UCSF FINDING COULD LEAD TO NEW CLASS OF PAIN RELIEVING DRUGS

John johnhkm at netsprintXXXX.net.au
Sat Sep 25 23:37:31 EST 1999


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Alice Trinkl, News Director
Source: Jennifer O'Brien
Email: jobrien at pubaff.ucsf.edu

for immediate release
September 23, 1999

UCSF FINDING COULD LEAD TO NEW CLASS OF PAIN RELIEVING DRUGS


UC San Francisco researchers have identified a new molecular pathway through
which chemical signals alert the body to pain, and inhibiting the key
protein
in this pathway could bring relief in a broad spectrum of pain syndromes,
they
say.

The finding, drawn from a study in mice and rats, applies to inflammatory
pain
associated with such conditions as arthritis and colitis, torn ligaments and
sprained ankles, and post-operative pain. However, the researchers expect
the
finding will apply even more broadly.

"This discovery is extremely important," said the director of the National
Institutes of Health Pain Center at UCSF, Jon Levine, PhD, a professor of
oral
and maxillofacial surgery and medicine and a senior author of the paper. "I
think this signaling pathway will be shown to play a role in many kinds of
pain."

The study, published in the Sept. 24 issue of Neuron, was funded by the
Ernest
Gallo Clinical and Research Center at UCSF and the National Institutes of
Health.

The body's immune system responds to many forms of tissue injury by
producing
an inflammatory response, which includes the release of chemical signals
into
injured tissue, where they sensitize pain-sensing neurons. As a result,
stimuli that normally would not cause pain, such as the brush of a shirt
being
drawn onto the body, become painful when the skin is sunburned; likewise,
the
movement of a joint, normally unnoticed, would cause pain in the presence of
arthritis.

Chemical signals act on pain-sensing neurons by latching on to specific
cell-surface receptors that convey the signals into the cell. Once inside,
the
chemical signal initiates a cascade of molecular events that culminates with
the neurons transmitting pain signals out of the cell body and into the
central
nervous system, where pain is felt.

Current inflammatory-pain drugs -- the nonsteroidal anti-inflammatory drugs,
or
NSAIDS, including the new COX-2 inhibitors -- act by blocking the production
of
some of these chemical signals, or inflammatory "mediators." However,
because
these drugs block only a small percentage of these messages, their
effectiveness is limited.

The significance of the UCSF finding is that the researchers have identified
a
protein enzyme inside pain-sensing neurons through which they believe many
of
these inflammatory mediators - including those targeted by NSAIDS - act,
suggesting a possible target for broad-based pain therapy.

"Identifying the common signaling pathways inside these pain-sensing cells
would prevent us from having to identify blocks for every inflammatory
mediator," said Levine. "I think this enzyme will prove to be the central
signaling pathway by which most chemical mediators act on pain-sensing
neurons."

For more than a decade, researchers have thought that the protein kinase C
(PKC) enzyme played a role in the pain-sensing neurons' activity, but they
have
not known which of the ten known forms of the enzyme might be involved. In
the
current study, the researchers discovered the role played by protein kinase
C
epsilon (PKC).

The researchers discovered the PKC signaling pathway by conducting studies
in
mice that lacked the enzyme and in rats in which the enzyme was inhibited by
a
drug.

In one study, they compared the responses of normal mice, and mice lacking
the
PKC enzyme, to painful stimuli, and determined that the mice responded
equally
to stimulation. However, when they added epinephrine, an inflammatory
mediator
that heightens the sensitivity of pain sensing neurons, those without the
enzyme exhibited a "significantly reduced" reaction to stimulation.

In a second study, the researchers applied the chemical irritant acetic
acid.
The response to the painful stimulus, which causes inflammation, was "almost
completely blocked" in the mice lacking PKC, they said.
In a third study, the researchers examined rats in which PKC was inhibited.
Predictably, both these animals and control animals responded to
stimulation.
However, when epinephrine was added to increase pain sensitivity, the
animals
with the inhibited enzyme became markedly less sensitive to the pain.

Epinephrine acts on pain-sensing neurons, or nociceptors, by enhancing an
ion
channel known as TTX- RINA, which sensitizes the pain-sensing neurons to
previously innocuous stimuli. As a check on the animal study results, the
researchers examined whether inhibiting PKC would blunt epinephrine's action
in
pain-sensory neurons in laboratory cultures. It did. In cultured cells in
which
the enzyme was inhibited, epinephrine's effect was decreased by half,
demonstrating that epinephrine depends on PKC to prompt a full effect on the
TTX-RI NA channel in a critical group of pain-sensing neurons, the
researchers
said.

The researchers further demonstrated PKC's role by examining the response of
rats to a potent irritant known as carrageenan. When they applied the
seaweed
compound in rats exposed to stimulation, the animals exhibited pain. But
when
the animals were pretreated with the chemical that inhibits the PKC enzyme,
the
painful response was "almost completely reversed," the researchers report.
Carrageenan is commonly used by the pharmaceutical industry as a model to
screen for pain-reducing drugs.

Finally, the researchers showed that PKC modulates the pain response induced
by
the chemical known as nerve growth factor. When the factor was injected into
normal rats exposed to stimulation, the animals experienced heightened pain.
But when the factor was injected in animals in which PKC was inhibited,
their
pain threshold was higher.

"These results suggest that PKC plays a key role in regulating pain
sensitivity," said a senior author of the UCSF paper, Robert Messing, MD, an
associate professor of neurology. "The fact that inhibiting PKC reduced pain
in response to several different sensitizing agents is significant."

Since absence or inhibition of PKC does not disturb basic pain-sensory
thresholds, needed to help alert the body to possible danger, and the mice
in
which the enzyme was missing appeared normal, it may be possible, the
researcher said, to develop PKC inhibitors that reduce pathologic pain
without
producing serious systemic side effects or interfering with normal pain
responses.

Co-authors of the UCSF study were Sachia G. Khasar, PhD, an assistant
research
pharmacologist, K.O. Aley, PhD, an assistant research pharmacologist,
William
Isenberg, MD, PhD, an assistant reseach endocrinologist, Gordon McCarter,
PhD,
a post-doctoral fellow, Paul G. Green, PhD, an assistant professor, all in
the
Department of Internal Medicine and Oral Surgery and NIH/UCSF Pain Center;
and
Yu-Huei Lin, PhD, at the time a postdoctoral fellow, Annick Martin, PhD, a
post-graduate research fellow, Jahan Dadgar, BS, a staff research associate,
Thomas McMahon, BS, a staff research associate, Dan Wang, MS, BS, a a staff
research associate, Bhupinder Hundle, PhD, at the time a postdoctoral
fellow,
and Clyde Hodge, PhD, an assistant adjunct professor in the Department of
Neurology, Ernest Gallo Clinical and Research Center at UCSF.

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