YSM Issue 97.1

Biology FEATURE
DITCHING OPIOIDS
NEW COMPOUND MAY PROVIDE NON-OPIOID PAIN
BY MEGAN KERNIS
ART BY JIYA MODY
www.yalescientific.org
According to the CDC, overdoses
involving opioids claimed the
lives of 80,411 Americans in 2021.
Amid this crisis, healthcare professionals
increasingly rely on treatment strategies
that limit the use of opioids for patients
in need of pain relief. The CDC’s current
recommendations on opioid use suggest
alternative first-line therapies, low-dose
prescriptions, and goal-oriented treatments.
But to bring an end to opioid abuse without
compromising on quality of care, it might
be necessary to remove opioids from
clinical use altogether. To provide a safe
alternative, researchers are scrambling to
create non-opioid pain relief medications.
A team based out of the University of Texas
at Dallas recently published research on a
new compound that alleviates nerve pain
by changing the way cells send signals to
each other.
The new compound works by targeting
the sigma-2 receptor transmembrane
protein 97 (σ 2
R), an endoplasmic reticulumresident
protein. σ 2
R is widely expressed
in cells in the central nervous system
and is known to regulate cholesterol
transportation. Additional properties of this
protein have remained relatively unknown
for a long time. Stephen Martin and Jim
Sahn, chemistry professors at UT Dallas,
came across ligands that bind to σ 2
R while
synthesizing compounds for a study of
the receptor conducted by the National
Institutes of Health. Further experiments
revealed that these ligands reduced pain
hypersensitivity in a mouse model.
“In the beginning, it was really curiositydriven,”
Sahn said. “So [reducing
hypersensitivity] was motivating in the early
days.” With the prospect of pain relief on the
table, Martin and Sahn sought to translate
their discovery of these complex ligands
(FEM-1689 and DKR) into a simpler form
that resulted in the same outcome but was
easier to produce. Interestingly, Martin said
that the ligands were named after friends
and family, including Martin’s wife (FEM-
1689) and a decorated UT Dallas football
coach, Daryll K. Royal (DKR).
Originally, Martin and Sahn had a fuzzy
understanding of how the ligands worked.
They knew that the ligands inhibited
nerve pain, but they weren’t sure how.
To investigate this phenomenon, Martin
started talking to his colleagues, seeking
out someone who could help them work
out an answer. “Through networking […]
we traversed the path from Alzheimer’s
to traumatic brain injury,” Martin said. “I
wanted a risk-taking biologist who would
be willing to look at this.”
The biologist he found was Theodore
Price. Price and his colleague, Saad Yousuf,
elucidated the mechanism behind the
ligands’ action. Yousuf demonstrated
that the receptor σ 2
R is responsible for
regulating other proteins that have much
broader implications down a long chain—a
signaling pathway—leading to the cause
of nerve pain. Price, eager to make use of
Yousuf ’s discovery, coupled this signaling
mechanism with his own tests in mouse
models to develop a potential drug.
One novelty of their research is that
the scientists began experimenting
with animals directly. Typically, drug
developers work with cellular models
before moving to animal models and
eventually clinical trials. However, since
Price and his colleagues already knew
that the compound was bound to a specific
receptor, σ 2
R, they were able to jump straight
into animal testing. Beyond that, the drug’s
efficacy and long-lasting properties were
surprising to the researchers. “The thing
that has impressed me from the start is
how efficacious this is after a long period
of time,” Price said. “It’s something that is
unheard of,” Yousuf added.
The team was quick to credit Martin for
bringing them together and providing a
strong foundation for the entire project.
“[Martin] is really good at making friends,”
Sahn said. Martin, meanwhile, emphasized
the role of collaboration among scientists
across disciplines. “What I learned is you
get a name, you call them up, and you ask
them if they’re interested,” Martin said. “If
the answer is no, you ask them if they know
somebody who might be, and you call them
up until you find the right person.”
The team received a grant through the
initiative “Helping End Addiction Long-
Term” (HEAL), which will help develop
a drug using their foundational research.
“In four years, hopefully, we’ll be close
to submitting an IND [Investigational
New Drug] to the FDA and being able
to start the clinical trials soon after that,”
Price said. With an established group and
promising experimental findings, the
possibility of a non-opioid pain relief
drug is on the horizon. ■
March 2024 Yale Scientific Magazine 27