Animal Studies Show Promise Treating Severe Chronic Pain
Researchers may be on the trail of a new and more targeted treatment
for severe chronic pain. In the current issue of the Journal
of Clinical Investigation, a team of scientists established
in a series of animal studies the therapeutic potential of selectively
deleting specific nerve cells from the nervous system that convey
severe chronic pain.
So effective was the treatment in eight dogs severely affected by
osteroarthritis, cancer-related pain, or both, all eventually became
more active and later walked with slight or no limps. Just as importantly,
none showed any adverse side effects from the treatment, their temperaments
were improved, and their need for other pain-controlling medications
was eliminated or greatly reduced.
The authors also reported selectively deleting the nerve cells,
called C-fiber neurons, from among various human neurons cultured
together in the laboratory, an indication the strategy might work
in people. C-fibers convey to the central nervous system sensations
of noxious heat and certain inflammatory signals. "Some have
referred to the technique as using a 'molecular scalpel,'"
said Dr. Michael J. Iadarola, a scientist at the NIH's National
Institute of Dental and Craniofacial Research (NIDCR) and a senior
author on the paper. "The technique selectively deletes certain
neurons but leaves others untouched. As a result, the nervous system
functions normally, it's just a certain spectrum of pain responsiveness
that has been deleted."
Currently, doctors have no way of selectively eliminating nerve
cells involved in chronic pain. Opioid-based analgesics, the mainstay
of current treatments for moderate to severe chronic pain, cannot
provide universal relief, and other treatments are nonselective
and/or can cause serious side effects.
Iadarola said this month's paper stems from using the old drug resiniferatoxin,
or RTX, in a new way. First isolated in the 1970s, RTX is often
used as a laboratory tool because of its ability to bind to a much-studied
protein called vanilloid receptor 1 (VR1), which is displayed on
the surface of certain types of heat-pain-sensing neurons. As several
laboratories have reported previously, RTX attaches to VR1, and,
like opening a window, prompts a brief influx of calcium through
a channel, or pore, but only in those cells that manufacture the
Three years ago, Iadarola's group published data showing the RTX-induced
flow of calcium can overdose, seriously disable, and ultimately
kill these neurons. Because nerve cells in the peripheral nervous
system first transmit their signals to the spine, where they then
are processed and routed onward to the brain, their previous finding
raised an intriguing therapeutic scenario: The cell bodies of these
peripheral neurons bundle together in groups near the spine, called
dorsal root ganglia. If RTX were applied directly to the ganglia,
the scientists knew that they could selectively delete specific
neurons, such as C-fibers, that express large amounts of the VR1
protein on their surface. By doing this, they wondered whether they
could also permanently turn off their chronic pain signals, which
are involved in severe arthritis, peripheral neuromas, trigeminal
neuralgia, and advanced cancer?
"We realized that by focusing on RTX's ability to kill cells,
we could apply it therapeutically," said Dr. Laszlo Karai,
an NIDCR scientist and lead author on the paper. "That might
seem like a radical departure from the standard paradigm of blocking
protein receptors or desensitizing them to control pain, but our
laboratory data, obtained from cells in a dish, was so compelling
that we thought it just might work."
As reported this month, Karai et al. performed a series of experiments
in rats that showed a single injection into the trigeminal ganglion
(supplies sensation to the face), or into the cerebrospinal fluid
that bathes the dorsal root ganglia, (supply sensation to the body),
most likely deleted the C-fiber neurons permanently. The same held
true when they injected the drug into multiple ganglia that connect
to the tail and hind legs. In both experiments, rats maintained
their normal motor function as well as their ability to respond
to other sensory stimuli, such as warm and very hot thermal stimulation
and a mechanical pinch, an indication that RTX had only affected
"This showed us that the deficit in terms of overall pain sensation
was probably minimal," said Dr. Zoltan Olah, an NIDCR scientist
and one of the inventors of the technology. "What was lost
were the C-fiber neurons, which confer that sense of aching, chronic
The group then applied the technique to dogs, whose owners had brought
them into nearby veterinary hospitals with severe pain from arthritis
and cancer. "We were very encouraged to see a long-term therapeutic
benefit that did not diminish with the progression of the disease,"
said Iadarola. "When a cancer progresses, you often have to
increase the dose of conventional pain medications, such as opiate
analgesics, which can produce alterations of consciousness, activity
level, and other severe side effects that can impair overall quality
Based on these data, Iadarola said the RTX technique has tremendous
potential in veterinary care. But the group's ultimate goal is to
move the treatment into early stage clinical trials in the near
future for people with severe chronic pain. "One reason we
were successful is we have a vertically integrated, multipdisciplinary
group," said Iadarola. "There is a molecular/cell biologist,
a pharmacologist, an anaesthesiologist, and a pathologist. We realized
that permanently deleting cells wasn't a farfetched concept, and,
if we applied this approach correctly, we could get it to work.
And, that's what happened."
The study is titled, "hDeletion of vanilliod receptor 1-expressing
primary afferent neurons for pain control." It is published
in the May 2004 issue of The Journal of Clinical Investigation.
The authors are: Laszlo Karai, Dorthothy Brown, Andrew J. Mannes,
Stephan T. Connelly, Jacob Brown, Michael Gandal, Ofer W. Welisch,
John K. Neubert, Zoltan Olah, and Michael J. Iadarola. All are affiliated
with NIDCR, except Dr. Brown, who is in the School of Veterinary
Medicine at the University of Pennsylvania.