Nearly one-fifth of us will experience neuropathic pain during our lifetimes, with exaggerated pain sensations or pain in response to a stimulus that is not normally painful, such as a light touch. Now, researchers report that overly active immune cells in the spinal cord may be to blame.
Yves De Koninck at Laval University and Michael Salter at The Hospital for Sick Children in Toronto and colleagues have linked two earlier observations together to map of at least one route to neuropathic pain. The new data may suggest novel ways to treat the problem.
Normal pain is triggered by a stimulus somewhere in the body. The signal then passes through the spinal cord, where initial processing occurs, and travels to the brain, where it is perceived as pain. Any disruption along the way can lead to neuropathic pain, including abnormal processing of information from nonpainful stimuli.
In 2003, De Koninck’s team identified a key mechanism in the spinal cord that leads to neuropathic pain. In healthy people, some spinal cord neurons dampen pain signals, allowing individuals to tolerate intense stimuli at times, such as when a woman is giving birth or during a fight. During neuropathic pain, this inhibitory mechanism goes awry and actually amplifies the pain signal.
Normally, when a pain signal arrives from sensory nerves, it stimulates both relay neurons and inhibitory neurons in the spinal cord. The inhibitory neurons release a neurotransmitter called gamma-aminobutyric acid, or GABA, which also acts on the relay neurons. If the amount of GABA released by the inhibitory neuron is large enough, it will cause the interior of the relay neuron to become negatively charged and unresponsive to the signal from the sensory neuron. When that happens the pain signal will be stopped in its tracks, or at least decreased in strength.
However, in order for this local repression to work, the concentration of negatively charged chloride ions inside resting relay neurons must be much lower than the concentration outside them, a process that relies on a chloride pump. During neuropathic pain, this pump stops working.
Also in 2003, Salter’s group showed that microglia, which are central nervous system immune cells, play a role in neuropathic pain. After injury, microglia express a new receptor, called P2X4, on their surface. When the researchers prevented P2X4 receptors from being activated by ATP, a nucleotide that can act as a signaling molecule, they blocked hypersensitivity to normally nonpainful stimuli in rat models.
In the current study, which was published in the December 15, 2005, issue of Nature, De Koninck and colleagues report that the chloride pump and microglia are two parts of the same pathway that lead to neuropathic pain.
Salter and De Koninck found that when ATP binds to the P2X4 receptor on microglia, it starts a cascade of events. ATP activates the microglia, causing them to release a small peptide called brain-derived neurotrophic factor, or BDNF. BDNF then binds to a protein on the surface of relay neurons in the spinal cord, which causes the chloride ion pump to stop working. What would have been an inhibitory response becomes an amplifying one.
Significantly, the investigators found that if they blocked microglial activation or BDNF activity, they could reverse the problem in the spinal cords of rats. That could be a first step toward treating neuropathic pain in humans.
“Neuropathic pain is normally hard to treat,” says Amy MacDermott, a professor at Columbia University who also works on pain signaling in the spinal cord. “But they have figured out enough of the pathway that they could reverse, at least temporarily, an existing condition.”
Some of the BDNF released by the microglia may be involved in tissue repair, but a side effect of that is hypersensitivity, De Koninck says. “Everyone will develop hypersensitivity after an injury. That is a normal process. Our pain system is designed to sensitize itself, because it forces you to protect yourself. But after tissue repair, there are a certain number of people where the system doesn’t reset.”
The major question now—and one the group is working on—is why pain hypersensitivity becomes chronic in some people after an injury heals, while pain processing returns to a normal, pre-injury state in others.
In neuropathic pain, right, negatively charged chloride ions (Cl) inside neurons are more concentrated than ions outside them, resulting in a failure to limit the pain signal. Recent research shows that overactive immune cells called microglia play a role. Blocking microglia may offer treatment possibilities for neuropathic pain. Illustration courtesy of Sylvain Cote, Centre de Recherche Universit´Laval RobertGiffard.