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Open Access Research article

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

De-Yong Liang12, Ming Zheng2, Yuan Sun12, Peyman Sahbaie12, Sarah A Low23, Gary Peltz2, Grégory Scherrer23, Cecilia Flores4 and J David Clark12*

Author Affiliations

1 Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, USA

2 Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, USA

3 Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford, USA

4 Department of Psychiatry, McGill University, Montreal, Canada

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BMC Genomics 2014, 15:345  doi:10.1186/1471-2164-15-345

Published: 8 May 2014

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.

Keywords:
Genetics; Mapping; Opioid; Pain; Addiction