Genetic Variation in P2RX7 and Pain Tolerance

Overview

Journal Pain

Specialties Neurology
Psychiatry

Date 2018 Feb 23

PMID 29470314

Citations 19

Authors

Oleg Kambur

Mari A Kaunisto

Bendik S Winsvold

Tom Wilsgaard

Audun Stubhaug

John A Zwart

Eija Kalso

Christopher S Nielsen

Affiliations

Soon will be listed here.

Abstract

P2X7 is a nonselective cation channel activated by extracellular ATP. P2X7 activation contributes to the proinflammatory response to injury or bacterial invasion and mediates apoptosis. Recently, P2X7 function has been linked to chronic inflammatory and neuropathic pain. P2X7 may contribute to pain modulation both by effects on peripheral tissue injury underlying clinical pain states, and through alterations in central nervous system processing, as suggested by animal models. To further test its role in pain sensitivity, we examined whether variation within the P2RX7 gene, which encodes the P2X7 receptor, was associated with experimentally induced pain in human patients. Experimental pain was assessed in Tromsø 6, a longitudinal and cross-sectional population-based study (N = 3016), and the BrePainGen cohort, consisting of patients who underwent breast cancer surgery (N = 831). For both cohorts, experimental pain intensity and tolerance were assessed with the cold-pressor test. In addition, multisite chronic pain was assessed in Tromsø 6 and pain intensity 1 week after surgery was assessed in BrePainGen. We tested whether the single-nucleotide polymorphism rs7958311, previously implicated in clinical pain, was associated with experimental and clinical pain phenotypes. In addition, we examined effects of single-nucleotide polymorphisms rs208294 and rs208296, for which previous results have been equivocal. Rs7958311 was associated with experimental pain intensity in the meta-analysis of both cohorts. Significant associations were also found for multisite pain and postoperative pain. Our results strengthen the existing evidence and suggest that P2X7 and genetic variation in the P2RX7-gene may be involved in the modulation of human pain sensitivity.

Citing Articles

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P2X7-NLRP3-Caspase-1 signaling mediates activity-induced muscle pain in male but not female mice.

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Pharmacogenomics of Cancer Pain Treatment Outcomes in Asian Populations: A Review.

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References

Lettre G, Lange C, Hirschhorn J . Genetic model testing and statistical power in population-based association studies of quantitative traits. Genet Epidemiol. 2007; 31(4):358-62. DOI: 10.1002/gepi.20217. View

Arulkumaran N, Unwin R, Wk Tam F . A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases. Expert Opin Investig Drugs. 2011; 20(7):897-915. PMC: 3114873. DOI: 10.1517/13543784.2011.578068. View

Nielsen C, Staud R, Price D . Individual differences in pain sensitivity: measurement, causation, and consequences. J Pain. 2009; 10(3):231-7. DOI: 10.1016/j.jpain.2008.09.010. View

Ke H, Qi H, Weidema A, Zhang Q, Panupinthu N, Crawford D . Deletion of the P2X7 nucleotide receptor reveals its regulatory roles in bone formation and resorption. Mol Endocrinol. 2003; 17(7):1356-67. DOI: 10.1210/me.2003-0021. View

Ide S, Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Hayashida M . Haplotypes of P2RX7 gene polymorphisms are associated with both cold pain sensitivity and analgesic effect of fentanyl. Mol Pain. 2014; 10:75. PMC: 4265416. DOI: 10.1186/1744-8069-10-75. View

Aoyama R, Okada Y, Yokota S, Yasui Y, Fukuda K, Shinozaki Y . Spatiotemporal and anatomical analyses of P2X receptor-mediated neuronal and glial processing of sensory signals in the rat dorsal horn. Pain. 2011; 152(9):2085-2097. DOI: 10.1016/j.pain.2011.05.014. View

Monir M, Zhu J . Comparing GWAS Results of Complex Traits Using Full Genetic Model and Additive Models for Revealing Genetic Architecture. Sci Rep. 2017; 7:38600. PMC: 5227710. DOI: 10.1038/srep38600. View

Hsu S, Lin F, Wu W, Liang C, Huang W, Chan W . miRTarBase: a database curates experimentally validated microRNA-target interactions. Nucleic Acids Res. 2010; 39(Database issue):D163-9. PMC: 3013699. DOI: 10.1093/nar/gkq1107. View

Stabell N, Stubhaug A, Flaegstad T, Nielsen C . Increased pain sensitivity among adults reporting irritable bowel syndrome symptoms in a large population-based study. Pain. 2013; 154(3):385-392. DOI: 10.1016/j.pain.2012.11.012. View

10.

Kaunisto M, Jokela R, Tallgren M, Kambur O, Tikkanen E, Tasmuth T . Pain in 1,000 women treated for breast cancer: a prospective study of pain sensitivity and postoperative pain. Anesthesiology. 2013; 119(6):1410-21. DOI: 10.1097/ALN.0000000000000012. View

11.

Sun C, Chu J, Singh S, Salter R . Identification and characterization of a novel variant of the human P2X(7) receptor resulting in gain of function. Purinergic Signal. 2009; 6(1):31-45. PMC: 2837825. DOI: 10.1007/s11302-009-9168-9. View

12.

Zorina-Lichtenwalter K, Meloto C, Khoury S, Diatchenko L . Genetic predictors of human chronic pain conditions. Neuroscience. 2016; 338:36-62. DOI: 10.1016/j.neuroscience.2016.04.041. View

13.

Gormley P, Anttila V, Winsvold B, Palta P, Esko T, Pers T . Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet. 2016; 48(8):856-66. PMC: 5331903. DOI: 10.1038/ng.3598. View

14.

Ficker C, Rozmer K, Kato E, Ando R, Schumann L, Krugel U . Astrocyte-neuron interaction in the substantia gelatinosa of the spinal cord dorsal horn via P2X7 receptor-mediated release of glutamate and reactive oxygen species. Glia. 2014; 62(10):1671-86. DOI: 10.1002/glia.22707. View

15.

Abecasis G, Auton A, Brooks L, DePristo M, Durbin R, Handsaker R . An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491(7422):56-65. PMC: 3498066. DOI: 10.1038/nature11632. View

16.

Wiley J, Dao-Ung L, Li C, Shemon A, Gu B, Smart M . An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor. J Biol Chem. 2003; 278(19):17108-13. DOI: 10.1074/jbc.M212759200. View

17.

Raffaghello L, Chiozzi P, Falzoni S, Di Virgilio F, Pistoia V . The P2X7 receptor sustains the growth of human neuroblastoma cells through a substance P-dependent mechanism. Cancer Res. 2006; 66(2):907-14. DOI: 10.1158/0008-5472.CAN-05-3185. View

18.

Teixeira J, de Oliveira-Fusaro M, Parada C, Tambeli C . Peripheral P2X7 receptor-induced mechanical hyperalgesia is mediated by bradykinin. Neuroscience. 2014; 277:163-73. DOI: 10.1016/j.neuroscience.2014.06.057. View

19.

Fields R, Ni Y . Nonsynaptic communication through ATP release from volume-activated anion channels in axons. Sci Signal. 2010; 3(142):ra73. PMC: 5023281. DOI: 10.1126/scisignal.2001128. View

20.

Lewis C . Genetic association studies: design, analysis and interpretation. Brief Bioinform. 2002; 3(2):146-53. DOI: 10.1093/bib/3.2.146. View