Pain and itch regulated by different molecular mechanisms

Historically, scientists have regarded itching as a less intense version of the body's response to pain, but researchers at Washington University School of Medicine in St. Louis have determined that pain and itch actually are regulated by different molecular mechanisms.

Today at Neuroscience 2008, the annual meeting of the Society for Neuroscience and the world's largest source of emerging news about brain science and health, the researchers report they have separated itch and pain sensations in mice, a finding that could have important implications for treating both pain and chronic itching. The two problems often occur together because when patients are treated with strong drugs for pain, itching is a common side effect.

Last year, the research team, led by Zhou-Feng Chen, Ph.D., an investigator at Washington University's Pain Center, was the first to identify an itch gene. The scientists published those findings in the journal Nature. Now, further experiments have demonstrated that pain signals are not affected when mice are bred without the itch gene or the gene's actions are blocked.

The itch gene, called GRPR (gastrin-releasing peptide receptor), makes a receptor found in a very small population of nerve cells in the spinal cord. That region of the spinal cord transmits pain and itch signals, as well as temperature sensation, from the skin to the brain. When exposed to itchy stimuli, mice without the gene scratched less than their normal littermates.

"There are two major types of itching," says Chen, an associate professor of anesthesiology, psychiatry and developmental biology. "There is histamine-dependent itching caused by bug bites or allergic reactions, the kind of itching that can be treated with antihistamine drugs, such as Benadryl®. But the majority of chronic, severe itching is resistant to antihistamine treatment."

Many patients with chronic pain receive spinal injections of opioid drugs, such as morphine, to control their pain. One of the well-known side effects of that treatment is itchy skin.

"Most scientists believed that the itching could not be separated from the drug's pain-killing effects," Chen says. "This type of itching cannot be relieved by anti-histamine treatment. We hypothesized that GRPR may be responsible for the itching but not involved in the pain response."

So Chen's team went back to the mice bred with and without GRPR and compared both scratching behaviors and pain-killing effects following spinal injections of morphine. All of the mice got relief from a mildly painful stimulus, but those without the GRPR gene did not scratch.

Next they studied normal mice treated with a small peptide that interferes with GRPR function. When injected with the GRPR blocker, mice still got morphine's pain-killing benefits, but they did not itch.

"If we inject a GRPR inhibitor and morphine into the mouse spinal cord, the drug still has its normal analgesic effect, but the mice don't scratch," Chen says. "This is very interesting because it demonstrates that analgesia and itching can be separated. There may be itch-specific genetic pathways in the spinal cord that are not related to pain sensation."

This result contrasts with a previous finding from Chen's team. In prior studies when GRPR mutant mice were compared to normal, control mice, they demonstrated significantly decreased scratching behavior in response to itchy stimuli, but they still scratched a little. In this study, however, morphine-induced scratching behavior was completely eliminated in GRPR mutant mice, suggesting GRPR is essential in transmitting itching induced by opioids.

Chen says this genetic pathway for itch sensation seems to be conserved in all mammals. Like mice, humans also have GRPR genes, so he believes it may be possible to treat chronic itching in humans with a similar strategy. Those people, he says, would continue to get pain relief from drugs such as morphine, but they would not feel as itchy after receiving the drug.

"Our findings could have important therapeutic implications," Chen says. "More research needs to be done, but it may be possible to relieve itching in patients by blocking GRPR function without affecting the pain pathway."