title: Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity.
abstract: Chronic pain is highly variable between individuals, as is the response to analgesics. Although much of the variability in chronic pain and analgesic response is heritable, an understanding of the genetic determinants underlying this variability is rudimentary. Here we show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X7Rs, which are members of the family of ionotropic ATP-gated receptors, have two distinct modes of function: they can function through their intrinsic cationic channel or by forming nonselective pores that are permeable to molecules with a mass of up to 900 Da. Using genome-wide linkage analyses, we discovered an association between nerve-injury-induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7 gene, such that mice in which P2X7Rs have impaired pore formation as a result of this mutation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Moreover, in two independent human chronic pain cohorts, a cohort with pain after mastectomy and a cohort with osteoarthritis, we observed a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2RX7. Our findings suggest that selectively targeting P2X7R pore formation may be a new strategy for individualizing the treatment of chronic pain.
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sorge
authors.forename: Tuan
authors.initials: T
authors.lastname: Trang
authors.forename: Ruslan
authors.initials: R
authors.lastname: Dorfman
authors.forename: Shad B
authors.initials: SB
authors.lastname: Smith
authors.forename: Simon
authors.initials: S
authors.lastname: Beggs
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ritchie
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Austin
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Zaykin
authors.forename: Heather
authors.initials: H
authors.lastname: Vander Meulen
authors.forename: Michael
authors.initials: M
authors.lastname: Costigan
authors.forename: Teri A
authors.initials: TA
authors.lastname: Herbert
authors.forename: Merav
authors.initials: M
authors.lastname: Yarkoni-Abitbul
authors.forename: David
authors.initials: D
authors.lastname: Tichauer
authors.forename: Jessica
authors.initials: J
authors.lastname: Livneh
authors.forename: Edith
authors.initials: E
authors.lastname: Gershon
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Keith
authors.initials: K
authors.lastname: Tan
authors.forename: Sally L
authors.initials: SL
authors.lastname: John
authors.forename: Gary D
authors.initials: GD
authors.lastname: Slade
authors.forename: Joanne
authors.initials: J
authors.lastname: Jordan
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
authors.forename: William
authors.initials: W
authors.lastname: Maixner
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Seltzer
authors.forename: Michael W
authors.initials: MW
authors.lastname: Salter
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001583:Benzoxazoles / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002229:Carbenoxolone / Q000494:pharmacology; D002478:Cells, Cultured; D059350:Chronic Pain / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D017630:Connexins / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D005838:Genotype; D006639:Histidine / Q000235:genetics; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008408:Mastectomy / Q000009:adverse effects; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010003:Osteoarthritis / Q000150:complications; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011806:Quinolinium Compounds / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000235:genetics*; D012189:Retrospective Studies; D013045:Species Specificity; D013997:Time Factors; D014162:Transfection
chemical_list: D001583:Benzoxazoles; D017630:Connexins; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D010455:Peptides; D011806:Quinolinium Compounds; D058486:Receptors, Purinergic P2X7; C089813:YO-PRO 1; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D006639:Histidine; D000255:Adenosine Triphosphate; D002229:Carbenoxolone; D002118:Calcium