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PAR2 antagoniststhe next generation of anti- inflammatories?

Abi Berger , BMJ

New understanding of how sensory nerve cells transmit their signals to the central nervous system has been reached by researchers at the University of California in San Francisco.

Nigel Bunnett, professor of surgery and physiology, and his team have shown that tryptasea degradatory enzyme known to be involved in triggering the inflammatory processworks by activating a new class of receptor called PAR2 (proteinase activated 2 receptors).

Professor Bunnett's work suggests that substances that block these receptors could make good candidates for new anti-inflammatory drugs (Nature Medicine 2000;6:151-8).

When sensory nerve cells are activated, calcium levels inside these cells rise and the neuropeptides, such as substance P and calcitonin gene related peptide (CGRP) are released. Both of these are important in the formation of inflammatory oedema.

Mast cells sit in the vicinity of sensory nerve endings in both animals and humans. When mast cells degranulate they release tryptase, in addition to histamine and prostaglandins. It has been shown that tryptase activates PAR2 receptors, which are located on sensory neurons.

Professor Bunnett and his colleagues wanted to find out if the release of neuropeptides from neurons is mediated by tryptase activated PAR2 receptors. "We wanted to establish whether the mast cells were `talking' to neurons via tryptase," explained Professor Bunnett.

They first examined rat sensory nerves to see if they expressed PAR2 receptors and found that 63%of them did. Up to 40% of them also expressed substance P and CGRP.

The researchers then cultured sensory nerve cells and measured the level of intracellular calcium, as a measure of nerve cell excitation. When they then introduced pure human tryptase and trypsin (a PAR2 agonist), the intracellular calcium level went up, indicating excitation had occurred.

"We then wanted to see whether tryptase stimulated the release of substance P and CGRP from nerves," said Professor Bunnett. They did this by taking pieces of rat tissue, perfusing them with buffer, and adding tryptase and specific PAR2 agonists. Both substance P and CGRP were released.

In the final experiment, the team took a single rat paw and injected a PAR2 agonist into the pad. After six hours the paw had become swollen, and the amount of oedema was measured.

The team repeated this procedure in animals that had been pretreated with antagonists of the substance P and CGRP receptors or with capsaicina neurotoxin that ablates sensory nerves. When the researchers then introduced PAR2 agonists, very little oedema was produced.

"This confirmed to us that PAR2 receptors on sensory nerves are critical to the inflammatory process," said Professor Bunnett, "and substances that specifically block PAR2 receptors should make good anti-inflammatory agents."

(Credit: NATURE MEDICINE) A nerve cell releases neuropeptides, triggered by tryptase activated PAR2 receptor