Coming TO A Headache Near You
As researchers unravel the mysteries of chronic pain like Arthiritis 
and migraines, new kinds of pain-killers appear on the horizon

By Jamie Talan. STAFF WRITER


TAKE AN ASPIRIN and call back in, well, a few years. That's how long it
may take for the next generation of painkillers to arrive.
    But they are coming, and researchers say these new and powerful
substances  -  born from the most advanced knowledge of how pain
messages travel from skin cells to the brain  -  will revolutionize pain
treatment for chronic conditions such as migraines and arthritis.
    "It is a very exciting time," said Allan L. Basbaum, professor of
anatomy and physiology at the Keck Center for Integrative Neuroscience
at the University of California in San Francisco. "Some of these
substances are remarkable."
    At  meetings of the Society for Neuroscience and American Pain
Society late last fall, scientists were eagerly sharing snippets of work
 -  from how a key pain transmitter called Substance P works in the
body, to the chemical underpinnings of the pain response.
    And as researchers continue to unravel the mysteries of the ouch,
pharmaceutical companies are taking these findings and developing the
next generation of substances to quell every ache and pain imaginable.
    Some of the new research includes:
    experimental drugs that block substance P, a neurochemical crucial
to the complex pain process;
    a substance derived from marine cone snails that reduces pain
without causing numbness;
    PET scan studies of pain in action;
     adrenal cell transplants that bathe nerve cells in pain-relieving
natural substances called opioids and catecholamines.
    Millions of people suffer from chronic pain conditions and spend
billions on medicines that offer marginal relief. The old standards of
pain relief  -  morphine and aspirin and its chemical cousins  -  work
well on acute forms of pain, but offer little comfort for those with
long-lasting and severe pain conditions.
    What is pain, anyway?
    According to UCSF's Basbaum, "Pain is a complicated perception that
is influenced not only by the amount of sensory input, but also by mood
and experience."
    Some kinds of pain are straightforward responses to injury. When a
cook burns herself, for instance, the heat triggers sensory neurons
called nociceptors, which transmit the pain signal to the spinal cord.
From there, the signal is sent to the brain.
    In such cases, the input message at the nociceptor is key to the
pain signal. But researchers are finding that in chronic pain this input
message is less important, and more activity seems to be generated in
the central nervous system itself.
    For a minor injury, topical lotions such as lidocaine can be used to
block nerve transmission at the site, so that information about the
painful experience never reaches the central nervous system. Numbness
occurs when all the "pain" information is shut off.
   How drugs like aspirin and morphine work is far more complex. Studies
have shown that morphine, for instance, acts on at least three different
places in the brain. It works on opiate receptors, of which there are at
least seven different types, to make use of the naturally occurring
opiates that the body produces to block pain transmission.
    The new compounds scientists are developing  target chronic pain,
which doesn't really respond to current pain-altering medicines.
    One extremely effective compound, according to federal researchers
at the National Institute of Dental Research, is omega-conopeptide, one
of several incredibly toxic substances that marine cone snails use to
kill their prey. The researchers are testing an omega-conopeptide
formulation called SNX-11, developed by the California biotech firm
Neurex.
    The substance is so promising, says Gary Bennett, chief of NIDR's
neuropathic pain division, that he feels "it's probably better than the
most active drugs to date."
    Unlike other potent pain medicines, omega-conopeptides do not cause
numbness or paralysis around the injured area because they do not
interfere with normal nerve conduction. Instead, these substances work
by blocking the abnormal spontaneous nerve impulses that are
characteristic of chronic pain, Bennett said.
    "We are excited," Bennett said. "Just a drop at the site of a
chronic pain injury and the pain seems to go away."
    So far, animal studies suggest only minor side effects of
omega-conopeptides: a small release of histamines and a slight climb in
blood pressure, the equivalent of walking up the stairs.
    What causes chronic pain? Researchers say the laying down of pain
signals works in much the same way a memory is stored, eventually making
cells hyperexcitable to a familiar sensation.
    "Chronic pain changes the way the nervous system primes itself for
future messages," said Jacqueline Sagen, a University of Chicago
neurobiologist.
    Chronic pain initiates a series of events in the nervous system that
leads to its cumulative effects,  Sagen's studies suggest. An injury  -
 or a chronic hypersensitivity  -  causes peripheral nerves to release
abnormally high levels of an excitatory neurotransmitter called
glutamate. This stimulates receptors (called NMDA-glutamate receptors)
that let more calcium into the cell. But too much calcium can lead to
cell death or damage. Sagen is looking for ways of blocking the
hypersensitivity of the cells and this chemical cascade.
    Her lab is experimenting with transplants of adrenal cells, which
normally pump out pain-relieving opioids and catecholamines. In their
animal studies, the transplants  seemed to be blocking  pain, Sagen
said, and the levels of the NMDA-glutamate receptors were also in the
normal range.
    The Illinois researchers have also conducted five adrenal cell
transplants in terminal cancer patients. While autopsies were not
performed to see whether the transplants worked, or whether it changed
the NMDA-glutamate receptor level, the scientists said they do believe
it reduced pain. According to Sagen, four of the five were pain free for
the rest of their lives, which ranged from four months to one year.
Sagen has received approval for another five transplants.
    Swiss researchers are also taking adrenal cells from animals,
encapsulating them in membranes, and transplanting them into chronic
pain patients. Patrick Aebischer of Centre Hospitalier Universitaire
Veudois in Lausanne told colleagues last month that seven of 10 patients
showed marked improvement in pain ratings. Four of the patients were
able to reduce their intake of morphine.
    Another angle researchers are working on is interrupting pain
signals in midstream.
     When a person burns a finger, the area immediately becomes more
sensitive to touch. According to the work of Dr. James Campbell,
professor of neurosurgery at Johns Hopkins University School of
Medicine, the brain's system that governs a person's sense of texture
and form is recruited when pain occurs. Thus, touching something hurts.
The chemistry of how the tactile system is engaged links back to several
important chemicals, including Substance P, glutamate and nitric oxide.
    It has been known for more than a decade that Substance P is an
important chemical for pain transmission. The chemical is synthesized by
and stored in nerve fibers in the skin and joints that respond to
pain-producing events.
    According to UCSF's Basbaum, when an injury occurs these nerve
fibers send impulses to the dorsal horn of the spinal cord, which
triggers the release of Substance P and the activation of nerve cells in
the dorsal horn that transmit a pain message to the brain.
    Basbaum and Patrick Mantyh of the University of Minnesota have taken
pictures showing how Substance P diffuses throughout the dorsal horn,
binds on the surface of the cells there, and actually alters their
shape. The release of Substance P, Basbaum said, turns the cells into
what looks like "a pearl necklace" as the neurons reorganize in response
to the stimuli. The captured image of pain transmission peaks at five
minutes and returns to normal within the hour, Basbaum's studies have
shown.
    Scientists have found that arthritis is associated with the
production of too much Substance P. By comparison, the severe burning
sensation that is associated with nerve damage triggers a decrease in
substance P.
    The key is to figure out ways to selectively block abnormal pain
responses  -  both chronic, as in arthritis, and acute  -  without
interfering with normal pain, which protects the body. Pfizer, Merck and
Rhone-Poulenc Rorer are working on drugs that block Substance P by
stopping the inflammation process that is key to the duration of the
pain experience. "These are very impressive drugs," said Basbaum, who
said that he has heard that there are virtually no side effects.
    Scientists are also experimenting with injections of nerve growth
factor, which has been shown to alter pain fibers in tissue. Animal
studies have shown that NGF enhances sensitivity to pain stimuli. Thus,
blocking NGF may reduce pain, and clinical trials are set to start in
the treatment of diabetic neuropathy, a condition that leads to severe
pain of the limbs.
    Opiates may also have a wider berth on the pain scene in coming
years. Campbell said studies are showing that the drug in pill form
doesn't have the addictive properties that an injectable form of the
drug does. It could be that an injection hits the brain in seconds,
compared with the oral dose that courses through the blood stream before
it ever reaches the brain. Studies in Campbell's lab also suggest that
chronic pain patients taking opiates perform tasks better, not worse.
    Scientists used to think that morphine, an opiate,  worked only
through the central nervous system to block pain. But newer work by
researchers at the University of Minnesota suggest that it also works
directly on pain fibers at the site of injury, which has set off a hunt
for a morphine cream to rub on damaged skin. Such a product could be
developed so the painkiller would not enter the brain, thus eliminating
the possibility of craving and addiction.
    Understanding pain is a complex process that may be made easier by
seeing it. That is precisely what NIDR's Bennett and his colleagues are
doing when they inject themselves with pain-producing substances and
watch their brains in action.
    Bennett is using a brain scanning device to follow pain's path
through the central nervous system. Similar work is being conducted at a
half dozen other labs throughout the country.
    "I pulled rank and demanded that I be the first," said Bennett, who
works with Robert Coghill, Michael Iadarola, Karen Berman and Mitchell
Max. "It was an historic moment."
    He and his co-workers received an injection of capsaicin, the major
ingredient that gives chili peppers their hot flavor. Nerve cells in the
brain that respond to capsaicin elicit an increase in blood supply,
which can be captured on the scanning device.
    "It was a severe burning sensation," Bennett said. Another colleague
described it as a big big bee sting.
    Bennett said researchers have found 27 brain regions that play some
role in pain. The major ones seem to be the primary and secondary
somatosensory cortex, the insula, the anterior cingulate gyrus and the
thalamus.
    The researchers suspect that the anterior cingulate gyrus may be the
site of the "ouch" and that the other areas are involved in responding
to the painful information. Their results agree with Sagen's finding
that the brain acts differently in response to acute and chronic pain.
    The federal researchers are about to conduct more brain scans,
studying people on and off morphine, in pain and free of pain, to answer
more questions about the process.
        On the lighter side, researchers at the University of Wisconsin
discovered that ice cream and morphine may have something in common, at
least for ice cream lovers. The paper presented at the neuroscience
meeting was titled: "EEG Responses to Ice Cream and Pain: Opioid and
Preference Effects."
    Dean Krahn searched and found five ice-cream fanatics, people who
crave and consume ice cream daily. They also located three people who
don't like it.  Then, he and his colleagues went to their local campus
dairy  -  Wisconsin is the Dairy State  -  and bought some vanilla ice
cream.
    The tasters were hooked up to an electroencephalogram, or EEG, a
scan that measures the brain's electrical activity. The scans of the
cravers and those with no interest looked different.
    To figure out whether the brain's natural opioids were responsible
for the EEG changes, the researchers gave the subjects naloxone, which
blocks the action of opiates, a day before they consumed ice cream.
Saline was used as a control substance.
    Naloxone decreased the pleasantness of the ice cream, as well as
reducing the desire to consume the sweet, Krahn said. As he suspected,
the EEGs of the cravers were also shifted to look more like those who do
not like it. The saline made no difference.
    Other studies have shown that intake of sweet foods decreases
symptoms of morphine withdrawal and alters pain sensation, suggesting
that pain and preference may be two sides of a coin.
 
 
Pain Producer
 
Scientists are developing drugs that prevent the pain message from
reaching the brain. One method would prevent a key neurotransmitter
called Substance P from reaching receptors. Here is how Substance P
relays the pain signal to the brain:
 
1. An injury, such as a burn, occurs. Nerve fibers send impulses to the
dorsal horn region of the spinal cord.
 
 
2. Substance P -- stored in nerve fibers in the skin and joints -- is
released from the small-diameter fibers and reach receptors on spinal
cord nerve cells.
 
3. Substance P stimulates the spinal cord nerve cells to transmit the
pain message up the spinal cord and into the brain.





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