Evidence map›Paper›PMID 25972004›Full record

ArticleScience translational medicine2015

The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors.

Jeffrey S Wieskopf, Jayanti Mathur, Walrati Limapichat, Michael R Post, Mona Al-Qazzaz, Robert E Sorge, Loren J Martin, Dmitri V Zaykin, Shad B Smith, Kelen Freitas and 31 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Science translational medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
46citing papers in PubMed, 2 pooled it
7.4field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

46 citing papers in PubMed, 2 syntheses or guidelines pooled it, 111 citations in OpenAlex.

  1. Pooled it
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  6. Precision neuroscience.Nature biotechnology · 2025
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

41 authors at 9 institutions in 2 countries.

Jeffrey S WieskopfDepartment of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
Jayanti MathurGenomic Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Walrati LimapichatDivision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Michael R PostDivision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Mona Al-QazzazDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
Robert E SorgeDepartment of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
Loren J MartinDepartment of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
Dmitri V ZaykinNational Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Shad B SmithCenter for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Kelen FreitasDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23219, USA.
Jean-Sebastien AustinDepartment of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
Feng DaiDepartments of Anesthesiology and Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Jie ZhangGenomic Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Jaclyn MarcovitzDepartment of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
Alexander H TuttleDepartment of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
Peter M SlepianDepartment of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
Sarah ClarkeDepartment of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
Ryan M DrenanDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Jeff JanesGenomic Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Shakir Al SharariDepartment of Pharmacology, King Saud University, P. O. Box 2457, Riyadh 11451, Saudi Arabia.
Samantha K SegallCenter for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Eske K AasvangSection for Surgical Pathophysiology, Rigshospitalet, Copenhagen University, 2100 Copenhagen, Denmark.
Weike LaiDepartments of Anesthesiology and Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Reinhard BittnerDepartment of Surgery, Marienhospital Stuttgart, 70199 Stuttgart, Germany.
Christopher I RichardsDepartment of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
Gary D SladeDepartment of Dental Ecology, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Henrik KehletSection for Surgical Pathophysiology, Rigshospitalet, Copenhagen University, 2100 Copenhagen, Denmark.
John WalkerGenomic Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Uwe MaskosNeurobiologie Intégrative des Systèmes Cholinergiques, CNRS UMR 3571, Département de Neuroscience, Institute Pasteur, 75724 Paris, France.
Jean-Pierre ChangeuxNeurobiologie Intégrative des Systèmes Cholinergiques, CNRS UMR 3571, Département de Neuroscience, Institute Pasteur, 75724 Paris, France.
Marshall DevorDepartment of Cell and Developmental Biology, Institute of Life Sciences and Center for Research on Pain, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
William MaixnerCenter for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Luda DiatchenkoCenter for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Faculty of Dentistry, Department of Anesthesia, and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1G1, Canada.
Inna BelferDepartments of Anesthesiology and Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Dennis A DoughertyDivision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Andrew I SuDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Sarah C R LummisDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
M Imad DamajDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23219, USA.
Henry A LesterDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Ardem PatapoutianDepartment of Molecular and Cellular Neuroscience, The Scripps Research Institute, and Howard Hughes Medical Institute, La Jolla, CA 92037, USA.
Jeffrey S MogilDepartment of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada. jeffrey.mogil@mcgill.ca.
University of North Carolina at Chapel Hill · USCalifornia Institute of Technology · USGenomics Institute of the Novartis Research Foundation · USUniversity of Pittsburgh · USUniversity of Cambridge · GBNational Institute of Environmental Health Sciences · USPurdue University West Lafayette · USScripps Research Institute · USUniversity of Kentucky · US

Funding

Project 3 University of Colorado, BoulderU19DA019375 · NIDA · CALIFORNIA INSTITUTE OF TECHNOLOGY · PI MARKS, MICHAEL J · 2005 to 2014
$8.3M
Statistical, population genetics and genetic epidemiologyZIAES101866 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI ZAYKIN, DMITRI V · 2009 to 2021
$5.8M
PROBING RECEPTOR STRUCTURES WITH UNNATURAL AMINO ACIDSR01NS034407 · NINDS · CALIFORNIA INSTITUTE OF TECHNOLOGY · PI DOUGHERTY, DENNIS A · 1995 to 2016
$3.1M
Statistical, population genetics and genetic epidemiologyZ01ES101866 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI ZAYKIN, DMITRI V · 2005 to 2008
$911k
CIHRIntramural NIH HHS Z01 ES101866NIDA NIH HHS U19 DA019375NINDS NIH HHS R01 NS034407
6 · The paper itself

Abstract

Chronic pain is a highly prevalent and poorly managed human health problem. We used microarray-based expression genomics in 25 inbred mouse strains to identify dorsal root ganglion (DRG)-expressed genetic contributors to mechanical allodynia, a prominent symptom of chronic pain. We identified expression levels of Chrna6, which encodes the α6 subunit of the nicotinic acetylcholine receptor (nAChR), as highly associated with allodynia. We confirmed the importance of α6* (α6-containing) nAChRs by analyzing both gain- and loss-of-function mutants. We find that mechanical allodynia associated with neuropathic and inflammatory injuries is significantly altered in α6* mutants, and that α6* but not α4* nicotinic receptors are absolutely required for peripheral and/or spinal nicotine analgesia. Furthermore, we show that Chrna6's role in analgesia is at least partially due to direct interaction and cross-inhibition of α6* nAChRs with P2X2/3 receptors in DRG nociceptors. Finally, we establish the relevance of our results to humans by the observation of genetic association in patients suffering from chronic postsurgical and temporomandibular pain.

Indexed as

AnimalsChronic PainDown-RegulationFluorescence Resonance Energy TransferGanglia, SpinalHumansMiceMice, Mutant StrainsPurinergic P2X Receptor AntagonistsReceptors, NicotinicReceptors, Purinergic P2X2Receptors, Purinergic P2X3nicotinic receptor alpha6Purinergic P2X Receptor AntagonistsReceptors, NicotinicReceptors, Purinergic P2X2Receptors, Purinergic P2X3

Identifiers

PMID25972004
PMCPMC5018401
OpenAlexW1928871450

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.