Cell Protein Suppresses Pain Eight Times More Effectively Than Morphine

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Cell Protein Suppresses Pain Eight Times More Effectively Than

Morphine

http://medicalnewscenter.com/out/out.cgi?

http://www.sciencedaily.com/releases/2008/10/081008150453.htm

More people suffer from pain than from heart disease, diabetes and

cancer combined, but many of the drugs used to relieve suffering are

not completely effective or have harmful side effects.

Now researchers at the University of North Carolina at Chapel Hill

School of Medicine and the University of Helsinki have discovered a

new therapeutic target for pain control, one that appears to be eight

times more effective at suppressing pain than morphine.

The scientists pinpointed the identity and role of a particular

protein that acts in pain-sensing neurons, or nerve cells, to convert

the chemical messengers that cause pain into ones that suppress it.

" This protein has the potential to be a groundbreaking treatment for

pain and has previously not been studied in pain-sensing neurons, "

said lead study author Mark J. Zylka, Ph.D., assistant professor of

cell and molecular physiology at UNC. The results of the study will

be published online in the journal Neuron, on Wednesday (Oct. 8) and

in the print edition the following day.

The biological basis of pain is complex. To study the transmission of

painful signals throughout the body, many researchers use " marker "

proteins that label pain-sensing neurons. One such marker, FRAP

(fluoride-resistant acid phosphatase), has been employed for this

purpose for nearly 50 years, but the gene that codes for its

production was never identified.

That is, until researchers at UNC found that FRAP is identical to PAP

(prostatic acid phosphatase), a protein routinely used to diagnose

prostate cancer whose levels increase in the blood of patients with

metastatic prostate cancer.

Previous research hinted that FRAP and PAP may have a shared

identity. To determine whether or not this was the case, Zylka teamed

up with Dr. Pirkko Vihko, a professor from the University of Helsinki

who had genetically engineered mice that were missing the gene for

PAP. When Zylka and his colleagues studied tissues from these mutant

mice, they were happy to see that FRAP activity was missing. This

revealed that the two proteins were in fact identical.

Further, the mutant mice proved more sensitive than normal mice to

inflammatory pain and neuropathic pain, two common forms of chronic

pain in humans. These increased sensitivities diminished when

researchers injected excess amounts of PAP into the spinal cords of

the mutant mice.

" We were really blown away that a simple injection could have such a

potent effect on pain, " Zylka said. " Not only that, but it appeared

to work much better than the commonly used drug morphine. "

The new protein suppressed pain as effectively as morphine but for

substantially longer. One dose of PAP lasted for up to three days,

much longer than the five hours gained with a single dose of morphine.

The next question for the researchers was how PAP suppressed pain. It

is already known that when pain-sensing neurons are stimulated, they

release chemicals known as nucleotides, specifically adenosine

triphosphate (ATP). This in turn sets off the events that invoke a

painful sensation. But if ATP degrades to adenosine, that inhibits

the neurons that transmit pain signals, thus relieving pain. Through

a series of experiments, the UNC researchers showed that PAP removes

the phosphate group, generating adenosine. Their study is the first

to identify and characterize the role of such a protein in pain-

sensing neurons.

Zylka and his colleagues are now searching for additional proteins

that degrade nucleotides in these neurons. They are also working to

develop small molecules that interact with PAP to enhance or mimic

its activity.

" It is entirely possible that PAP itself could be used as a treatment

for pain, through an injection just like morphine, " Zylka said. " But

we would like to modify it to be taken in pill form. By taking this

field in a new direction, we are encouraged and hopeful that we will

be able to devise new treatments for pain. "

The research undertaken at UNC was supported by grants from the Sloan

Foundation, the Searle Scholars Program, the Klingenstein Foundation,

the Whitehall Foundation, the Rita Foundation and the National

Institute of Neurological Disorders and Stroke, part of the National

Institutes of Health. The research undertaken at the University of

Helsinki was supported by grants from the Sigrid Juselius Foundation,

the Finnish Cancer Foundation and the Research Council for Medicine

of the Academy of Finland.

Study co-authors include graduate student iel A. Sowa, research

analyst Bonnie -Blake and research technician Margaret A.

Twomey from UNC; and postdoctoral researchers kaisa Herrala and

Vootele Voikar from the University of Helskinki.