nisms are evolutionarily conserved across theanimal kingdom in both their short- and longer-term forms. As pain is ultimately a teaching signalfor limiting the extent of injury and promotingprotection of an injured site (Woolf 2010), theseamplification mechanisms serve an importantevolutionary purpose in protecting the individual.

Evidence for altered pain sensation and/orpain amplification in developmentaldisorders where self-injurious behaviouris observed

While the status of wind-up and LTP has not beenexamined in ID patients that engage in SIB, weanticipate that sensitisation due to wind-up and/orLTP would strongly discourage SIB. Moreover, it isformally possible that deficits in overall pain per-




ception might allow increased incidence or persis-tence of SIB in the ID population. Here we willreview evidence for changes in global painresponses and/or amplification of pain signallingin two genetic disorders where SIB is commonlyobserved, Rett syndrome (Sansom et al. 1993;Matson et al. 2008) and FxS (Symons et al. 2003;Hall et al. 2008).

Rett syndrome

Rett syndrome is an X-linked disorder caused bymutation in the methyl-CpG-binding protein 2

(MeCP2) gene (Van den Veyver & Zoghbi 2000).MeCP2 is a DNA binding protein that modifiesthe transcription of multiple gene targets. Onesignificant gene target for MeCP2 is the brain-derived neurotrophic factor (BDNF) gene. Lossof MeCP2 results in decreased BDNF geneexpression and this is associated with severalneurological deficits in the disease. Interestingly,overexpression of the BDNF gene in a mousemodel of the disease ameliorates several key defi-cits, while complete loss of BDNF and MeCP2

leads to enhanced disease progression (Changet al. 2006). BDNF plays a key role in neuronaldevelopment and is an important factor for synap-tic plasticity at adult synapses (e.g. LTP). As such,deficits in LTP are found in the mouse model ofRett syndrome (Moretti et al. 2006). Moreover,MeCP2 has been found to play a key role in painplasticity (Géranton et al. 2007, 2008). In a pre-clinical model of inflammation, enhanced nocicep-tion was associated with increased phosphorylationof MeCP2. This MeCP2 phosphorylation corre-lated with derepression of several established genetargets suppressed by MeCP2 and these genetargets were further shown to play a causative rolein the onset of inflammatory pain in this preclini-cal model. Although pain amplification mecha-nisms have not been examined in mice lacking theMeCP2 gene, mice harbouring a transgene thatleads to a 50% reduction in MeCP2 expression doshow deficits in acute thermal pain thresholds(Samaco et al. 2008). These preclinical investiga-tions led to a close examination of potentialdecreases in pain sensitivity in humans with Rettsyndrome. A large survey of families enrolled inthe Australian Rett Syndrome Database found that

decreased pain sensitivity, as measured by parentalrecall, was a common feature of Rett syndrome,suggesting that these preclinical findings may indi-cate a disruption in pain signalling in the humanpopulation (Downs et al. 2010). Further studiesto assess pain thresholds will be required in thispopulation. The potential intersection of decreasedpain signalling and/or amplification with SIB inthis disease has not been examined.

Fragile X mental retardation

Fragile X mental retardation is caused by silencingof the fragile X mental retardation gene (Fmr1).This gene encodes a protein, fragile X mental retar-dation protein (FMRP), which plays a multifunc-tional role in protein synthesis and neuronaldevelopment (Bagni & Greenough 2005). FMRPbinds to mRNAs and is involved in repressing theirtranslation while transporting them to distal sites incells. In neurons, upon intense synaptic stimulation,FMRP is thought to dissociate from its targetmRNA leading to a derepression of translation(Bassell & Warren 2008). Synaptic synthesis of newproteins plays a key role in initiation and mainte-nance of plasticity and all evidence indicates thatFMRP plays a crucial role in this process (Bassell &Warren 2008). Two forms of synaptic plasticityare altered in several brain regions in the Fmr1-knockout mouse, a model of FxS: long-termdepression is enhanced (Bear et al. 2004) and LTPis absent in some, but not all, brain regions (Liet al. 2002; Larson et al. 2005; Wilson & Cox 2007;Hu et al. 2008). The long-standing existence of thismouse model for FxS (The Dutch-Belgian FragileX Consortium 1994), coupled with interest in therole of translation regulation in synaptic plasticity(Kelleher et al. 2004) and the high prevalence ofFxS (Turner et al. 1996), has led to an extraordinar-ily in-depth understanding of the role of FMRP insynaptic plasticity.

One of us, TJP, conducted a detailed study ofaltered nociception in the mouse model of FxS(Price et al. 2007). While these mice had normalacute pain thresholds to mechanical and thermalstimuli, they showed a marked reduction in assaysdesigned to assess amplification in pain pathways.One of the strongest phenotypes of the FMRP-knockout mouse was a lack of wind-up in dorsal




horn neurons. As mentioned above, wind-up is amajor mechanism of short-term plasticity in painpathways and its near absence in this mouse modelsuggests that a severe deficit in spinal pain process-ing is present in this disease. In fact, not only didwe observe a lack of wind-up in these mice, but wealso noted wind-down in several preparations, indi-cating that there may be a loss of synaptic respon-siveness with repetitive stimulation of nociceptors inthe absence of FMRP. In addition to this deficit inwind-up, longer-term forms of pain plasticity werealso lacking in these mice. These included a longdelay (3 weeks in Fmr1-knockout mice vs. immedi-ate sensitisation in wild-type animals) in the devel-opment of neuropathic pain after peripheral nerveinjury and a lack of metabotropic glutamate recep-tor 1/5 (mGluR1/5)-mediated nociceptive sensitisa-tion. Because FMRP is strongly expressed inneurons of the pain pathway (Price et al. 2006) andtranslation regulation is known to play a key role inpain amplification processes (Price & Geranton2009; Melemedjian et al. 2010; Asiedu et al. 2011),these findings are likely directly linked toFMRP-mediated control of nociceptive plasticityand not associated with other behavioural deficitspresent in this mouse model of the humandisorder.

In contrast to Rett syndrome, studies directlyassessing pain thresholds in FxS have not been con-ducted. Based on studies in the preclinical model,we would not anticipate changes in acute painthresholds in FxS, but rather that pain amplificationwould be impaired. In keeping with this hypothesis,the fragile X premutation tremor/ataxia syndrome(FXTAS) does provide some interesting potentialinsight into this hypothesis. FXTAS, unlike the fullmutation that leads to FxS (Hagerman & Hager-man 2002), does not repress FMRP expression butrather leads to an increase in FMRP mRNA expres-sion (Hessl et al. 2005). Humans with FXTAS fre-quently develop peripheral neuropathies that havea high frequency of associated pain (Berry-Kraviset al. 2007; Brega et al. 2009). Moreover, the inci-dence of the functional pain amplification disorder,fibromyalgia, is significantly increased in patientswith FXTAS (Coffey et al. 2008). Taken together,the preclinical and clinical evidence stronglysuggests a major role for the Fmr1 gene in painamplification.

From preclinical evidence toself-injurious behaviour

While the available evidence clearly points to defi-cits in either acute pain perception or pain amplifi-cation in the absence of MeCP2 or FMRP, a linkbetween these proteins, their disorders and SIB hasyet to be established. One limitation is that mousemodels of Rett syndrome and FxS do not demon-strate SIB or even repetitive grooming behaviourswhich may be interpreted as SIB in mice (Silver-man et al. 2010). On the other hand, we feel thatthe preclinical evidence detailed above creates auseful framework through which testable hypothesescan be made. It is feasible that decreased painthresholds and/or a lack of amplification underliethe persistence of SIB. In such a model, initiationof nociceptor discharge by SIB would be expectedto lead to both wind-up and LTP in pain pathwaysbased on the intensity and duration of SIB bouts(Newell et al. 2002a). This would lead to an amplifi-cation of pain signalling initiating a protectivereflex, an evolutionarily conserved process thatwould be self-limiting. In contrast, in the absence ofsuch amplification mechanisms, as is likely in Rettsyndrome and demonstrated in a preclinical modelof FxS, these protective reflex mechanisms mightfail to engage leading to the persistence of SIBeither within bout or as a consistent stereotypy.While this model would have to be tested in humansubjects, there are several methods that have beenemployed in other settings that could be utilised.LTP can be induced in human pain pathwaysthrough stimulation of dermatomes with electricalcurrent. This procedure leads to brief pain and alonger lasting primary hyperalgesia and secondaryallodynia, on the order of 30 min (Klein et al. 2004,2008; Lang et al. 2007). This procedure, coupledwith the advent of a validated quantitative sensorytesting score for non-verbal adults with neurodevel-opmental disorders (Symons et al. 2010), could beutilised to test for an absence of perceptual corre-lates of LTP in Rett syndrome and FxS. Anotherpotential approach could involve functional mag-netic resonance imaging (fMRI). The LTP protocolmentioned above would be expected to stimulateactivity in the so-called pain axis (Apkarian et al.2005) in control subjects, while activation of thesebrain centres in Rett syndrome or FxS would be




attenuated. Less invasive procedures, such as a briefnoxious pinch or wind-up protocols, may becapable of revealing major differences in engage-ment of brain centres involved in pain processing inthese syndromes. Furthermore, the utilisation ofthese techniques to compare individuals with theseor similar disorders that self-injure versus those thatdo not may reveal additional differences in painprocessing within syndrome populations that wouldbe informative in understanding the potential con-nection between decreased pain amplificationmechanisms and SIB. Finally, and most simply, SIBshould lead to the presence of both hyperalgesiaand secondary allodynia directly following its termi-nation if pain amplification pathways are intact. Wewould hypothesise that such effects would not beobserved in individuals with Rett syndrome, FxS orother similar disorders. This hypothesis is immedi-ately testable in many observational settingsthrough the use of non-verbal pain inventories andquantitative sensory testing (Symons et al. 2010).While we do not deny that these approaches maypresent major technical (fMRI) and complex ethicalhurdles, gaining a further understanding of the roleof pain amplification deficits in SIB may lead tonew treatment approaches and a better grasp on theneurobiological underpinnings of the problem.

There is ongoing discussion in the ID communityregarding reduced pain sensation and ID patients.Several studies have indicated that baseline painthresholds are normal in ID patients (Hennequinet al. 2000; Defrin et al. 2004). To the best of ourknowledge, all studies in the ID population addressbaseline pain thresholds and not pain amplification.A key aspect of the proposal discussed herein is thatpain amplification may be dysregulated in certainID patients, even if baseline pain thresholds arenormal. In addition, very few published reports onpain sensation in ID patients specify the type of IDunder investigation. Differences in pain sensationamong ID syndromes could explain conflictinginterpretations in the literature. For example, it ispossible that patients with Rett syndrome havereduced pain sensation as observed in the Austra-lian study (Downs et al. 2010), while those withDown syndrome have normal pain thresholds, asdemonstrated by Defrin et al. (2004). It is impor-tant to note that the Australian study was a reviewof parental recall regarding pain thresholds in Rett

patients (Downs et al. 2010), while the study byDefrin et al. employed formal sensory thresholdtesting (Defrin et al. 2004); however, including IDtype in future publications assessing pain and SIBwould shed light on conflicting data from studiesthat have pooled all patients with severe ID into asingle group. Also, we wish to acknowledge therisk in speculating about capacity to experiencepain in this sensitive population that often cannotadequately express their needs or may have corticaldeficits that fundamentally change the pain experi-ence. Any clinical study addressing pain amplifica-tion should be thoroughly reviewed for ethicalintegrity and measures should be standardised toavoid a priori bias of investigators. Investigatorsmust take great care in interpreting and reportingtheir data because many caregivers believe that chil-dren with severe ID do not experience pain nor-mally and these beliefs may influence the quality ofcare provided (Breau et al. 2003b). It is possiblethat pain signalling is defective in a subset of IDpatients and identifying those individuals mostlikely to have altered pain processing may allow fortailored treatment for SIB.

Self-injury as a coping mechanism for painin patients with intellectual disability

Several groups have proposed that SIB may serve asa coping mechanism for severe pain because self-injury should activate descending inhibitory mecha-nisms in the pain pathway (Bosch et al. 1997; Breauet al. 2003a; Symons & Danov 2005). In a cohortof ID children with and without various types ofchronic pain and exhibiting varying degrees of SIB,Breau et al. (2003a) found children with chronicpain tended to engage in SIB less frequently, injurea smaller body area and target the site where painoriginated, while those patients without identifiablepain who engaged in SIB tended to self-injure morefrequently and in a diffuse pattern. These findingsraise the possibility that there are qualitatively dif-ferent forms of SIB initiated and propagated fordifferent reasons (Breau et al. 2003a). CompulsiveSIB directed towards painful areas also can occurin children (Symons & Danov 2005) and adults(Mailis 1996) with intact mental status sufferingfrom neuropathic pain and treatment of the under-




lying pain condition resolves SIB in many cases(Mailis 1996). Thus, the occurrence of SIB as acoping mechanism for chronic pain may not belimited to the ID population. Multiple factors con-tribute to initiation, nature and perpetuation ofSIB, thus coping with pain should be considered asa motive on an individual basis. It may be beneficialto include type of ID syndrome and nature of self-injury (e.g. diffuse vs. targeted and which sites) infuture studies to identify factors indicative of SIB asa coping mechanism for pain.

Diffuse noxious inhibitory control

In cases where SIB is associated with chronic pain,self-injury may be working in a similar fashion tothe counter-irritation principle as proposed byseveral groups in the 1980s (Le Bars et al. 1979a;Pertovaara et al. 1982; Willer et al. 1982). Based onthe intensity and duration of self-injury exhibited byID patients (Newell et al. 2002b), this behaviourshould engage reflexive diffuse noxious inhibitorycontrol (DNIC). DNIC was first described as anexperimental paradigm in which a painful condi-tioning stimulus increases hetero- or homotypicpain thresholds in distal locations in rats (Le Barset al. 1979a) and humans (Willer et al. 1984) asmeasured by withdrawal reflexes. In the healthypopulation, DNIC is activated by noxious stimulivery close to the detection threshold. However, ifpain processing is attenuated in ID patients, thestimulus required to engage DNIC may be muchhigher than what is observed in normal individuals.DNIC is a result of inhibitory signalling derivedfrom the brain and brainstem because spinalisedanimals [animals with brain/spinal cord connectionsdisrupted (Le Bars et al. 1979b)] and humans withlesions that interrupt communication betweenhigher structures and the spinal cord (Roby-Bramiet al. 1987; De Broucker et al. 1990) do not exhibitaltered reflex withdrawal thresholds under condi-tions that stimulate DNIC in intact animals or indi-viduals (Le Bars et al. 1979a). DNIC depends inpart upon the endogenous opioid system as a lowdose of the m-opioid receptor antagonist naloxonethat does not affect reflexes in the absence of condi-tioning stimulus (Boureau et al. 1978; Willer et al.1990) completely blocks DNIC in rats (Le Barset al. 1981) and humans (Willer et al. 1990). A

meta-analysis has indicated that the m-opioid recep-tor antagonist naltrexone improves SIB in 50–80%of ID patients (Symons et al. 2004). This study sup-ports the hypothesis that engaging the endogenousopioid system is a motivating factor for some IDpatients, consistent with a scenario in which IDpatients activate DNIC through SIB to cope withpain.

Gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is one ofthe best studied causes for SIB in ID patients withchronic pain. GERD causes severe visceral pain andoccurs with greater frequency among children withdifferent types of severe ID compared to mentallyhealthy children (Sondheimer & Morris 1979; Cateset al. 1989; Spitz et al. 1993; Motil et al. 1999;Gössler et al. 2007). Multiple studies have linkedthe presence of GERD with SIB in ID children andin some cases GERD treatment reduced the inci-dence of SIB (Bosch et al. 1997; Luzzani et al.2003). Swender et al. were among the first to spe-cifically test the a priori hypothesis that GERDmay be causally related to handmouthing in Rettpatients. This group also identified a correlationbetween GERD and SIB in ID children; however,they found that GERD treatment did not alterbehaviour and concluded that SIB may take on sec-ondary functions in this population (Swender et al.2006). Nevertheless, pharmacological interventionto alleviate pain due to GERD may be an impor-tant component of treatment of SIB, and GERDstatus should be assessed in susceptible patients.

Mechanistic work (Mittal et al. 1995; Young et al.2007) has revealed a promising pharmacologicaltarget for GERD treatment. GERD is caused bytransient relaxation of the lower oesophagealsphincter (LES) due to poor neural control (Hollo-way & Dent 1990; Dent 1998). The vagus nervesenses stomach distension after eating, triggeringLES relaxation (Mittal et al. 1995). Inhibiting themetabotropic glutamate receptor 5 (mGluR5)decreases the sensitivity of vagal mechanoreceptorsreducing frequency of LES relaxations (Young et al.2007). Treatment with the mGluR5 antagonist2-methyl-6-(phenylethynyl)pyridine (MPEP)reduces transient LES relaxations by up to 90% inanimal models (Frisby et al. 2005; Jensen et al.




2005) and the negative allosteric modulator ofmGluR5, ADX10059 has demonstrated efficacy forGERD treatment in phase I (Keywood et al. 2009;Zerbib et al. 2010) and phase II (Zerbib et al. 2011)clinical trials in otherwise healthy individuals.Excessive mGluR5 signalling is implicated in thepathology of FxS and the inhibitors under investiga-tion in clinical studies for FxS have been well toler-ated in this population (Berry-Kravis et al. 2009;Jacquemont et al. 2011). These trials were notdesigned to test the effect of mGluR5 inhibition onGERD-associated visceral pain and SIB. Includingthese measures as primary endpoints in subsequenttrials will provide needed evidence to test thehypothesis that SIB might be managed throughbetter GERD control in the ID population.

Ongoing pain should be considered as a potentialdriving factor for SIB in ID patients, but furtherwork is required to assess the relationship betweenself-injury, chronic pain and DNIC. Discovery ofmechanisms linking self-injury to pain and DNICmay reveal additional pharmacological targets,similar to the mGluR5 inhibitors mentioned above.It is worth noting that pain treatment would beuseful only in the subset of ID patients that initiateself-injury in response to pain, and that each patientshould be evaluated individually for the contribu-tion of pain to SIB. Furthermore, if SIB is initiateddue to pain but adopts secondary functions, painmanagement may improve behaviour, but resolutionof SIB will likely require a multipronged approach.Improved methodologies for pain assessment inchildren with severe ID (Symons et al. 2010) canfacilitate the study of the relationship between painand self-injury. Further clinical studies addressingthe role of pain in self-injury initiation and persis-tence should lead to improved strategies for con-trolling SIB.

Concluding remarks

Pain and pain amplification are evolutionarily con-served phenomena critical for survival but can bedysregulated in some disease states (Woolf 2010).The extent of pain experienced by an individualdepends upon spinal gating (Melzack & Wall 1965;Woolf & Salter 2000), which is in turn regulated byhigher centres in the brainstem and brain (Ossipov

et al. 2010). Preclinical and some clinical studiesindicate that pain amplification may be diminishedin certain syndromes that cause severe ID such asFxS (Price et al. 2007) and Rett syndrome (Downset al. 2010). There is conflicting evidence regardingpain thresholds in the ID population with Rettpatients appearing to have decreased sensitivity,albeit as assessed by parental recall and requiringfurther threshold testing (Downs et al. 2010) andDown syndrome patients having normal or possiblyenhanced pain thresholds (Defrin et al. 2004). Thiscould reflect differences in pain processing amongID syndromes as individual molecular defectsleading to clinical features of each disease mayimpact the nociceptive system differently. Further-more, we are unaware of any published clinicalstudies evaluating aberrant pain amplification in IDpatients. Baseline thresholds may remain normalin certain ID patients, but without effective painamplification, pain due to self-injury may not besufficient to deter SIB. Studies evaluating painamplification in ID patients have the potential toreveal the extent to which pain amplification maybe dysregulated in ID patients and linking alteredpain processing to SIB may reveal new pharmaco-logical targets for this difficult behaviour (e.g.mGluR5 antagonists). Some existing clinical datasupport the hypothesis that SIB may be a copingmechanism for certain ID patients dealing withchronic pain. In this paradigm, self-injury activatesDNIC, a centrally mediated, opioid-dependentdampening of spinal pain processing that decreasesthe severity of pain sensation. Identifying IDpatients suffering from chronic pain and incorporat-ing pain management into their treatment mayimprove therapeutic outcomes for SIB. Evaluatingpain amplification and/or processing as well aschronic pain status in clinical studies of ID patientsmay provide insight into mechanisms driving SIB inthis population.

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Accepted 16 August 2011




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Self-injurious behaviour in intellectual disability syndromes: evidence for aberrant pain signalling as a contributing factor