Researchers at King’s College London have found how paracetamol works at a molecular level in the body, which may help in the development of new painkillers.
Paracetamol, known as acetaminophen in the US and Asia, is a common over-the-counter pain reliever and fever reducer. It is also found in many widely used medicines, such as Panadol, Lemsip and Anadin Extra.
Despite its worldwide use since the 1950s, the drug has dodged attempts by scientists to understand how it works.
Until now, researchers have suggested that paracetamol works in the same way as anti-inflammatory drugs, such as aspirin and ibuprofen, by targeting the cyclooxygenase enzymes that are responsible for bringing about pain and inflammation.
A novel protein function
The new study, led by Professor Stuart Bevan and published in Nature Communications, identifies the protein TRPA1 as the key in paracetamol’s pain-relieving ability in mice.
TRPA1 is a protein found on the surface of some cells, and it normally acts as a sensor to toxic stimuli such as environmental irritants or pain. Thus, pain relief is a brand new function for the TRPA1 protein.
To test the pain-relief properties of paracetamol, researchers measured how long it took for a mouse to withdraw its paw from a hot surface.
Under normal conditions, paracetamol injection increases the time mice leave their paw on the surface, showing that the drug reduces the heat-induced pain.
However, the King’s College team found that when TRPA1 was completely removed from mice by ‘knocking out’ the gene that carries it, paracetamol injection failed to bring about any pain-relieving effects; and the mice withdrew their paws quickly. The results indicate that TRPA1 is essential in the pain-relief signalling of paracetamol.
Paracetamol metabolites crucial for signalling
Understanding the mechanism behind paracetamol’s action could help to find other molecules that work in the same way. Paracetamol can, in rare instances, cause harmful side effects in some patients. In addition, an overdose of paracetamol can cause serious, even fatal, liver damage.
Researchers would therefore like to develop alternatives which relieve pain similarly to paracetamol but have fewer negative side effects.
The King’s team suggests that paracetamol activates TRPA1 after it is metabolised and breaks down into smaller molecules NAPQI and p-BQ. These molecules are powerful TRPA1 activators. By measuring the increase in their concentration in the mice spinal cord, where information about pain is processed, researchers proposed that NAPQI in particular is responsible for the TRPA1-mediated pain-relief signalling.
Professor Bevan said: “When [TRPA1] was activated, it appeared to interfere with the transmission of information from that nerve cell to other nerve cells, which would normally send a signal up to the brain, signalling pain.”
The future of analgesics
NAPQI is, however, the same molecule responsible for the toxic side effects seen in the liver following paracetamol overdoses. Therefore, the researchers investigated other non-tissue damaging molecules which activate TRPA1 in a similar manner when injected into the spinal cord of mice.
One of the most effective was a molecule similar to Tetrahydrocannabinol, or THC, which is derived from the cannabis plant. Dr David Andersson, co-author from King’s College London, said: “we synthesised a number of analogues of THC to identify compounds that lack the effects of cannabis but retained the activity on TRPA1.”
THC, and similar compounds, will be the focus of future research as they provide a new target for developing pain-relieving drugs without paracetamol’s side effects.
Dr Andersson said: “This study validates TRPA1 as a new target for pain relief drugs. Many targets have been identified in the past, but as paracetamol is a medicine that we know works well in humans, this gives us a head-start in looking for effective molecules that utilise the same pathways but are less harmful.”
Dr Dean Willis, pharmacology lecturer from University College London, said: “this is a well conducted experiment but the results are preliminary..[we] need further work to determine if this is the way paracetamol works in the clinic…many questions remain with regard paracetamol effects in humans.”
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Andersson, D., Gentry, C., Alenmyr, L., Killander, D., Lewis, S., Andersson, A., Bucher, B., Galzi, J., Sterner, O., Bevan, S., Högestätt, E., & Zygmunt, P. (2011). TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol Nature Communications, 2 DOI: 10.1038/ncomms1559