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Researchers Devise Decoy Molecule to Block Pain Where It Starts

neurosciencestuff:

For anyone who has accidentally injured themselves, Dr. Zachary
Campbell not only sympathizes, he’s developing new ways to blunt pain.

“If
you have ever hit yourself with a hammer, afterward, even a light touch
can be painful for days or even weeks,” said Campbell, who researches
pain on the molecular level at The University of Texas at Dallas. “While
many of us may not be coordinated enough to avoid an accident, my goal
is to disrupt the inception and persistence of pain memories.”

Campbell directs the Laboratory of RNA Control and recently published a study in the journal Nature Communications in close collaboration with Dr. Ted Price, an associate professor from the Pain Neurobiology Research Group, and Dr. Michael Burton, a new assistant professor from the School of Behavioral and Brain Sciences who conducted postdoctoral work at UT Dallas.

This
work describes a new method of reducing pain-associated behaviors with
RNA-based medicine, creating a new class of decoy molecules that prevent
the onset of pain.

“Even simple memories are nothing short of
extraordinary,” Campbell said. “To promote healing, our nervous system
catalogs our sensory experiences and, under normal circumstances,
eventually forgets. Defects in this process can result in chronic pain —
a root cause of enormous suffering.”

Reducing Behavioral Response to Pain

The need for research in this field is easy to understand.

“Pain
is a pervasive and devastating problem,” Campbell said. “It’s the most
prominent reason why Americans seek medical attention. Poorly treated
pain causes enormous human suffering, as well as a tremendous burden on
medical care systems and our society.”

Campbell’s team took the
approach of blocking the creation of the proteins that set pain in
motion. After an injury, instructions provided by the genome — the full
set of genetic instructions present in each cell — are translated to
create pain-signaling proteins. Those instructions are encoded in
molecules called messenger RNA, or mRNA. The decoy Campbell’s team
constructed interrupts the pain-protein synthesis process that mRNA
facilitates, reducing signs of inflammation and impairing pain
behaviors.

“When you have an injury, certain molecules are made rapidly,” said Campbell, an assistant professor in the Department of Biological Sciences in the School of Natural Sciences and Mathematics.
“With this Achilles’ heel in mind, we set out to sabotage the normal
series of events that produce pain at the site of an injury. In essence,
we eliminate the potential for a pathological pain state to emerge.”

The
RNA mimic that Campbell’s team designed was injected at the site of an
injury in experiments on mice, and showed the ability to reduce
behavioral response to pain.

“We’re manipulating one step of
protein synthesis,” Campbell said. “Our results indicate that local
treatment with the decoy can prevent pain and inflammation brought about
by a tissue injury.”

Overcoming a Molecular Challenge

One huge hurdle in creating such an RNA-based compound was overcoming the rapid metabolism of these molecules.

“Molecules
that degrade quickly in cells are not great drug candidates. The
stability of our compounds is an order of magnitude greater than
unmodified RNA.” Campbell said.

Campbell explained that
specialized nerve cells called nociceptors communicate with your brain
in response to thermal, chemical and mechanical stimuli.

“Imagine
touching a hot stovetop, walking into a wall or getting a paper cut,” he
said. “Part of the cellular origin that causes subsequent pain is
initiated by nociceptors, but the molecular mechanisms behind these
persistent changes are poorly understood. Our study developed a targeted
inhibitor that both shed light on these processes and reduced pain
sensitization following an injury.”

Campbell emphasized the importance of treating pain at the site of an
injury; a major problem with drugs that interact with the central
nervous system is that they also can affect the reward center of the
brain.

“The ongoing opioid crisis highlights the need for pain
treatments that don’t create addictions,” he said. “Hopefully, this is a
step in that direction.”

Campbell credits the role of team-based science for the discovery.

“This
work was made possible through a tight collaboration between my lab and
that of Dr. Price,” Campbell said. “These experiments would not have
been possible without Ted’s tremendous support, dedication and broadly
insightful character. Ted is an eminent scholar at the interface of
translational control and pain. His deep expertise in pain mechanisms
permeates the manuscript.

“I feel incredibly fortunate to benefit
from outstanding collaborators here at UT Dallas, which has emerged as a
key player on the national stage of pain research,” said Campbell, who
arrived at the University in 2015.

This study was supported by a
$2 million, five-year grant from the National Institutes of Health to
study RNA-binding proteins in peripheral neurons. Price and Dr. Joseph
Pancrazio, a professor in the Department of Bioengineering in the Erik Jonsson School of Engineering and Computer Science, are collaborators on the grant.

Campbell believes this effort proposes a new method of treating a broad range of medical issues.

“To
the best of our knowledge, this is the first attempt to create a
chemically stabilized mimic to competitively inhibit RNA to disrupt
RNA-protein interactions,” he said. “Our approach suggests that
targeting those interactions may provide a new source of pharmacological
agents. This proof of concept allows us to open a whole new area of
science by virtue of the route that we’re attacking it.”

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