Stopping a Pain Memory Before It Forms: A SPOT-ON Approach

A new drug halts the creation of proteins that set pain in motion, according to a recent study in mice. Image credit: rszarvas/123RF Stock Photo.

After an injury that leads to pain, the neurons (nerve cells) that detect threats to the body, such as dangerous chemicals or excessive heat, “remember” the pain. Such neurons (known as nociceptors) do so by making new proteins. The formation of a so-called pain memory—also called pain sensitization—occurs so that proper steps are taken to protect the injury and allow it to fully heal.

For most people, once the injury gets better, the pain memory fades away. But for those with chronic pain, the neurons never “forget.”

Now, researchers report a novel strategy to stop a pain memory from ever forming in the first place, in a mouse study.

In a collaboration between two labs at the University of Texas at Dallas, researchers have designed a new molecule, called Poly(A) SPOT-ON, that stops creation of the proteins that neurons need to become sensitized to pain following an injury.

Theodore Price, an expert in chronic pain, teamed up with Zachary Campbell, an expert in how proteins interact with RNA, a family of molecules that resemble DNA. The two labs find that treatment of mice with SPOT-ON reduces both acute and chronic pain.

The strategy worked because they designed SPOT-ON to act as a “decoy” by mimicking the structure of messenger RNA (a type of RNA).

SPOT-ON represents an entirely new class of drugs and could one day prove useful to people with pain.

“This is very cool,” says Cheryl Stucky from Medical College of Wisconsin in Milwaukee, a pain researcher who was not involved in the study. “The way they are targeting translation with this RNA mimic has broad implications, not just in chronic pain.” Translation refers to the process by which new proteins are made.

The study appeared in the journal Nature Communications in January 2018.

A new strategy
Recently, scientists have found that hundreds of newly made proteins are responsible for creating and maintaining a pain memory following an injury. This led Campbell and Price to turn their attention to translation.

A fundamental idea in the field of molecular biology describes a two-step process where a gene is first “read” to create an intermediary, messenger RNA. This first “reading” step is known as transcription. Then, the messenger RNA is read to create a protein. This second reading step is known as translation.

New proteins help cells accomplish a task, such as sensitizing the nerve cells that detect potential bodily harm. The researchers wanted to figure out a way to stop translation of messenger RNA into protein, and thus prevent the formation of a new pain memory.

When the messenger RNA intermediary is first created, a so-called Poly(A) tail is attached to the end of it. This tail is made up of a number of molecules called adenosines.

But for the messenger RNA to then be translated into protein, this tail must first be coated with dozens of proteins called PABP proteins

“We saw this as a potential Achilles’ heel of protein translation,” explains Price.

That is, by preventing the interaction of PABP proteins with the Poly(A) tail of the messenger RNA, they thought they could destabilize the messenger RNA and prevent it from being translated into new protein.

So they created Poly(A) SPOT-ON. They designed this molecule to look much like the Poly(A) tail of the messenger RNA. As a result, the PABP proteins attached to SPOT-ON, rather than to the messenger RNA. In this sense, SPOT-ON acted as a “decoy” to prevent the synthesis of new proteins.

And, indeed, the maneuver stopped cells in a petri dish from making new proteins, just as the researchers had hoped.

Could this strategy actually stop pain? The investigators found that it did, at least in mouse models of pain. In fact, when they gave the animals SPOT-ON, this soothed both acute and chronic pain.

What about people—could SPOT-ON help ease chronic pain? It’s too early to know, as the new study only looked at mice. But, Price thinks it’s possible, especially to treat pain after surgery.

“It would be exciting to use SPOT-ON for postsurgical pain where you would give it along with a nerve block to stop translation locally and inhibit the development of persistent pain after surgery,” he says.

To read about the research in more detail, see the related IASP Pain Research Forum news story here.

Nathan Fried is a postdoctoral fellow at the University of Pennsylvania, Philadelphia, US.