New insights into pain signaling in the brain

Summary: Study reveals how a neuropeptide called Big Dynorphin binds to the acid-sensing ion channel receptor, causing pain signals to be sent around the body.

Source: University of Copenhagen

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

Some of these peptides are involved in causing the feeling of pain. In a new study, researchers from the University of Copenhagen 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 to the study Stephan Pless, Professor at the Department of Drug Design and Pharmacology.

Relevant for inflammation and chronic pain

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

They made manipulations on the peptide and the receptor using technologies such as electrophysiology, genetically encoded cross-linkers, as well as CRISPR. Normally, the biological interaction within the brain cell occurs very fast, but their approach allowed the researchers to trap the interactions and map them.

This shows the outline of a head
Other researchers have previously shown that if they knock out the ASIC receptor, they have been able to reduce pain in mouse models. The image is in the public domain.

“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. This means that our result could have implications for these diseases in terms of drug development,” says co-first author of the study Dr Nina Braun.

Potential for pain reduction

Other researchers have previously shown that if they knock out the ASIC receptor, they have been able to reduce pain in mouse models. This underlines the potential of the new findings from the University of Copenhagen.

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

About this pain research article

University of Copenhagen
Media Contacts:
Stephan Pless – University of Copenhagen
Image Source:
The image is in the public domain.

Original Research: Closed access
“Mechanism and site of action of big dynorphin on ASIC1a”. Stephan Pless et al.
PNAS doi:10.1073/pnas.1919323117.


Mechanism and site of action of big dynorphin on ASIC1a

Acid-sensing ion channels (ASICs) are proton-gated cation channels that contribute to neurotransmission, as well as initiation of pain and neuronal death following ischemic stroke. As such, there is a great interest in understanding the in vivo regulation of ASICs, especially by endogenous neuropeptides that potently modulate ASICs. The most potent endogenous ASIC modulator known to date is the opioid neuropeptide big dynorphin (BigDyn). BigDyn is up-regulated in chronic pain and increases ASIC-mediated neuronal death during acidosis. Understanding the mechanism and site of action of BigDyn on ASICs could thus enable the rational design of compounds potentially useful in the treatment of pain and ischemic stroke. To this end, we employ a combination of electrophysiology, voltage-clamp fluorometry, synthetic BigDyn analogs, and noncanonical amino acid-mediated photocrosslinking. We demonstrate that BigDyn binding results in an ASIC1a closed resting conformation that is distinct from open and desensitized states induced by protons. Using alanine-substituted BigDyn analogs, we find that the BigDyn modulation of ASIC1a is primarily mediated through electrostatic interactions of basic amino acids in the BigDyn N terminus. Furthermore, neutralizing acidic amino acids in the ASIC1a extracellular domain reduces BigDyn effects, suggesting a binding site at the acidic pocket. This is confirmed by photocrosslinking using the noncanonical amino acid azidophenylalanine. Overall, our data define the mechanism of how BigDyn modulates ASIC1a, identify the acidic pocket as the binding site for BigDyn, and thus highlight this cavity as an important site for the development of ASIC-targeting therapeutics.

Feel Free To Share This Neurology News.
Join our Newsletter
I agree to have my personal information transferred to AWeber for Neuroscience Newsletter ( more information )
Sign up to receive our recent neuroscience headlines and summaries sent to your email once a day, totally free.
We hate spam and only use your email to contact you about newsletters. You can cancel your subscription any time.