13 November 2002 16:00 EST

by Tabitha M. Powledge

US researchers have identified two key enzymes in the brain that allow chronic pain to persist despite treatment. The finding for the first time offers the brain as a possible target for therapy.

Most approaches for pain relief have focused on peripheral nerves and the spinal cord. But while researchers have thought of the brain as the reporter of pain, it is actually the amplifier and even the interpreter of pain, says Min Zhuo, professor of neurobiology at Washington University in St. Louis. "So we have to fix the interpreter, not just try to stop the activity coming in," he said.

Using knockout mice, Zhuo and his colleagues provide genetic, pharmacological, and behavioral evidence that two enzymes - adenylyl cyclase 1 and 8 - acting chiefly in the forebrain, are important for synaptic potentiation and behavioral sensitization after tissue injury and inflammation.

AC1 and AC8, the two major isoforms of adenylyl cyclase that are sensitive to calcium signals, are highly expressed in the anterior cingulate cortex (ACC), a forebrain region known to be central to feeling pain.

There are 11 adenylyl cyclases in all. The enzymes link receptors for the neurotransmitter NMDA to cyclic AMP signaling pathways, which are essential for brain functions like learning, memory, and development.

Neuroscientists say chronic pain is also a form of learning. It probably causes permanent changes in neurons, one reason why it has proved so hard to treat.

In their experiments, the researchers compared wild-type mice to mouse knockouts for AC1 and AC8. Both knockout and normal mice reacted the same way in tests of acute pain.

But in tests that simulate chronic pain, the knockouts failed to react, evidence that they were not experiencing pain. When the researchers gave the knockouts forskolin, a chemical that elevates cyclic AMP by activating adenylyl cyclase, they were "rescued" - that is, they behaved as if they were experiencing pain.

The knockouts' failure to respond to chronic pain stimulus was therefore a direct result of AC inactivation, not an indirect product of developmental defects, the researchers say. The results are to be published tomorrow in Neuron.

The work is "exciting," and offers "strong evidence that a key site of action of AC1 and AC8 is in the anterior cingulate cortex," said Michael W. Salter, who heads the pain research center at the University of Toronto. The research also raises the intriguing possibility that inhibiting AC1 and AC8 can relieve chronic pain, he added.

But translating the results to humans may not be that simple, warns A.D. Craig, who studies brain mechanisms of pain at the Barrow Neurological Institute in Phoenix.

Any drug that affects brain function will affect many aspects of behavior, Craig said, so researchers would need to develop a drug that would be very selective. Still, he conceded, "mice aren't people, but it sounds like [Zhuo and his colleagues] have found a reasonable target."

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