Neurons injected into mice help treat chronic
pain at its roots, rather than simply alleviating its symptoms.
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, orengineered
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.
Ed Yong
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