Chronic pain gene discovered

By Dr. Ananya Mandal, MDSep 12 2011

Scientists have found the gene responsible for chronic pain. It said that this could lead to drugs for treating long-lasting back pain.

Researchers from the University of Cambridge and the University of Cadiz found that deleting a gene called HCN2 from the pain-sensing nerves in mice stopped them from having the chronic hypersensitivity to pain caused by nerve damage. However, their ability to sense short-term (acute) pain, for example from heat or pressure, was not affected.

This research has highlighted a potential role for HCN2 in one type of chronic pain, called neuropathic pain, produced by damage to nerves themselves.

However, it’s important to note that this study was in mice, and looked at the effect of removing the HCN2 gene rather than using chemicals to block its function. Therefore it cannot tell us whether this strategy will be successful in treating human forms of chronic pain.

Ion channels are protein “pores” in the cell membrane that controls the flow of electrically charged atoms into or out of the cell. In nerves this flow of ions is essential for allowing them to transmit signals. The researchers say that the frequency with which the nerves involved in sensing pain send signals to the brain (called their rate of firing) affects how intense a pain is felt to be. This rate could be influenced by ion channels, including the HCN ion channel family.

The HCN1 and HCN2 members of the HCN ion channel family are present at high levels in nerves involved in sensations such as pain and touch. Previous experiments have suggested that HCN1 does not play a large role in sensing pain, so the researchers wanted to investigate whether HCN2 might be important in sensing pain.

The researchers looked at the role of the HCN2 ion channel in mice by genetically engineering them to lack the gene that produces this protein in their pain-sensing nerves. They then looked at what effect this had on the ability of the pain-sensing nerves to send signals, and on how the mice sensed pain.

The researchers tested the mice’s responses to pain using standard tests. For example, they tested how quickly they withdrew their feet in response to touching a hot or cold surface or to the application of pressure (called painful ‘stimuli’). They also tested these responses after injecting the mice with chemicals that cause inflammation and make normal mice hypersensitive to these painful stimuli.

Finally, they looked at the effect of exposing these mice to long-lasting pain caused by damage to their nerves. This type of pain is called neuropathic pain. They used a standard way of replicating this type of pain, by placing pressure on the mice’s sciatic nerve. This usually makes mice more sensitive to painful stimuli.

The researchers found that mice that were genetically engineered to lack the gene for HCN2 in their pain-sensing nerves had disruptions to the normal electrical processes that led to firing of these nerves. The HCN2-lacking mice did not show any change to their pain threshold on short-term exposure to heat or pressure. However, when injected with chemicals that cause inflammation and make normal mice hyper-sensitive to heat and pressure induced pain, the HCN2 lacking mice did not show hyper-sensitivity to heat induced pain.

Study leader Peter McNaughton said people suffering from neuropathic pain often have little or no respite because of the lack of effective medications. “Our research lays the groundwork for the development of new drugs to treat chronic pain by blocking HCN2,” McNaughton said.

Chronic pain brought about by nerve damage in Europe affects around 8 per cent of the population. John Wood, who researches pain at University College London, thinks that developing an HCN2-blocking therapy will be difficult and perhaps impossible. HCN2 is also thought to play a role in regulating heartbeat, says Wood. “Drug companies have developed HCN2 blockers already, but this area of work has been abandoned for fear of adverse side effects”, he says.

McNaughton, however, remains positive. “An HCN4 blocker is already used to treat angina,” he says. “We were able to give mice a dose of this drug that affected their neuropathic pain but didn't significantly alter their heartbeat.” Although it might be too risky to trial the drug in people with neuropathic pain but no heart-related problems, tweaking it so that it targets only HCN2 protein ion channels in neurons responsible for pain processing could be the way to go, he said.

Funding for the study was provided by the UK Biotechnology and Biological Sciences Research Council, the European Union, Organon Inc. and a Cambridge Gates Foundation studentship. The study was published in the peer-reviewed journal Science.