Team maps how brain signals trigger pain

New research shows how a potent neuropeptide binds to a brain receptor involved in causing human pain.

The researchers expect that they could exploit the mechanism as a new avenue for painkilling medicine.

Fast communication between our brain cells—called neurotransmission—is hugely important for our brain to work properly. Some of the messengers involved in this form of communication are neuropeptides, chemicals produced in the brain.

Some of these peptides have to do with causing the feeling of pain. In the new study, researchers show how the neuropeptide Big Dynorphin binds to a receptor involved in sending pain signals around the brain.

“We have mapped exactly how and where Big Dynorphin binds to this receptor, which can cause a pain signal to be sent inside the body. Big Dynorphin is the most potent regulator of this particular receptor discovered in the human body so far.

“The painkillers that we use today affect other types of receptors. This means that our discovery could pave the way for a new type of painkilling medicine via this receptor, potentially helping to circumvent some of the typical adverse effects of opioids.” says author Stephan Pless, professor in the drug design and pharmacology at the University of Copenhagen.

The new study investigates the interaction between Big Dynorphin and the receptor called Acid-Sensing Ion Channel (ASIC). The researchers mapped this interaction and signaling using a wide range of methods.

They manipulated the peptide and receptor using technologies such as electrophysiology, genetically encoded cross-linkers, and CRISPR. Normally, the biological interaction within the brain cell occurs quickly, but the new approach allowed the researchers to trap the interactions and map them.

“We know that both the receptor and Big Dynorphin are upregulated in patients with inflammation and chronic pain. This means that there are many more of them than under normal conditions. And that, in theory at least, can lead to more pain and the risk of long-lasting negative effect on brain health,” says co-first author Nina Braun.

“This means that our result could have implications for these diseases in terms of drug development.”

Other researchers have previously shown that knocking out the ASIC receptor reduces pain in mouse models. This points to the potential of the new findings.

The researchers are looking forward to exploiting the mechanism pharmacologically in coming studies and hope to find relevant compounds that could show potential for pain reduction for these vulnerable patient-groups.

Source: University of Copenhagen

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