Rodent research reveals clues for chronic pain and long COVID

Mechanisms underlying chronic pain in long COVID patients may be pinpointed by promising new research using an animal model of SARS-CoV-2 infection.

Since the pandemic began, the bulk of scientific research and reporting has focused on hospitalisations and deaths caused by COVID-19.

However, there is mounting evidence that many people who recover from acute SARS-CoV-2 infection experience lingering symptoms including pain, fatigue and brain fog – even if their initial infection was mild.

Medical researchers from the Mount Sinai Hospital and New York University in the US set out to investigate chronic pain symptoms linked to previous SARS-CoV-2 infection.

The research was presented this week at the 2022 Experimental Biology meeting in Pennsylvania, US, and has not yet been peer-reviewed.

Using an established hamster model of long COVID, the research team showed that hamsters who had recovered from SARS-CoV-2 infection became hypersensitive to touch – analogous to chronic pain in humans. This hypersensitivity worsened over up time, up to 28 days after infection, even though the animals had generally cleared the virus within seven days. By contrast, hamsters did not show long-term hypersensitivity following influenza infection.

At 31 days, the hamsters were euthanised and RNA from an area of their brains called the basal root ganglia was sequenced.

“We used RNA sequencing to get a snapshot of the biochemical changes SARS-CoV-2 triggers in a pain-transmitting structure called dorsal root ganglia,” explains Randal (Alex) Serafini, an MD/PhD candidate at the Icahn School of Medicine at Mount Sinai, who co-led the study.

Sanam Mustafa, a molecular pharmacologist and research fellow at the University of Adelaide, who was not involved in the new study, says: “It’s been known for many years that the basal root ganglia is home to sensory neurons and therefore much research has been conducted to understand its role in chronic pain.”

The US research team noticed that the hamsters’ gene expression signatures in the basal root ganglia were similar to those previously seen in mice experiencing pain caused by inflammation or nerve injury.

Further analysis of the gene expression patterns in the hamsters highlighted that SARS-CoV-2 infection appeared to be linked to downregulation of several pain regulators. Expression of a protein known as interleukin enhancer binding factor 3 (ILF3) was also downregulated at timepoints when the hamsters’ hypersensitivity behaviours were comparatively mild.

The researchers tested an existing anti-cancer drug that inhibits ILF3 activity in a mouse model of localised inflammation and found that it was effective in treating the mice’s pain.

“We think therapeutic candidates derived from our gene expression data, such as ILF3 inhibitors, could potentially target pain mechanisms that are specific to COVID patients,” says Serafini.

“Interestingly, we saw a few cancer-associated proteins come up as predicted pain targets, which is exciting because many drugs have already been developed to act against some of these proteins and have been clinically tested.

“If we can repurpose these drugs, it could drastically cut down the therapeutic development timeline.”

We are still in the early days of improving our understanding of long COVID, but experts already suspect that long COVID symptoms may be linked to the innate immune system.

Mustafa points out that the basal root ganglia contain specialised immune cells called glia.

The glia are the brain’s immune surveillance system – cells that recognise and stimulate a protective response against dangers like infectious disease.

“I think this is really interesting research and confirms what many in the neuroimmunology field have been thinking or researching,” says Mustafa.

“Our innate immune system does more than fight off infection – activation of the innate immune system can have longstanding impacts on our normal functions, including our perception of pain.”

She notes that there are some differences between the basal root ganglia of humans and rodents, such as differences in cellular makeup, so more clinical research into chronic pain and long COVID is needed to determine whether the findings can translate to humans.

“What is really important about this research is that it validates the experiences of so many people around the world; what they are feeling is not just in their head, but is due to real biological changes,” says Mustafa.

“Now that these biological changes are being uncovered, researchers are in a much stronger position to now work out what can be done to manage, treat or prevent long COVID.”