UC San Francisco researchers have identified a new molecular pathway throughwhich chemical signals alert the body to pain, and inhibiting the key proteinin this pathway could bring relief in a broad spectrum of pain syndromes, theysay.
The finding, drawn from a study in mice and rats, applies to inflammatory painassociated with such conditions as arthritis and colitis, torn ligaments andsprained ankles, and post-operative pain. However, the researchers expect thefinding will apply even more broadly.
"This discovery is extremely important," said the director of the NationalInstitutes of Health Pain Center at UCSF, Jon Levine, PhD, a professor of oraland maxillofacial surgery and medicine and a senior author of the paper. "Ithink this signaling pathway will be shown to play a role in many kinds ofpain."
The study, published in the Sept. 24 issue of Neuron, was funded by the ErnestGallo Clinical and Research Center at UCSF and the National Institutes ofHealth.
The body's immune system responds to many forms of tissue injury by producingan inflammatory response, which includes the release of chemical signals intoinjured tissue, where they sensitize pain-sensing neurons. As a result,stimuli that normally would not cause pain, such as the brush of a shirt beingdrawn onto the body, become painful when the skin is sunburned; likewise, themovement of a joint, normally unnoticed, would cause pain in the presence ofarthritis.
Chemical signals act on pain-sensing neurons by latching on to specificcell-surface receptors that convey the signals into the cell. Once inside, thechemical signal initiates a cascade of molecular events that culminates withthe neurons transmitting pain signals out of the cell body and into the centralnervous system, where pain is felt.
Current inflammatory-pain drugs -- the nonsteroidal anti-inflammatory drugs, orNSAIDS, including the new COX-2 inhibitors -- act by blocking the production ofsome of these chemical signals, or inflammatory "mediators." However, becausethese drugs block only a small percentage of these messages, theireffectiveness is limited.
The significance of the UCSF finding is that the researchers have identified aprotein enzyme inside pain-sensing neurons through which they believe many ofthese 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 cellswould prevent us from having to identify blocks for every inflammatorymediator," said Levine. "I think this enzyme will prove to be the centralsignaling pathway by which most chemical mediators act on pain-sensingneurons."
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 havenot known which of the ten known forms of the enzyme might be involved. In thecurrent study, the researchers discovered the role played by protein kinase Cepsilon (PKC).
The researchers discovered the PKC signaling pathway by conducting studies inmice that lacked the enzyme and in rats in which the enzyme was inhibited by adrug.
In one study, they compared the responses of normal mice, and mice lacking thePKC enzyme, to painful stimuli, and determined that the mice responded equallyto stimulation. However, when they added epinephrine, an inflammatory mediatorthat heightens the sensitivity of pain sensing neurons, those without theenzyme 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 "almostcompletely 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 animalswith the inhibited enzyme became markedly less sensitive to the pain.
Epinephrine acts on pain-sensing neurons, or nociceptors, by enhancing an ionchannel known as TTX- RINA, which sensitizes the pain-sensing neurons topreviously innocuous stimuli. As a check on the animal study results, theresearchers examined whether inhibiting PKC would blunt epinephrine's action inpain-sensory neurons in laboratory cultures. It did. In cultured cells in whichthe enzyme was inhibited, epinephrine's effect was decreased by half,demonstrating that epinephrine depends on PKC to prompt a full effect on theTTX-RI NA channel in a critical group of pain-sensing neurons, the researcherssaid.
The researchers further demonstrated PKC's role by examining the response ofrats to a potent irritant known as carrageenan. When they applied the seaweedcompound in rats exposed to stimulation, the animals exhibited pain. But whenthe animals were pretreated with the chemical that inhibits the PKC enzyme, thepainful response was "almost completely reversed," the researchers report.Carrageenan is commonly used by the pharmaceutical industry as a model toscreen for pain-reducing drugs.
Finally, the researchers showed that PKC modulates the pain response induced bythe chemical known as nerve growth factor. When the factor was injected intonormal rats exposed to stimulation, the animals experienced heightened pain.But when the factor was injected in animals in which PKC was inhibited, theirpain threshold was higher.
"These results suggest that PKC plays a key role in regulating painsensitivity," said a senior author of the UCSF paper, Robert Messing, MD, anassociate professor of neurology. "The fact that inhibiting PKC reduced painin response to several different sensitizing agents is significant."
Since absence or inhibition of PKC does not disturb basic pain-sensorythresholds, needed to help alert the body to possible danger, and the mice inwhich the enzyme was missing appeared normal, it may be possible, theresearcher said, to develop PKC inhibitors that reduce pathologic pain withoutproducing serious systemic side effects or interfering with normal painresponses.
Co-authors of the UCSF study were Sachia G. Khasar, PhD, an assistant researchpharmacologist, K.O. Aley, PhD, an assistant research pharmacologist, WilliamIsenberg, MD, PhD, an assistant reseach endocrinologist, Gordon McCarter, PhD,a post-doctoral fellow, Paul G. Green, PhD, an assistant professor, all in theDepartment of Internal Medicine and Oral Surgery and NIH/UCSF Pain Center; andYu-Huei Lin, PhD, at the time a postdoctoral fellow, Annick Martin, PhD, apost-graduate research fellow, Jahan Dadgar, BS, a staff research associate,Thomas McMahon, BS, a staff research associate, Dan Wang, MS, BS, a a staffresearch associate, Bhupinder Hundle, PhD, at the time a postdoctoral fellow,and Clyde Hodge, PhD, an assistant adjunct professor in the Department ofNeurology, Ernest Gallo Clinical and Research Center at UCSF.
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