Researchers identify gene associated with susceptibility to chronic pain caused by nerve injury

Researchers at the Hebrew University of Jerusalem and elsewhere have succeeded in identifying for the first time a gene associated with susceptibility to chronic pain caused by nerve injury in humans, signaling a significant step toward better understanding and treating of the condition.

Chronic pain is a serious medical problem, afflicting approximately 20% of adults. Some individuals are more susceptible than others, and the degree of pain experienced after injury or surgery is known to be highly variable between patients, even under nearly identical circumstances.

The basis for this has remained largely unknown, prompting researchers to search for the contribution of genetics to chronic pain susceptibility. To accelerate research in this field, animal models are proving to be critical to understanding the underlying biology of chronic pain in human patients.

In a report to be published online on Aug. 5 in Genome Research (www.genome.org), Prof. Ariel Darvasi of the Alexander Silberman Institute of Life Sciences at the Hebrew University of Jerusalem and colleagues identified a region of mouse chromosome 15 that likely contained a genetic variant or variants contributing to pain. However, this region contains many genes, and the responsible variant remained unknown.

Darvasi and an international team of researchers that included Prof. Marshall Devor of the Hebrew University and Canadian and European scientists undertook two fine-mapping approaches to narrow down the chromosomal locus to an interval of 155 genes.

By applying bioinformatics approaches and whole genome microarray analysis, they then were able to confidently identify a single gene, Cacgn2, as the likely candidate.

To further test the potential role for Cacgn2 in chronic pain, the authors utilized a mouse strain harboring a mutant version of the gene that had previously been used in epilepsy research. In testing the mice for behavioral and electrophysiological characteristics of chronic pain, they found that, the observations were consistent with a functional role for Cacgn2 in pain, even though it might be modest.

However, the question still remained as to whether the human version of the gene also is important for chronic pain. Analyzing a cohort of breast cancer patients who experienced chronic pain half a year or more after they that had undergone removal or partial removal of a breast, they found that genetic variants of Cacng2 were significantly associated with this chronic pain. The authors cautioned that although this association will need to be analyzed further, the result is encouraging at pointing to this gene as a significant factor in experiencing pain.

"The immediate significance is the mere awareness that differences in pain perception may have a genetic predisposition," Darvasi explained. "Our discovery may provide insights for treating chronic pain through previously unthought-of mechanisms."