Science, 9 September 2011: 1462-1466. DOI:10.1126/science.1206243.
Emery, et al.“
“HCN2 Ion Channels Play a Central Role in Inflammatory and Neuropathic Pain”..
Chronic nerve-related pain could one day be eased by targeting a gene – but first, we must be sure that the treatment won’t interfere with closely related genes that are vital for controlling heartbeat.
The four HCN genes code for proteins that form ion channels in neurons. It is the flow of sodium ions through these channels that triggers the burst of electrical activity known as an action potential that prompts a neuron to send signals to other neurons. HCN4 is known to play a key role in making the heart beat faster, but the role of the other three is something of a mystery, says Peter McNaughton at theUniversity ofCambridge.
McNaughton and his colleagues suspected, however, that HCN2 might have something to do with pain – it is known to be expressed in nerve cells that process pain signals as well as other types of neuron.
The group first knocked out the HCN2 gene in mice before removing some of the mice’s pain-sensitive nerves to study in a dish. They then added PGE2, a chemical released by damaged tissue that normally increases the frequency of action potentials along a nerve, resulting in more intense pain. PGE2 failed to boost activity in the neurons that had no HCN2. “This suggests to us that HCN2 is involved in pain,” says McNaughton.
After making this discovery, McNaughton wondered whether the gene might also play a role in neuropathic pain – chronic pain brought about by nerve damage, which in Europeaffects around 8 per cent of the population.
Pain drain
His team bred mice that lacked the HCN2 gene in their pain-sensitive nerves only: before, they had been working with mice that had no HCN2 anywhere in their bodies. The group then surgically damaged one leg nerve in both normal mice and mice with HCN2-free pain nerves. Once the mice had recovered from the surgery, the normal mice behaved much like humans with neuropathic pain: they guarded the affected limb, which seemed to have become extremely sensitive to touch. The mice lacking HCN2, however, showed no such response. “The mice appeared to have no neuropathic pain,” McNaughton says.
The team now hope to develop a way of selectively blocking the gene in people with neuropathic pain. Injuries, diabetes and shingles can cause this kind of pain, and current treatment options help only a few sufferers.
