Fruit flies lead scientists to new human pain gene

While it has become clear in recent years that susceptibility to pain has a strong inherited component, very little is known about actual "pain genes" and how they work. In the November 12th issue of Cell, researchers at Children's Hospital Boston and their collaborators report on a novel human pain gene. People with minor variations in this gene showed clear differences in susceptibility to acute heat pain and chronic back pain. Corroborating mouse studies give some clues as to how the gene controls pain sensitivity. The gene was uncovered in a genome-wide hunt for pain genes in fruit flies, which revealed hundreds of other candidate pain genes that await further study.

Understanding the genetic basis of pain will lead to the development of new analgesics, the identification of risk factors for chronic pain and improved decision-making about the suitability of surgical treatment for different patients, says Clifford Woolf, MB, BCh, PhD, the study's senior co-author and director of the F.M. Kirby Center and Program in Neurobiology at Children's.

Classic studies of twins indicate that about 50 percent of variance in pain sensitivity is inherited. "Across a number of different kinds of pain, genes seem to be at least half the driver of how much pain you experience," Woolf says. "Genes give us an amazing and powerful tool to begin to understand how pain is generated, and which functional pathways and specific proteins are involved."

The new gene, discovered in a collaboration with the Institute of Molecular Biotechnology of the Austrian Academy of Sciences and others, encodes part of a calcium channel called alpha 2 delta 3 (α2δ3). Calcium channels are pores in the cell membrane through which calcium ions pass, and are critical for the electrical excitability of nerve cells.

The study, co-led by Joseph Penninger, PhD, scientific director of the Institute of Molecular Biotechnology in Vienna, took advantage of the relative ease of conducting genetic screens in fruit flies. Nearly 12,000 genes were targeted for mutations specifically in nerve cells, using RNA interference (RNAi) technology. The team then exposed the different mutant flies to noxious heat, and identified the ones that failed to fly away. After eliminating flies with other complications, such as an inability to see or fly, they zeroed in on those with mutations that appeared to be specific to pain.

Of the nearly 600 candidate pain genes identified, α2δ3 was one chosen for further study, in part because calcium channels are a known target of some existing analgesics. (Another member of the α2δ family of calcium channels, α2δ1, is a target of gabapentin and pregablin, commonly prescribed for neuropathic pain.)

Studies of mice lacking α2δ3 demonstrated that this gene controls sensitivity to noxious heat in mammals as well as flies. Further, functional MRI imaging of the mutant mice revealed that α2δ3 controls the processing of thermal pain signals in the brain: the heat pain signal seems to arrive appropriately at the thalamus, an early processing center, but does not travel to higher order pain centers in the cortex. Instead, the MRI images showed a surprising cross-activation of vision, olfaction and hearing cortical areas. This cross-activation, or synesthesia, was noted with tactile stimulation in addition to the heat pain stimulus.

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