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THE LANCET Neurology Vol 2 April 2003 http://neurology.thelancet.com 205

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Pain, like beauty, seems to be in the eyeof the beholder. But could a geneinfluence our perception of pain, andthe feelings that pain evokes? The teamthat has recently discovered the firstsuch gene is cautious to point out whatauthor Jon-Kar Zubieta (University ofMichigan, Ann Arbor, MI, USA) calls“the whole picture”. Nevertheless, thefindings—which link single-genevariants with differences in subjectivepain experience and brain responses—“represent a major breakthrough”,says Martin Ingvar (KarolinskaHospital, Stockholm, Sweden).

“As we learn more about thepsychological components that deter-mine the pain experience, the moreimportant it is to understand factorsthat determine individual differences”,says Ingvar. Knowledge of the roles ofdopamine-innervated brain regions andthe �-opioid system in modulating painled Zubieta to investigate catechol-O-methyl transferase (COMT), whichdegrades brain monoamines, theactivity of which is determined by valand met alleles. They hypothesised thatCOMT gene variants might influenceresponses to sustained pain, especiallyactivation of the �-opioid system.

PET in 29 volunteers revealeddiminished regional �-opioid systemresponses to a standard pain stressor inmethionine homozygotes, compared

with heterozygotes. “These effects wereaccompanied by higher sensory andaffective ratings of pain and a morenegative internal affective state”, theteam report (Science 2003; 299:1240–43). By contrast, valine hetero-zygotes had increased �-opioidresponses, notably in the cingulatecortex, thalamus, and basal ganglia, andthey “withstood quite a bit more painthan others in the study, while at thesame time reporting that they felt less

pain and fewer pain-related negativeemotions”, notes Zubieta.

“The results speak of the complexityof mechanisms regulating how werespond to pain and by extension, otherstressors”, says Zubieta. Such variationscould induce particular vulnerabilitiesto develop chronic pain, or associateddisorders, such as depression or anxiety.“Also, while some subjects may respondto some medications, others may not.”For Ingvar, the study underlines theneed for better tools to assess pain andfor “a competent assessment of ‘stress’level in the patient, an importantdeterminant if we are to be successful inpain treatment”.

“The $10 000 question is not whychronic pain develops but rather whyonly some develop chronic pain”, saysIngvar, who is convinced that othergenetic markers will be found thatcould influence an individual’s risk ofdeveloping chronic pain. “It is notenough to understand whether there isa connection between a gene and aparticular response, or an illness”,stresses Zubieta. “We need to know thebrain neurochemistry that links thegene with the behaviour.” Kelly Morris

Pain gains first genetic marker

Blockade of the RAGE immuno-globulin receptor can stop T cellsmigrating into the CNS—one of the keyevents in the pathogenesis of multiple-sclerosis-like syndromes—according toShirly ShiDu Yan and colleagues(Columbia University, NY, USA).

The receptor for advanced glycationend products (RAGE) is a member ofthe immunoglobulin superfamily of cellsurface molecules. Its proinflammatoryligands, the S100-calgranulins, areknown to be upregulated in multiplesclerosis (MS) and in the related rodentmodel, experimental autoimmuneencephalomyelitis (EAE).

Yan and colleagues first establishedthat RAGE is involved in MS and EAEby measuring the amount of RAGEimmunoreactivity in spinal-cord tissuefrom patients with MS and mice withEAE. They found upregulation of

RAGE and its ligands in bothsyndromes, particularly in CD4+T cells, which are associated with theinflammatory lesions linked to diseaseepisodes in patients with MS (Nat Med,2003, 9: 287–93).

RAGE expression is known toincrease with increasing concentrationsof its ligands. Therefore, Yan’s teamhypothesised that “mopping up” theexcess ligand with truncated solubleRAGE receptor (sRAGE) may helpprevent immune-mediated damage tothe myelin sheath by decreasingexpression of RAGE.

“Blocking encephalitogenic CD4+T-cell entry to CNS is well known tohave a strong protective effect on thedevelopment EAE/MS”, Yan explains.“But the key issue is to delineate thepathways of T-cell activation and assesswhich are most relevant.” Identification

of these pathways means they could, intheory, be selectively blocked andtherefore provide a potential target fortherapeutic intervention.

The researchers gave sRAGE tomice with EAE and found that, asexpected, it had a protective effect.Further investigations revealed thatRAGE is essential for infiltration ofCD4+ T cells into the CNS. This is a keystage in the pathogenesis of MS,preceding restimulation of the T cellsby microglia and subsequent initiationof a destructive inflammatory cascade.

“Our study delineates RAGE as onerelevant pathway and highlights a newaxis in immune/inflammation processesof EAE/MS”, says Yan. “In the future,RAGE antagonists or a small-moleculeRAGE inhibitor may be an option for atherapeutic approach in MS.”James Butcher

T-cell activation pathway provides target for MS treatment

Mapping the genetics of pain in the brain

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