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The Journal of Neuroscience, April 22, 2009, 29(16):5295-5307; doi:10.1523/JNEUROSCI.4020-08.2009

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Behavioral/Systems/Cognitive
Identification of Candidate Genes and Gene Networks Specifically Associated with Analgesic Tolerance to Morphine

Jenica D. Tapocik,¹ Noah Letwin,² Cheryl L. Mayo,¹ Bryan Frank,² Troung Luu,² Ovokeraye Achinike,² Carrie House,² Russell Williams,² Greg I. Elmer,¹ and Norman H. Lee²

¹Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland, Baltimore, Baltimore, Maryland 21228, and ²Department of Pharmacology and Physiology, George Washington University Medical Center, Washington, DC 20037

Correspondence should be addressed to either of the following: Greg I. Elmer, Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland, Baltimore, Maple and Locust Street, Baltimore, MD 21228, Email: gelmer{at}mprc.umaryland.edu; or Norman H. Lee, Department of Pharmacology and Physiology, George Washington University Medical Center, 2300 I Street, Washington, DC 20037, E-mail: Email: phmnhl{at}gwumc.edu

Chronic morphine administration may alter the expression of hundreds to thousands of genes. However, only a subset of these genes is likely involved in analgesic tolerance. In this report, we used a behavior genetics strategy to identify candidate genes specifically linked to the development of morphine tolerance. Two inbred genotypes [C57BL/6J (B6), DBA2/J (D2)] and two reciprocal congenic genotypes (B6D2, D2B6) with the proximal region of chromosome 10 (Chr10) introgressed into opposing backgrounds served as the behavior genetic filter. Tolerance after therapeutically relevant doses of morphine developed most rapidly in the B6 followed by the B6D2 genotype and did not develop in the D2 mice and only slightly in the D2B6 animals indicating a strong influence of the proximal region of Chr10 in the development of tolerance. Gene expression profiling and pattern matching identified 64, 53, 86, and 123 predisposition genes and 81, 96, 106, and 82 tolerance genes in the periaqueductal gray (PAG), prefrontal cortex, temporal lobe, and ventral striatum, respectively. A potential gene network was identified in the PAG in which 19 of the 34 genes were strongly associated with tolerance. Eleven of the network genes were found to reside in quantitative trait loci previously associated with morphine-related behaviors, whereas seven were predictive of tolerance (morphine-naive condition). Overall, the genes modified by chronic morphine administration show a strong presence in canonical pathways representative of neuroadaptation. A potentially significant role for the micro-RNA and epigenetic mechanisms in response to chronic administration of pharmacologically relevant doses of morphine was highlighted by candidate genes Dicer and H19.

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Received Aug. 22, 2008; revised Nov. 30, 2008; accepted March 13, 2009.

Correspondence should be addressed to either of the following: Greg I. Elmer, Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland, Baltimore, Maple and Locust Street, Baltimore, MD 21228, Email: gelmer{at}mprc.umaryland.edu; or Norman H. Lee, Department of Pharmacology and Physiology, George Washington University Medical Center, 2300 I Street, Washington, DC 20037, E-mail: Email: phmnhl{at}gwumc.edu

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