Science 28Feb2020

966 28 FEBRUARY 2020 • VOL 367 ISSUE 6481 sciencemag.org SCIENCE

T

he dark side of opioids’ ability to
deaden pain is the risk that they might
kill their user. The same brain recep-
tors that blunt pain when drugs such
as morphine or oxycodone bind to
them can also signal breathing to slow
down. It’s this respiratory suppression that
causes most overdose deaths.
So scientists have hoped to design opi-
oids that are “biased” toward activating
painkilling signals while leaving respiratory
signaling alone. Several companies have
cropped up to develop and test biased opi-
oids (Science, 17 November 2017, p. 847).

But two new studies in mice contest a key
hypothesis underlying these efforts—that
a signaling protein called beta-arrestin2 is
fundamental to opioids’ effect on breathing.
“It seems like the premise was wrong,” says
Gaspard Montandon, a neuroscientist and re-
spiratory physiologist at the University of To-
ronto. He and others doubt that the good and
bad effects of opioids can be disentangled.
Hopes first arose in the late 1990s and
early 2000s, as neuroscientist Laura Bohn,
biochemist Robert Lefkowitz, and colleagues
at Duke University explored the cascades of
signals triggered when a drug binds to mu-
opioid receptors on a neuron. This binding
changes the receptor’s structure and its inter-
actions with two types of proteins inside

the cell—signaling molecules known as

G-proteins, and beta-arrestins, which, among

other effects, inhibit G-protein signaling.

It’s still not clear how the resulting signal

cascades influence cells or brain circuits. But

the researchers reported in 1999 that mice

engineered to lack the gene for beta-arrestin

got stronger and longer lasting pain relief

from morphine. And in 2005, Bohn and her

colleagues found that two morphine-induced

side effects, constipation and slowed breath-

ing, were dramatically reduced in these

“knockout” mice. The findings suggested

that a drug able to nudge the mu-opioid

receptors toward G-protein signaling and

away from beta-arrestin2 signaling would

prompt more pain relief with fewer risks.

A hunt for biased opioids ensued. A com-

mercial front-runner was Trevena, which

tested its intravenous drug candidate oliceri-

dine for postsurgical pain. But at high doses,

the compound failed to show significantly

better respiratory safety than morphine. In

2018, the U.S. Food and Drug Administration

rejected oliceridine. Trevena resubmitted its

application with additional data this month.

But some researchers question the mouse

studies that inspired the hunt. Last year in

Nature Communications, a group including

pharmacologists Andrea Kliewer and Stefan

Schulz at Friedrich Schiller University of Jena

described experiments with mice carrying

mutations in the mu-opioid receptor gene

that prevented the receptor from interacting

with beta-arrestin2. When given morphine,

these animals had constipation and sup-

pressed breathing that was sometimes more

severe than in mice without a mutation.

Since then, the Jena team and labs in Bris-

tol, U.K., and Sydney have tried to replicate

the 2005 finding directly using beta-arrestin

knockout mice. All three labs observed opi-

oid-induced constipation and breathing side

effects similar to those in mice that could

produce beta-arrestin2. The idea that G-

protein–biased opioids would be safer was

“too easy,” Kliewer says.

The results, published 12 February in

the British Journal of Pharmacology, are

“quite convincing,” says Charles Chavkin, a

pharmacologist at the University of Washing-

ton, Seattle. Opioid side effects are unlikely to

rely solely on beta-arrestin2, he says.

Perhaps the simplest explanation for the

conflicting 2005 and 2020 results is that the

mice were genetically different. Mice in the

initial studies were a mix of multiple strains;

further crossing and inbreeding may have

changed the way they respond to opioids. “I

have every bit of confidence in the early data,”

says Bohn, now at Scripps Research. “There’s

no way for us to go back and have that same

mix of animal that we had 20 years ago.”

Bohn says her original findings were

“oversold and oversimplified” by commer-

cial interests. “G doesn’t stand for good and

beta doesn’t stand for bad,” she says. Beta-

arrestin2 knockout mice were an important

starting point, she says, but they’re an imper-

fect model of drug response, in part because

they may have somehow compensated to sur-

vive without this key protein. Her group is

now creating new biased opioids and compar-

ing them with traditional opioids in animal

studies that measure breathing suppression

and other negative effects such as the devel-

opment of tolerance and dependence.

“I believe both sets of data, because both

groups are careful,” says Bryan Roth, a mo-

lecular pharmacologist at the University of

North Carolina, Chapel Hill, who helped de-

velop a biased opioid known as PZM21 and

holds stock in a company that licensed it. Re-

solving the role of beta-arrestin2 will require

more strongly biased opioids, he says. “If the

[biased opioid] hypothesis is true, it would

be tremendously beneficial for the human

race,” he says. “It’s a hypothesis that should

be tested.” j

By Kelly Servick

Safety benefits of ‘biased’ opioids scrutinized

Mouse studies challenge premise of efforts to reduce painkillers’ fatal side effect

N

Extracellular mu-opioid receptor

Intracellular

Cell membrane

G-protein

signaling

G-protein

signaling

beta-arrestin

pathway

beta-arrestin

pathway

Morphine SR-

Biased

opioids

Classical
opioids

Powerful

pain relief

Powerful

pain relief

Respiratory depression

and constipation

Less respiratory depression

and constipation

Cl

Cl

Cl

O

H

HO

HO

HH

N

HN

N

O

Accentuate the positive
Researchers have long hoped that opioids that favor G-protein signaling would be safer (below, right),
but studies of mice genetically engineered to mimic the effects of that bias have raised doubts.

NEUROSCIENCE

GRAPHIC: KATHERINE SUTLIFF AND V. ALTOUNIAN/

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