Giving pain a boost. When PGE2 binds to the α3 receptor, it causes a chemical change to the receptor that blocks chloride influx and boosts neural activity.

Locating a Key Step in Pain’s Pathway

As pain sufferers can attest, there's room for improvement in painkilling medications. Many of the current ones can cause side effects, such as stomach ulcers, particularly in people who have to take them over long periods of time for conditions such as arthritis. Now, recent research points to what may be a good new target for analgesic drugs. It also sheds light on inflammatory pain sensitization, which causes patients to feel intense pain even in response to normally innocuous stimuli, such as a light touch.

In the 7 May issue of Science, an international team led by Ulrike Müller of the Max Planck Institute for Brain Research in Frankfurt, Germany, reports having identified the α3 form of the receptor for the neurotransmitter glycine as a key intermediate in transmitting pain signals from the spinal cord to the brain. The work shows that the receptor is needed for pain sensitization--the first time that a function has been identified for this particular receptor.

In one phase of the work, the team found that the α3 receptor occurs only in a particular layer where pain neurons from the peripheral tissues terminate. That suggested it might somehow be involved in transmitting pain signals, an idea consistent with previous findings that a pain-sensitizing signaling molecule called prostaglandin E2 (PGE2) inhibits glycine receptor activity in the same spinal cord layer. Because glycine receptors suppress neuronal firing, inhibiting them with PGE2 could facilitate transmission of pain signals to the brain. Further work confirmed that PGE2 exerts its inhibitory effects through the α3 receptor, not one of the other glycine receptors in the spinal cord.To pin down the receptor's role, Müller and colleagues compared pain responses in mice lacking the α3 receptor gene with those in normal animals. The two groups responded the same way to acute pain stimuli. But, when the researchers first induced inflammation in the animals' paws by injecting an irritant, they found that the prolonged sensitization to further pain stimuli seen in normal animals did not occur in the knockouts. “Central prostaglandins work only through this one receptor” to promote pain sensitization, says pain expert Clifford Woolf of Harvard's Massachusetts General Hospital in Boston.That also means that aspirin and other so-called nonsteroidal anti-inflammatory painkillers, which block prostaglandin production, exert their effects in the spinal cord, not just in peripheral tissues, as was once thought. And, if researchers identify drugs that stimulate the α3 receptor, they may find powerful additions to the arsenal of analgesics.

Related site
Ulrike Müller and colleagues' Science paper

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