Researchers at the University of California, San Francisco, have alleviated chronic pain in mice by transplanting neurons into their spinal cords. The study, which is published today in Neuron, could lead to better treatments for neuropathic pain, the persistent condition caused by nerve injuries, where pain occurs spontaneously or at the lightest touch.
The transplanted cells released a signalling chemical called gamma aminobutyric acid (GABA), which silences excitable neurons. This inhibition is often missing in neural diseases like epilepsy and chronic pain, leading to uncontrolled neural activity.
Many drugs for chronic pain also increase GABA signalling, but these “alleviate the symptoms without acting on the cause,” said Allan Basbaum, who led the new study. “In contrast, our approach restores the inhibitory control that is missing in the injured tissue. We can expect much longer and conceivably permanent effects.”
“It is a milestone paper,” said Hanns Zeilhofer from the University of Zurich, who was not involved in the study. “It demonstrates very impressive pain relief. In the long run, it may pave the path to a cell-based therapy of otherwise intractable pain.”
Other groups have reduced epileptic seizures in mice by implanting foetal GABA-releasing neurons into their brains. Basbaum wanted to see if the same neurons could be successfully transplanted into the spine to treat chronic pain.
Joao Braz, a postdoc in Basbaum’s lab, extracted immature precursors of GABA-releasing neurons from the brains of fetal mice, and injected them into adults with injured spinal nerves, whose paws were extremely sensitive to touch. He delivered the neurons to the dorsal horn—a structure in the spine that receives sensory information from around the body. Loss of GABA signalling in the horn is thought to underlie many hard-to-treat pain conditions.
The transplanted neurons survived and gave rise to mature GABA-releasing cells, which formed connections with the local spinal circuits. Within a month, the sensitivity brought on by the rodents’ injured nerves had been completely reversed.
The transplants did not alleviate the symptoms of inflammatory pain, caused by injuries to tissues rather than nerves. This suggests that rather than providing general pain relief, the new neurons were addressing the root cause of neuropathic pain: a lack of GABA.
Theodore Price from the University of Arizona said the study settles a debate about how nerve injuries alter GABA signalling in the spinal cord. “Some studies might have been construed to suggest that enhancing GABA signalling would actually enhance pain rather than inhibit it,” he said. Braz’s work clearly shows that the latter is correct. “I think it has exciting therapeutic applications for not only neural transplants [to reduce pain] but also generation of novel pharmacological therapies targeting the GABAergic system," Price added.
Some existing drugs can already boost GABA signalling but they do not work for many patients with chronic pain. Even for those who do respond to treatment, the effects are temporary, so drugs need to be taken regularly for a long time. Furthermore, by activating GABA receptors in the brain, the drugs can cause unwanted side effects like sedation or addiction.
“The transplantation of neurons which release GABA into the spinal cord would circumvent these problems,” said Zeilhofer. “Apparently, the neurons survive for long periods and their action remains restricted to the spinal dorsal horn.”
Other groups have tried to use viruses to introduce GABA-producing genes into spinal neurons, or engineered human stem cells to produce the chemical. Both approaches have alleviated neuropathic pain in rodents. However, Basbaum said, neither technique produces neurons that integrated into the animals’ nervous systems, so they are unlikely to produce long-lasting effects. Both methods could also increase the risk of cancer, as the viruses can disrupt important genes, and the stem cells can keep on growing after they are transplanted. Transplanting fetal neurons avoids both problems.
Basbaum now plans to follow the fates of the transplanted mice to see if they improve further or deteriorate. He also wants to see if transplants from human fetal tissues will work as well as those from mice, and he has approval to begin such experiments.
“It will definitely be a very long way until such approaches can be applied in human patients,” said Zeilhofer. He doubts that the technique will become a routine part of pain treatment, since it will require surgery, immune suppression, and a source of donor cells. However, he adds, “in the far future, it may offer a promising alternative for cases in which no other satisfactory treatment can be found, and these may be very many.”
J. Braz et al., “Forebrain GABAergic neuron precursors integrate into adult spinal cord and reduce injury-induced neuropathic pain,” Neuron doi:10.1016/j.neuron.2012.02.033, 2012.