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The Scripps Research Institute News

Search For Safer Pain 17018, which activates In the current report, the authors have made strides in

Relief Advances With New the same pain- understanding why these drugs seem so different.
“We demonstrate that these compounds bind to a different

relieving receptor as
Engineered Compounds opioid drugs including site on the receptor than a typical opioid. Because of that,
morphine, oxycodone
they seem to leave the receptor on and yet are still receptive
Chronic use of most opioids causes tolerance; the new and fentanyl; however, to endogenous opioids,” says Bohn, who chairs the Scripps
compounds avoid this and other unwanted qualities. it binds to opioid Research Department of Molecular Medicine in Jupiter,
Scientists at Scripps Research in Florida have created receptors in a different Fla. “In neuropathy pain, we show they are far superior to
a collection of new pain-relieving compounds that, like way from those drugs, morphine and oxycodone; moreover, SR-17018 does not
morphine and other drugs, provide relief via activation of leaving the opioid receptor open and available to the decrease breathing.”
opioid receptors, but without inducing many dangerous body’s own natural pain-relieving substances, apparently The authors also described a related compound that,
and unwanted side effects that have driven opioid-related augmenting pain relief. In a study published earlier this being more potent, induces respiratory suppression, but at
overdose and deaths. year (Pantouli et al., 2021, Neuropharmacology), the group higher doses than are needed to relieve pain. Importantly
Writing Nov. 22 in the journal The Proceedings of the showed that the compound performed particularly well in for safety, this compound, SR-14968, proved responsive to
National Academies of Sciences, biochemist Laura Bohn, mouse studies of chemotherapy-induced neuropathic pain, overdose rescue medication naloxone, when given at doses
Ph.D., and colleagues describe a compound called SR- the scientists write. high enough to suppress breathing.
Perhaps most importantly for people with severe chronic
pain, SR-17018 showed an ability to provide sustained
pain relief over time without development of tolerance, the
problem of reduced efficacy over time that requires increased
doses, increasing danger of overdose.
The paper’s first author, Edward L. Stahl, notes that
the new compounds are referred to as “biased agonists,”
because they activate the mu opioid receptor in a way that
preferentially engages one of its signaling pathways, the one
that provides pain relief, over other pathways such as those
that lead to suppressed breathing. “The compound SR-17018
is the first biased agonist of the mu opioid receptor that does
not lead to tolerance with chronic use,” says Stahl, a senior
staff scientist in the Bohn lab. “This is a desirable feature
for potential use in the context of chronic, severe pain.”
The new compounds were engineered to avoid the “beta-
arrestin” signaling cascade that leads to opioids’ dangerous
and unwanted traits, including respiratory suppression, a
cause of overdose, and constipation, he adds.
Opioid medications remain a go-to treatment for severe
pain, whether it’s from surgery, a sudden injury, or nerve
damage. But as opioid addiction and overdose deaths reach
new highs in the United States, the need for safer ways to
treat acute pain has grown more urgent, Bohn says.
In work spanning more than two decades, Bohn and her
team have demonstrated the feasibility of untangling the pain-
relieving properties of opioids from their negative traits. Her
work has not only broadened understanding of how opioid
receptors work to direct multiple physiological responses,
it has pointed the field toward potentially safer options for
providing relief from severe pain.
Bohn’s research group has engineered multiple
compounds which, in mouse studies, diminish activation
of beta-arrestin signaling. Additional problems of opioids
continue to pose challenges, including dependance, or
addiction. The fact that SR-17018 avoids tolerance with
chronic use is good news, Bohn says. Also, good news is
how it wears off, she adds.
“The compound showed a nice, slow tapering. That, in
itself, may help curb some of the dependence problems. A
drug like morphine provides a quick rush then a quick clear,
and you need the rush again.”
Going forward, the team is continuing to refine and test
Home Away Home Away the compounds so that they could eventually be tested in a
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“Severe and chronic pain associated with surgery, nerve
damage, and trauma require strong pain relief,” Bohn
Individual Tickets go on sale says. “Safer solutions are needed. We believe these new
compounds are a big step in the right direction.”
JANUARY 8! G protein-signaling biased mu opioid receptor agonists that

In addition to Bohn and Stahl, the co-authors of the paper,
produce sustained G protein activation are noncompetitive
agonists, are Cullen L. Schmid, Agnes Acevedo-Canabal,
Cai Read, Travis Grim, Nicole Kennedy and Thomas D.
Bannister.
Grants from the National Institutes on Drug
Abuse supported the work, including R01DA038964,
R01DA033073, and F32DA052124.

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