Journal Article

Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity

Tichauer, David, Dorfman, Ruslan, Tan, Keith, Herbert, Teri A, Smith, Shad B, Austin, Jean-Sebastien, Slade, Gary D, Ritchie, Jennifer, Gershon, Edith, Zaykin, Dmitri V, Yarkoni-Abitbul, Merav, Beggs, Simon, Zheng, Ming, Jordan, Joanne, Mogil, Jeffrey S, Salter, Michael W, Trang, Tuan, John, Sally L, Seltzer, Ze'ev, Costigan, Michael, Meulen, Heather Vander, Sorge, Robert E, Diatchenko, Luda, Maixner, William, Peltz, Gary, Livneh, Jessica, Woolf, Clifford J

2012

Overview

Individual variation in pain sensation makes pain clinical trials quite challenging to interpret. Now, Michael Salter and colleagues report that genetic variation in the P2RX7 gene affects pore formation of the protein and pain sensation in humans. 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 1 . 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 2 , 3 . 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208 / 631/378/1689/2610 / 631/45/269 / Adenosine Triphosphate - analogs & derivatives / Adenosine Triphosphate - pharmacology / Analgesics / Animals / ATP / Benzoxazoles - metabolism / Biomedical and Life Sciences / Biomedicine / Calcium - metabolism / Cancer Research / Carbenoxolone - pharmacology / Care and treatment / Cell receptors / Cells, Cultured / Chronic illnesses / Chronic pain / Chronic Pain - etiology / Chronic Pain - genetics / Chronic Pain - pathology / Cohort Studies / Connexins - metabolism / Development and progression / Disease Models, Animal / Enzyme Inhibitors - pharmacology / Female / Genetic aspects / Genetic Linkage / Genome-Wide Association Study / Genotype / Genotype & phenotype / Histidine - genetics / Humans / Hyperalgesia - genetics / Hyperalgesia - physiopathology / Infectious Diseases / letter / Macrophages - drug effects / Macrophages - metabolism / Male / Mastectomy - adverse effects / Metabolic Diseases / Mice / Mice, Inbred Strains / Molecular Medicine / Mutation / Mutation - genetics / Nerve Tissue Proteins - metabolism / Neurosciences / Osteoarthritis / Osteoarthritis - complications / Pain / Pain Measurement / Pain Threshold - physiology / Peptides - pharmacology / Physiological aspects / Polymorphism, Single Nucleotide - genetics / Pores / Quinolinium Compounds - metabolism / Receptors, Purinergic P2X7 - genetics / Retrospective Studies / Sensory perception / Species Specificity / Time Factors / Transfection