Monday, May 10, 2010

Possible Genetic Mechanism for Chronic Pain Identified - Medscape Medical News

Chronic pain may be caused by the inadvertent reprogramming of numerous genes in the peripheral nervous system, according to new research in a rodent model of neuropathic pain.

"Our results suggest that transcriptome reprogramming may be an important mechanism of neurological diseases such as chronic pain," Andreas Beutler, MD, from the Department of Oncology and Anesthesiology, Mayo Clinic, Rochester, Minnesota, noted in an email to Medscape Neurology. The finding could eventually lead to the identification of targets for "transcription therapy," he and colleagues conclude.

Dr. Beutler and colleagues describe their research using what they call a "paradigm-shifting" sequencing technique online May 7 in Genome Research.

Ultra–high throughput mRNA sequencing (mRNA-seq) "offers greater sensitivity, dynamic range and more efficient unbiased genetic mapping compared to the previous microarray-based methods and may be an efficient new approach to a wide array of problems in neuroscience research," Dr. Beutler explained in written statement from the Mayo Clinic.

"Importantly, our study is the first to apply the technology to a neurological disease model," Dr. Beutler told Medscape Neurology.

He and colleagues performed mRNA-seq on the L4 dorsal root ganglion of rats with chronic neuropathic pain induced by spinal nerve ligation of the neighboring L5 spinal nerve.

The researchers chose chronic pain because it is a common neurological disorder that is "incompletely understood at the functional genomic level," the team explains in their report.

Two weeks after spinal nerve ligation, 12.4% of known genes were induced and 7% were suppressed in the dysfunctional but anatomically intact L4 dorsal root ganglion, the researchers report. These alterations were still apparent 2 months after spinal nerve ligation.

Using a read cluster classifier with strong test characteristics (receiver operating characteristic area, 97%), the authors discovered 10,464 novel exons in the dorsal root ganglion potentially involved in chronic pain, including a 64-exon coreceptor for the nociceptive transmitter substance P.

According to the scientists, 21.9% of the newly discovered exons were found to be dysregulated in this animal model of neuropathic pain.

With mRNA-seq, they say they identified significantly more gene expression changes than expected based on previous microarray studies performed on dorsal root ganglion in similar rat pain models.

"Importantly, mRNA-seq demonstrates that transcriptome reprogramming in the nervous system may be more extensive than recognized by microarray studies raising the possibility that some neurological disorders such as pain may be recast in the future as diseases of altered gene expression amenable to transcription therapy."

Genome Res. Published online May 7, 2010.

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