Two weeks ago, Hydra Biosciences Inc. announced that it had signed a deal with Pfizer Inc. for targeting the cation channel TRPV3 to treat pain. (See BioWorld Today, July 27, 2007.)

Now, Hydra scientists and their colleagues at the University of California at San Francisco have published data in the Aug. 6, 2007 issue of the Proceedings of the National Academy of Sciences indicating that targeting another family member also may be a good bet for fighting pain: TRPA1.

There are almost 30 channels in the TRP family, and they are "very different from voltage-gated ion channels," Magdalene Moran, Hydra senior scientist, told BioWorld Today. For one thing, they are more diverse in their amino acid sequence, which should aid the discovery of drugs that are selective for specific family members.

TRP channels are involved in a variety of senses and open in response to numerous different stimuli. TRPA1 is responsive to, among other things, wasabi mustard.

Hydra President and CEO Russell Herndon told BioWorld Today that the TRP family of channels appears to be involved in "many disease states" including heart and kidney disease.

Hydra's initial foray into pain is due to the fact that the biological understanding of TRP receptors' role in pain is most advanced, as well as the fact that there is a "tremendous unmet medical need" to treat pain. The company hopes to enter the clinic with a TRPA1 antagonist by the second half of 2008.

In their PNAS paper, the researchers used the formalin model to study TPA1's role in pain. Rats that are injected with the chemical formalin into one paw showed an immediate pain response that lasted for less than 10 minutes, and a delayed response after 30-60 minutes.

Moran termed it "one of the most popular models" for studying acute pain - but despite all that, how formalin actually caused pain has been unclear to date. Formalin, which is used as a tissue fixative, cross-links proteins, and the pain it causes often has been assumed to be due to tissue damage caused by such cross-linking.

Many scientists thought that the early pain component was due directly to the irritation of peripheral nerves, while the later component reflects both peripheral and central nervous system responses. On the basic science side, Moran said that the PNAS paper might lead to a reinterpretation of a number of studies that have been based on those assumptions.

Moran and her colleagues showed data supporting the idea that all of the immediate and much of the delayed response is directly due to the activation of TRPA1 channels. In both cultured cells expressing TRPA1 channels and isolated sensory neurons, which transmit pain impulses, formalin activated TRPA1 channels and caused a calcium influx. That influx could be blocked through a TRPA1 antagonist. Rats that were given the same TRPA1 antagonist, as well as TRPA1 knockouts, showed less of an immediate and early delayed pain response to formalin.

Together with previous research showing TRPA1 is involved in inflammatory pain, the findings suggested that the receptor might be responsive to a broad group of irritants that act through primary sensory neurons.

"There's an emerging idea that TRPA1 may act as an irritant receptor," Moran said - an idea that suggests the receptor could be targeted for a variety of pain conditions.

However, Moran also cautioned that pain researchers are moving away from the idea that pain is a single phenomenon that could be cured if only the right magic bullet shows up on a high-throughput screen: "Pain due to nerve injury or thalamic stroke can occur in the absence of irritation of primary sensory neurons," she explained. "Even though we refer to pain as one sensation, it's really a very mixed group of diseases with very different underlying mechanisms."