http://unisci.com/stories/20013/0730015.htm
30-Jul-2001
Some people just learn about pain
all too well. That's the growing notion among neuroscientists and anesthesiologists,
who are finding evidence that chronic, persistent pain, including the phantom
pain experienced by many amputees and people with spinal cord injuries,
is learned, much like our own memories.
Within weeks or months of the initial
injury, more patients than not report tingling, pins-and-needles pain,
and burning and stabbing pain that may never go away. The same can be true
with other profound injuries, such as bullet or stab wounds, or from conditions
such as cancer, diabetes or arthritis.
"There's good pain and there's bad
pain," says anesthesiologist Jay Yang, M.D., Ph.D., of the University of
Rochester Medical Center. "Good pain, though we don't usually think of
it as 'good,' is the usual kind we all experience. We cut ourselves and
it hurts, or we touch a hot burner and we pull away because we feel pain.
That helps us survive and protects us. Bad pain is pathological pain that
persists long after your wound has healed. It serves no purpose."
Physicians like Yang are looking
at the physical similarities between the way a memory is formed and the
way that pain becomes persistent and chronic.
In recent years, scientists have
recognized that the brain and the rest of the nervous system is much more
flexible and adaptable than was once thought; they describe the ways our
nerves adapt as "neuronal plasticity" or "synaptic plasticity."
For instance, the neurons that store
the memory of a loved one's facial features are actually wired together
more closely and completely than other neurons, and the ability of those
cells to pass signals to each other is enhanced, like two close friends
who can communicate reams of data with a simple knowing nod. The enhanced
signaling and connection is part of an ongoing, lifelong process that forms
the physical basis for memory and learning.
Yang and other neuroscientists are
coming to the conclusion that the same sort of process may underlie persistent
and chronic neuropathic pain, which results from damage to nerves.
Usually, such pain is based on an
initial event, such as an amputation, that immediately causes a tremendous
discharge of electrical and chemical energy along the nerves of the nervous
system. Subsequently, nerves in the spinal cord continue to register pain
signals even though there is no physical cause for the pain, and indeed,
in the case of phantom pain, there may not even be a limb to initiate or
transmit pain signals.
"We believe that the pain no longer
originates with the tissue that was originally damaged, but that it actually
begins in the central nervous system, in the spinal cord and the brain,"
says Yang, a professor in the Departments of Anesthesiology and Pharmacology
and Physiology.
"The experience changes the nervous
system, just like learning. It's like a memory of pain that recurs again
and again in the nervous system."
Yang says that because of past experience,
the nervous system has been primed to transmit pain signals more efficiently:
Small pain signals may be amplified, resulting in a sensation of pain way
out of proportion to the amount of hurt one would normally experience.
And more nerve cells become involved in the process.
Such pain often leaves physicians
stymied. Opiates such as morphine are the first choice, but oftentimes
they don't work well until side effects like constipation, confusion and
sleepiness become burdensome. Sometimes medications normally used to treat
depression and seizures help ease the pain somewhat.
Yang and his collaborators, John
Kulli and Raymond Zollo of the University of Rochester, are exploring a
totally new way to control neuropathic pain: gene therapy.
Yang and Christopher Wu, a former
Rochester faculty member now at Johns Hopkins University, have published
a review of the status of gene therapy as a possible future treatment for
chronic pain in the June and July issues of the journal Anesthesiology.
The body presents many attractive
targets for gene therapy for pain, since dozens of proteins are involved
in the body's creation and transmission of pain signals.
Yang is focusing on a compound known
as protein kinase C (PKC). Other scientists have created mice that lack
the protein completely; those mice feel normal pain but seem immune to
neuropathic or pathological pain.
But scientists are a long way from
testing in people a way to knock out the protein completely, and there
is no drug available that selectively targets PKC.
So Yang is experimenting with a type
of gene therapy that "knocks down" or lessens the amount of one form of
PKC. He is using tiny molecules known as oligonucleotides that bind up
the messenger RNA that directs the manufacture of PKC, tying up the messenger
in a sort of molecular straitjacket and preventing it from making the protein.
Yang tested more than 20 sites on
the gene before zeroing in on two that allowed him to reduce in rats the
amount of PKC to one-fifth its usual level.
He found that the rats with the lower
level of PKC were much less sensitive to pain.
Yang is not the only one finding
links between memory and pain. Earlier this year, scientists at Washington
University in St. Louis reported that a protein that allows nerve cells
to communicate may enhance perceptions of chronic pain. The team showed
that mice with more NMDA receptors have enhanced memory and learning skills
-- they're smarter -- but they're also more sensitive to pain.
"This type of work reinforces the
idea that the basic process that leads to memory formation may be the same
as the process that causes chronic pain," Yang says.
Such basic research about pain ultimately
benefits patients, Yang says. For instance, many doctors now do pre-emptive
analgesia, giving pain medication to patients before surgery.
Patients are deeply asleep when surgery
is performed, and so they feel nothing even when they have received no
pain medication before an operation. But surgery is still traumatic, and
recent research suggests that minimizing the effects of would-be pain on
the nervous system could help patients later, Yang says. Now, thanks to
basic research, many anesthesiologists give pain medication before surgery.
"With the surgeon's knife, you may
introduce a huge pain response, which may result in a change in the spinal
cord that will result in heightened post-operative pain," Yang says. Now
many anesthesiologists recommend pain treatment before surgery, and initial
clinical trials suggest that it's effective and reduces pain when patients
wake up after surgery, Yang says.
Yang's research is funded by the
National Institutes of Health, the New York State Department of Health
and the Department of Defense. He spends more than half his time doing
research, even though the demand for anesthesiologists is so great that
it's difficult to take time away from the operating room to do basic research
that may or may not pay off.
"I spend a little less time with
patients now, but if by doing such research we can ultimately control pain
more effectively in hundreds or thousands of patients, my gosh, that's
wonderful," he says. - By Tom Rickey
[Contact: Jay Yang, Tom Rickey]
Such pain is very real and oftentimes
severe. Approximately 60 percent of patients with spinal cord injuries
suffer phantom pain -- though they have no sensation or ability to move
their arms or legs, they still feel pain from those limbs.