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      Is Open Access

      Expression genetics identifies spinal mechanisms supporting formalin late phase behaviors

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Formalin injection into rodent hind paws is one of the most commonly employed pain assays. The resulting nocifensive behaviors can be divided into two phases differing in timing, duration and underlying mechanisms. Spinal sensitization has long been felt to participate in the second phase of this response, although this sensitization is incompletely understood. By using correlative analysis between spinal gene expression and mouse strain-dependent intensity of late phase behavior, we hypothesized genes participating in variability of the response could be identified.

          Results

          Late phase formalin behavior scores among 10 inbred mouse strains were correlated with a spinal cord gene expression database constructed using expression arrays. Messenger RNA levels for several genes were highly correlated with the late phase behavioral responses. Most of these genes had already been implicated in mechanisms regulating pain and analgesia. One of the most strongly correlated genes, Mapk8 coding for c-Jun N-terminal kinase 1 (JNK1), was chosen for further analysis. Studies using additional strains of mice confirmed that spinal cord mRNA expression levels of Mapk8 followed the pattern predicted by strain-specific levels of formalin behavior. Interestingly, spinal cord JNK1 protein levels displayed an inverse relationship with mRNA measurements. Finally, intrathecal injections of the selective JNK inhibitor, SP600125, selectively reduced late phase licking behavior.

          Conclusions

          Wide differences in pain behaviors, including those resulting from the injection of formalin, can be observed in inbred strains of mice suggesting strong genetic influences. Correlating levels of gene expression in tissues established to be mechanistically implicated in the expression of specific behaviors can identify genes involved in the behaviors of interest. Comparing formalin late phase behavior levels with spinal cord gene expression yielded several plausible gene candidates, including the Mapk8 gene. Additional molecular and pharmacologic evidence confirmed a functional role for this gene in supporting formalin late phase responses.

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          Most cited references 45

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          affy--analysis of Affymetrix GeneChip data at the probe level.

          The processing of the Affymetrix GeneChip data has been a recent focus for data analysts. Alternatives to the original procedure have been proposed and some of these new methods are widely used. The affy package is an R package of functions and classes for the analysis of oligonucleotide arrays manufactured by Affymetrix. The package is currently in its second release, affy provides the user with extreme flexibility when carrying out an analysis and make it possible to access and manipulate probe intensity data. In this paper, we present the main classes and functions in the package and demonstrate how they can be used to process probe-level data. We also demonstrate the importance of probe-level analysis when using the Affymetrix GeneChip platform.
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            Summaries of Affymetrix GeneChip probe level data.

            High density oligonucleotide array technology is widely used in many areas of biomedical research for quantitative and highly parallel measurements of gene expression. Affymetrix GeneChip arrays are the most popular. In this technology each gene is typically represented by a set of 11-20 pairs of probes. In order to obtain expression measures it is necessary to summarize the probe level data. Using two extensive spike-in studies and a dilution study, we developed a set of tools for assessing the effectiveness of expression measures. We found that the performance of the current version of the default expression measure provided by Affymetrix Microarray Suite can be significantly improved by the use of probe level summaries derived from empirically motivated statistical models. In particular, improvements in the ability to detect differentially expressed genes are demonstrated.
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              From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels.

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                Author and article information

                Journal
                Mol Pain
                Molecular Pain
                BioMed Central
                1744-8069
                2010
                11 February 2010
                : 6
                : 11
                Affiliations
                [1 ]Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA
                [2 ]Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA
                [3 ]Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada
                Article
                1744-8069-6-11
                10.1186/1744-8069-6-11
                2831877
                20149257
                Copyright ©2010 Li 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), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Research

                Molecular medicine

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