C57BL/6 substrain differences in inflammatory and neuropathic nociception and genetic mapping of a major quantitative trait locus underlying acute thermal nociception

Camron D. Bryant, Deniz Bagdas, Lisa R. Goldberg, Tala Khalefa, Eric R. Reed, Stacey L. Kirkpatrick, Julia C. Kelliher, Melanie M. Chen, William E. Johnson, Megan Mulligan, M. Imad Damaj

Research output: Contribution to journalArticle

Abstract

Sensitivity to different pain modalities has a genetic basis that remains largely unknown. Employing closely related inbred mouse substrains can facilitate gene mapping of nociceptive behaviors in preclinical pain models. We previously reported enhanced sensitivity to acute thermal nociception in C57BL/6J (B6J) versus C57BL/6N (B6N) substrains. Here, we expanded on nociceptive phenotypes and observed an increase in formalin-induced inflammatory nociceptive behaviors and paw diameter in B6J versus B6N mice (Charles River Laboratories). No strain differences were observed in mechanical or thermal hypersensitivity or in edema following the Complete Freund’s Adjuvant model of inflammatory pain, indicating specificity in the inflammatory nociceptive stimulus. In the chronic constrictive nerve injury, a model of neuropathic pain, no strain differences were observed in baseline mechanical threshold or in mechanical hypersensitivity up to one month post-chronic constrictive nerve injury. We replicated the enhanced thermal nociception in the 52.5°C hot plate test in B6J versus B6N mice from The Jackson Laboratory. Using a B6J × B6N-F2 cross (N = 164), we mapped a major quantitative trait locus underlying hot plate sensitivity to chromosome 7 that peaked at 26 Mb (log of the odds [LOD] = 3.81, p < 0.01; 8.74 Mb-36.50 Mb) that was more pronounced in males. Genes containing expression quantitative trait loci associated with the peak nociceptive marker that are implicated in pain and inflammation include Ryr1, Cyp2a5, Pou2f2, Clip3, Sirt2, Actn4, and Ltbp4 (false discovery rate < 0.05). Future studies involving positional cloning and gene editing will determine the quantitative trait gene(s) and potential pleiotropy of this locus across pain modalities.

Original languageEnglish (US)
JournalMolecular Pain
Volume15
DOIs
StatePublished - Feb 1 2019

Fingerprint

Nociception
Quantitative Trait Loci
Hot Temperature
Pain
Hypersensitivity
Ryanodine Receptor Calcium Release Channel
Chromosomes, Human, Pair 7
Freund's Adjuvant
Chromosome Mapping
Wounds and Injuries
Neuralgia
Rivers
Formaldehyde
Organism Cloning
Edema
Inflammation
Phenotype
Gene Expression
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Cellular and Molecular Neuroscience
  • Anesthesiology and Pain Medicine

Cite this

C57BL/6 substrain differences in inflammatory and neuropathic nociception and genetic mapping of a major quantitative trait locus underlying acute thermal nociception. / Bryant, Camron D.; Bagdas, Deniz; Goldberg, Lisa R.; Khalefa, Tala; Reed, Eric R.; Kirkpatrick, Stacey L.; Kelliher, Julia C.; Chen, Melanie M.; Johnson, William E.; Mulligan, Megan; Imad Damaj, M.

In: Molecular Pain, Vol. 15, 01.02.2019.

Research output: Contribution to journalArticle

Bryant, Camron D. ; Bagdas, Deniz ; Goldberg, Lisa R. ; Khalefa, Tala ; Reed, Eric R. ; Kirkpatrick, Stacey L. ; Kelliher, Julia C. ; Chen, Melanie M. ; Johnson, William E. ; Mulligan, Megan ; Imad Damaj, M. / C57BL/6 substrain differences in inflammatory and neuropathic nociception and genetic mapping of a major quantitative trait locus underlying acute thermal nociception. In: Molecular Pain. 2019 ; Vol. 15.
@article{66cb39dc647f45b8880e1292c61a6479,
title = "C57BL/6 substrain differences in inflammatory and neuropathic nociception and genetic mapping of a major quantitative trait locus underlying acute thermal nociception",
abstract = "Sensitivity to different pain modalities has a genetic basis that remains largely unknown. Employing closely related inbred mouse substrains can facilitate gene mapping of nociceptive behaviors in preclinical pain models. We previously reported enhanced sensitivity to acute thermal nociception in C57BL/6J (B6J) versus C57BL/6N (B6N) substrains. Here, we expanded on nociceptive phenotypes and observed an increase in formalin-induced inflammatory nociceptive behaviors and paw diameter in B6J versus B6N mice (Charles River Laboratories). No strain differences were observed in mechanical or thermal hypersensitivity or in edema following the Complete Freund’s Adjuvant model of inflammatory pain, indicating specificity in the inflammatory nociceptive stimulus. In the chronic constrictive nerve injury, a model of neuropathic pain, no strain differences were observed in baseline mechanical threshold or in mechanical hypersensitivity up to one month post-chronic constrictive nerve injury. We replicated the enhanced thermal nociception in the 52.5°C hot plate test in B6J versus B6N mice from The Jackson Laboratory. Using a B6J × B6N-F2 cross (N = 164), we mapped a major quantitative trait locus underlying hot plate sensitivity to chromosome 7 that peaked at 26 Mb (log of the odds [LOD] = 3.81, p < 0.01; 8.74 Mb-36.50 Mb) that was more pronounced in males. Genes containing expression quantitative trait loci associated with the peak nociceptive marker that are implicated in pain and inflammation include Ryr1, Cyp2a5, Pou2f2, Clip3, Sirt2, Actn4, and Ltbp4 (false discovery rate < 0.05). Future studies involving positional cloning and gene editing will determine the quantitative trait gene(s) and potential pleiotropy of this locus across pain modalities.",
author = "Bryant, {Camron D.} and Deniz Bagdas and Goldberg, {Lisa R.} and Tala Khalefa and Reed, {Eric R.} and Kirkpatrick, {Stacey L.} and Kelliher, {Julia C.} and Chen, {Melanie M.} and Johnson, {William E.} and Megan Mulligan and {Imad Damaj}, M.",
year = "2019",
month = "2",
day = "1",
doi = "10.1177/1744806918825046",
language = "English (US)",
volume = "15",
journal = "Molecular Pain",
issn = "1744-8069",
publisher = "BioMed Central",

}

TY - JOUR

T1 - C57BL/6 substrain differences in inflammatory and neuropathic nociception and genetic mapping of a major quantitative trait locus underlying acute thermal nociception

AU - Bryant, Camron D.

AU - Bagdas, Deniz

AU - Goldberg, Lisa R.

AU - Khalefa, Tala

AU - Reed, Eric R.

AU - Kirkpatrick, Stacey L.

AU - Kelliher, Julia C.

AU - Chen, Melanie M.

AU - Johnson, William E.

AU - Mulligan, Megan

AU - Imad Damaj, M.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Sensitivity to different pain modalities has a genetic basis that remains largely unknown. Employing closely related inbred mouse substrains can facilitate gene mapping of nociceptive behaviors in preclinical pain models. We previously reported enhanced sensitivity to acute thermal nociception in C57BL/6J (B6J) versus C57BL/6N (B6N) substrains. Here, we expanded on nociceptive phenotypes and observed an increase in formalin-induced inflammatory nociceptive behaviors and paw diameter in B6J versus B6N mice (Charles River Laboratories). No strain differences were observed in mechanical or thermal hypersensitivity or in edema following the Complete Freund’s Adjuvant model of inflammatory pain, indicating specificity in the inflammatory nociceptive stimulus. In the chronic constrictive nerve injury, a model of neuropathic pain, no strain differences were observed in baseline mechanical threshold or in mechanical hypersensitivity up to one month post-chronic constrictive nerve injury. We replicated the enhanced thermal nociception in the 52.5°C hot plate test in B6J versus B6N mice from The Jackson Laboratory. Using a B6J × B6N-F2 cross (N = 164), we mapped a major quantitative trait locus underlying hot plate sensitivity to chromosome 7 that peaked at 26 Mb (log of the odds [LOD] = 3.81, p < 0.01; 8.74 Mb-36.50 Mb) that was more pronounced in males. Genes containing expression quantitative trait loci associated with the peak nociceptive marker that are implicated in pain and inflammation include Ryr1, Cyp2a5, Pou2f2, Clip3, Sirt2, Actn4, and Ltbp4 (false discovery rate < 0.05). Future studies involving positional cloning and gene editing will determine the quantitative trait gene(s) and potential pleiotropy of this locus across pain modalities.

AB - Sensitivity to different pain modalities has a genetic basis that remains largely unknown. Employing closely related inbred mouse substrains can facilitate gene mapping of nociceptive behaviors in preclinical pain models. We previously reported enhanced sensitivity to acute thermal nociception in C57BL/6J (B6J) versus C57BL/6N (B6N) substrains. Here, we expanded on nociceptive phenotypes and observed an increase in formalin-induced inflammatory nociceptive behaviors and paw diameter in B6J versus B6N mice (Charles River Laboratories). No strain differences were observed in mechanical or thermal hypersensitivity or in edema following the Complete Freund’s Adjuvant model of inflammatory pain, indicating specificity in the inflammatory nociceptive stimulus. In the chronic constrictive nerve injury, a model of neuropathic pain, no strain differences were observed in baseline mechanical threshold or in mechanical hypersensitivity up to one month post-chronic constrictive nerve injury. We replicated the enhanced thermal nociception in the 52.5°C hot plate test in B6J versus B6N mice from The Jackson Laboratory. Using a B6J × B6N-F2 cross (N = 164), we mapped a major quantitative trait locus underlying hot plate sensitivity to chromosome 7 that peaked at 26 Mb (log of the odds [LOD] = 3.81, p < 0.01; 8.74 Mb-36.50 Mb) that was more pronounced in males. Genes containing expression quantitative trait loci associated with the peak nociceptive marker that are implicated in pain and inflammation include Ryr1, Cyp2a5, Pou2f2, Clip3, Sirt2, Actn4, and Ltbp4 (false discovery rate < 0.05). Future studies involving positional cloning and gene editing will determine the quantitative trait gene(s) and potential pleiotropy of this locus across pain modalities.

UR - http://www.scopus.com/inward/record.url?scp=85061139407&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061139407&partnerID=8YFLogxK

U2 - 10.1177/1744806918825046

DO - 10.1177/1744806918825046

M3 - Article

VL - 15

JO - Molecular Pain

JF - Molecular Pain

SN - 1744-8069

ER -