The Netrin-1 receptor DCC is a regulator of maladaptive responses to chronic morphine administration

Persistent Link:
http://hdl.handle.net/10150/610027
Title:
The Netrin-1 receptor DCC is a regulator of maladaptive responses to chronic morphine administration
Author:
Liang, De-Yong; Zheng, Ming; Sun, Yuan; Sahbaie, Peyman; Low, Sarah; Peltz, Gary; Scherrer, Gregory; Flores, Cecilia; Clark, J.
Affiliation:
Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, USA; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, USA; Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford, USA; Department of Psychiatry, McGill University, Montreal, Canada
Issue Date:
2014
Publisher:
BioMed Central
Citation:
Liang et al. BMC Genomics 2014, 15:345 http://www.biomedcentral.com/1471-2164/15/345
Journal:
BMC Genomics
Rights:
© 2014 Liang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
Abstract:
BACKGROUND:Opioids are the cornerstone of treatment for moderate to severe pain, but chronic use leads to maladaptations that include: tolerance, dependence and opioid-induced hyperalgesia (OIH). These responses limit the utility of opioids, as well as our ability to control chronic pain. Despite decades of research, we have no therapies or proven strategies to overcome this problem. However, murine haplotype based computational genetic mapping and a SNP data base generated from analysis of whole-genome sequence data (whole-genome HBCGM), provides a hypothesis-free method for discovering novel genes affecting opioid maladaptive responses.RESULTS:Whole genome-HBCGM was used to analyze phenotypic data on morphine-induced tolerance, dependence and hyperalgesia obtained from 23 inbred strains. The robustness of the genetic mapping results was analyzed using strain subsets. In addition, the results of analyzing all of the opioid-related traits together were examined. To characterize the functional role of the leading candidate gene, we analyzed transgenic animals, mRNA and protein expression in behaviorally divergent mouse strains, and immunohistochemistry in spinal cord tissue. Our mapping procedure identified the allelic pattern within the netrin-1 receptor gene (Dcc) as most robustly associated with OIH, and it was also strongly associated with the combination of the other maladaptive opioid traits analyzed. Adult mice heterozygous for the Dcc gene had significantly less tendency to develop OIH, become tolerant or show evidence of dependence after chronic exposure to morphine. The difference in opiate responses was shown not to be due to basal or morphine-stimulated differences in the level of Dcc expression in spinal cord tissue, and was not associated with nociceptive neurochemical or anatomical alterations in the spinal cord or dorsal root ganglia in adult animals.CONCLUSIONS:Whole-genome HBCGM is a powerful tool for identifying genes affecting biomedical traits such as opioid maladaptations. We demonstrate that Dcc affects tolerance, dependence and OIH after chronic opioid exposure, though not through simple differences in expression in the adult spinal cord.
EISSN:
1471-2164
DOI:
10.1186/1471-2164-15-345
Keywords:
Genetics; Mapping; Opioid; Pain; Addiction
Version:
Final published version
Additional Links:
http://www.biomedcentral.com/1471-2164/15/345

Full metadata record

DC FieldValue Language
dc.contributor.authorLiang, De-Yongen
dc.contributor.authorZheng, Mingen
dc.contributor.authorSun, Yuanen
dc.contributor.authorSahbaie, Peymanen
dc.contributor.authorLow, Sarahen
dc.contributor.authorPeltz, Garyen
dc.contributor.authorScherrer, Gregoryen
dc.contributor.authorFlores, Ceciliaen
dc.contributor.authorClark, J.en
dc.date.accessioned2016-05-20T08:56:51Z-
dc.date.available2016-05-20T08:56:51Z-
dc.date.issued2014en
dc.identifier.citationLiang et al. BMC Genomics 2014, 15:345 http://www.biomedcentral.com/1471-2164/15/345en
dc.identifier.doi10.1186/1471-2164-15-345en
dc.identifier.urihttp://hdl.handle.net/10150/610027-
dc.description.abstractBACKGROUND:Opioids are the cornerstone of treatment for moderate to severe pain, but chronic use leads to maladaptations that include: tolerance, dependence and opioid-induced hyperalgesia (OIH). These responses limit the utility of opioids, as well as our ability to control chronic pain. Despite decades of research, we have no therapies or proven strategies to overcome this problem. However, murine haplotype based computational genetic mapping and a SNP data base generated from analysis of whole-genome sequence data (whole-genome HBCGM), provides a hypothesis-free method for discovering novel genes affecting opioid maladaptive responses.RESULTS:Whole genome-HBCGM was used to analyze phenotypic data on morphine-induced tolerance, dependence and hyperalgesia obtained from 23 inbred strains. The robustness of the genetic mapping results was analyzed using strain subsets. In addition, the results of analyzing all of the opioid-related traits together were examined. To characterize the functional role of the leading candidate gene, we analyzed transgenic animals, mRNA and protein expression in behaviorally divergent mouse strains, and immunohistochemistry in spinal cord tissue. Our mapping procedure identified the allelic pattern within the netrin-1 receptor gene (Dcc) as most robustly associated with OIH, and it was also strongly associated with the combination of the other maladaptive opioid traits analyzed. Adult mice heterozygous for the Dcc gene had significantly less tendency to develop OIH, become tolerant or show evidence of dependence after chronic exposure to morphine. The difference in opiate responses was shown not to be due to basal or morphine-stimulated differences in the level of Dcc expression in spinal cord tissue, and was not associated with nociceptive neurochemical or anatomical alterations in the spinal cord or dorsal root ganglia in adult animals.CONCLUSIONS:Whole-genome HBCGM is a powerful tool for identifying genes affecting biomedical traits such as opioid maladaptations. We demonstrate that Dcc affects tolerance, dependence and OIH after chronic opioid exposure, though not through simple differences in expression in the adult spinal cord.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://www.biomedcentral.com/1471-2164/15/345en
dc.rights© 2014 Liang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)en
dc.subjectGeneticsen
dc.subjectMappingen
dc.subjectOpioiden
dc.subjectPainen
dc.subjectAddictionen
dc.titleThe Netrin-1 receptor DCC is a regulator of maladaptive responses to chronic morphine administrationen
dc.typeArticleen
dc.identifier.eissn1471-2164en
dc.contributor.departmentAnesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, USAen
dc.contributor.departmentDepartment of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, USAen
dc.contributor.departmentStanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford, USAen
dc.contributor.departmentDepartment of Psychiatry, McGill University, Montreal, Canadaen
dc.identifier.journalBMC Genomicsen
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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