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; Jean-Sebastien Austin; Feng Dai; Jie Zhang; Jaclyn Marcovitz; Alexander H Tuttle; Peter M Slepian; Sarah Clarke; Ryan M Drenan; Jeff Janes; Shakir Al Sharari; Samantha K Segall; Eske K Aasvang; Weike Lai; Reinhard Bittner; Christopher I Richards; Gary D Slade; Henrik Kehlet; John Walker; Uwe Maskos; Jean-Pierre Changeux; Marshall Devor; William Maixner; Luda Diatchenko; Inna Belfer; Dennis A Dougherty; Andrew I Su; Sarah C R Lummis; M Imad Damaj; Henry A Lester; Ardem Patapoutian; Jeffrey S Mogil

doi:10.1126/scitranslmed.3009986

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, Jean-Sebastien Austin, Feng Dai, Jie Zhang, Jaclyn Marcovitz, Alexander H Tuttle, Peter M Slepian, Sarah Clarke, Ryan M Drenan, Jeff Janes, Shakir Al SharariSamantha K Segall, Eske K Aasvang, Weike Lai, Reinhard Bittner, Christopher I Richards, Gary D Slade, Henrik Kehlet, John Walker, Uwe Maskos, Jean-Pierre Changeux, Marshall Devor, William Maixner, Luda Diatchenko, Inna Belfer, Dennis A Dougherty, Andrew I Su, Sarah C R Lummis, M Imad Damaj, Henry A Lester, Ardem Patapoutian, Jeffrey S Mogil

Department of Clinical Medicine

39 Citations (Scopus)

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 a6 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 a6∗ 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.

Original language	English
Article number	287ra72
Journal	Science Translational Medicine
Volume	7
Issue number	287
Pages (from-to)	1-16
Number of pages	16
ISSN	1946-6234
DOIs	https://doi.org/10.1126/scitranslmed.3009986
Publication status	Published - 13 May 2015

Keywords

Animals
Chronic Pain
Down-Regulation
Fluorescence Resonance Energy Transfer
Ganglia, Spinal
Humans
Mice
Mice, Mutant Strains
Purinergic P2X Receptor Antagonists
Receptors, Nicotinic
Receptors, Purinergic P2X2
Receptors, Purinergic P2X3

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Wieskopf, J. S., Mathur, J., Limapichat, W., Post, M. R., Al-Qazzaz, M., Sorge, R. E., Martin, L. J., Zaykin, D. V., Smith, S. B., Freitas, K., Austin, J-S., Dai, F., Zhang, J., Marcovitz, J., Tuttle, A. H., Slepian, P. M., Clarke, S., Drenan, R. M., Janes, J., ... Mogil, J. S. (2015). The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors. Science Translational Medicine, 7(287), 1-16. [287ra72]. https://doi.org/10.1126/scitranslmed.3009986

Wieskopf, JS, Mathur, J, Limapichat, W, Post, MR, Al-Qazzaz, M, Sorge, RE, Martin, LJ, Zaykin, DV, Smith, SB, Freitas, K, Austin, J-S, Dai, F, Zhang, J, Marcovitz, J, Tuttle, AH, Slepian, PM, Clarke, S, Drenan, RM, Janes, J, Al Sharari, S, Segall, SK, Aasvang, EK, Lai, W, Bittner, R, Richards, CI, Slade, GD, Kehlet, H, Walker, J, Maskos, U, Changeux, J-P, Devor, M, Maixner, W, Diatchenko, L, Belfer, I, Dougherty, DA, Su, AI, Lummis, SCR, Imad Damaj, M, Lester, HA, Patapoutian, A & Mogil, JS 2015, 'The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors', Science Translational Medicine, vol. 7, no. 287, 287ra72, pp. 1-16. https://doi.org/10.1126/scitranslmed.3009986

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

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 a6 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 a6∗ 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.",

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author = "Wieskopf, {Jeffrey S} and Jayanti Mathur and Walrati Limapichat and Post, {Michael R} and Mona Al-Qazzaz and Sorge, {Robert E} and Martin, {Loren J} and Zaykin, {Dmitri V} and Smith, {Shad B} and Kelen Freitas and Jean-Sebastien Austin and Feng Dai and Jie Zhang and Jaclyn Marcovitz and Tuttle, {Alexander H} and Slepian, {Peter M} and Sarah Clarke and Drenan, {Ryan M} and Jeff Janes and {Al Sharari}, Shakir and Segall, {Samantha K} and Aasvang, {Eske K} and Weike Lai and Reinhard Bittner and Richards, {Christopher I} and Slade, {Gary D} and Henrik Kehlet and John Walker and Uwe Maskos and Jean-Pierre Changeux and Marshall Devor and William Maixner and Luda Diatchenko and Inna Belfer and Dougherty, {Dennis A} and Su, {Andrew I} and Lummis, {Sarah C R} and {Imad Damaj}, M and Lester, {Henry A} and Ardem Patapoutian and Mogil, {Jeffrey S}",

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T1 - The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors

AU - Wieskopf, Jeffrey S

AU - Mathur, Jayanti

AU - Limapichat, Walrati

AU - Post, Michael R

AU - Al-Qazzaz, Mona

AU - Sorge, Robert E

AU - Martin, Loren J

AU - Zaykin, Dmitri V

AU - Smith, Shad B

AU - Freitas, Kelen

AU - Austin, Jean-Sebastien

AU - Dai, Feng

AU - Zhang, Jie

AU - Marcovitz, Jaclyn

AU - Tuttle, Alexander H

AU - Slepian, Peter M

AU - Clarke, Sarah

AU - Drenan, Ryan M

AU - Janes, Jeff

AU - Al Sharari, Shakir

AU - Segall, Samantha K

AU - Aasvang, Eske K

AU - Lai, Weike

AU - Bittner, Reinhard

AU - Richards, Christopher I

AU - Slade, Gary D

AU - Kehlet, Henrik

AU - Walker, John

AU - Maskos, Uwe

AU - Changeux, Jean-Pierre

AU - Devor, Marshall

AU - Maixner, William

AU - Diatchenko, Luda

AU - Belfer, Inna

AU - Dougherty, Dennis A

AU - Su, Andrew I

AU - Lummis, Sarah C R

AU - Imad Damaj, M

AU - Lester, Henry A

AU - Patapoutian, Ardem

AU - Mogil, Jeffrey S

PY - 2015/5/13

Y1 - 2015/5/13

N2 - 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 a6 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 a6∗ 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.

AB - 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 a6 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 a6∗ 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.

KW - Animals

KW - Chronic Pain

KW - Down-Regulation

KW - Fluorescence Resonance Energy Transfer

KW - Ganglia, Spinal

KW - Humans

KW - Mice

KW - Mice, Mutant Strains

KW - Purinergic P2X Receptor Antagonists

KW - Receptors, Nicotinic

KW - Receptors, Purinergic P2X2

KW - Receptors, Purinergic P2X3

U2 - 10.1126/scitranslmed.3009986

DO - 10.1126/scitranslmed.3009986

M3 - Journal article

C2 - 25972004

SN - 1946-6234

VL - 7

SP - 1

EP - 16

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 287

M1 - 287ra72

ER -

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

Abstract

Keywords

UN SDGs

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