pain research

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Contact: O'Brien

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University of California, San Francisco

UCSF finding could lead to a 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, 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, Isenberg, MD, PhD, an assistant reseach

endocrinologist, Gordon Mc, PhD, a post-doctoral fellow, 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 , PhD, a

post-graduate research fellow, Jahan Dadgar, BS, a staff research

associate, 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.

[Guest guest]

An article on general neuropathic pain research, dated from April 2003.

(OSU is the same University the NT-3 research is taking place)

OSU PHYSICIAN GIVES TREATMENT GUIDANCE FOR NEUROPATHY PAIN

Posted 4/21/2003

COLUMBUS, Ohio – An analysis of research related to neuropathy pain

treatment

suggests most medications cannot relieve pain by more than 30 percent to

50

percent, and though no single agent is best for all, seizure medications

are an

excellent starting point for most patients, according to Dr. Jerry

Mendell, chair of

neurology at The Ohio State University Medical Center. Neuropathy, pain

associated

with damage to nerves, has many causes it is among the most common

complications of diabetes and often responds poorly to treatment. One of

the most common of all painful neuropathies is seen in patients after

age 50. It has no known cause, severely alters the quality of life,

interferes with work productivity and interrupts sleep.

A number of studies are in progress to determine the best way to manage

the

debilitating pain of neuropathy, which can be similar in symptoms

regardless of the

cause. The most common descriptions of this pain characterize it as

burning,

knife-like, shooting or tingling in affected areas.

Finding and treating the cause of neuropathy is the best long-term

strategy, but isn't

always possible,said Mendell, who is lead author of a recent New England

Journal of Medicine article advising practicing physicians of clinical

treatment options for

neuropathy. And even once treatment begins, it may not relieve pain for

many months or longer.

Why is that? Mendell notes that even though treating the underlying

cause of the

damage such as disease or exposure to hazardous materials, for example

should

prevent further injury to nerves, the relief of pain requires nerve

regeneration. And

for conditions without known cause, nerve regeneration is chronically

impaired and

the pain persists indefinitely, sometimes for years.

Immediate pain relief is the top priority for patients suffering from

neuropathy. The

challenge for doctors is finding either a single medication or a

combination of drugs

that can relieve pain without causing too many side effects while the

search

continues for the cause, which, if identified, can lead to lasting pain

relief by

removing the underlying insult.

To date, researchers have studied the pain-relief effects of a number of

agents,

ranging from antidepressants and anticonvulsants (seizure medication) to

narcotics

and alternative therapies, in patients suffering from painful sensory

neuropathy,

which results from degeneration of nerve endings.

Based on an examination of such studies, Mendell recommends initial

treatment with

gabapentin (Neuronton), one of four anticonvulsant agents subjected to

clinical trials, and the addition of Tramadol (Ultram), a nonnarcotic

analgesic,

if needed. Tricyclic antidepressants have been the best studied, but

patients,

especially the elderly, tend not to tolerate these medications very

well. A third seizure medication, oxcarbazepine, is recommended before

tricyclics are considered.

Mendell said it is reasonable for physicians to introduce a narcotic

painkiller if

three-drug regimens prove ineffective, but even some of the most potent

of these

medication are unlikely to provide complete pain relief in patients with

painful

sensory neuropathy, he said.

Because neuropathy treatment continues to present such enormous

challenges to

clinicians and researchers, Mendell said among the most critical

components of

patient care is education to define realistic goals and expectations for

relief of their pain.

The clinical practice articles in the New England Journal of Medicine

are review

articles on medical problems seen by providers in practice, ranging from

screening

to evaluation and management of specific disorders.

Caldwell

Medical Center Communications

OSU