Biological
Psychiatry Commentary
Novel Application for G Protein–Biased Mu Opioid
Receptor Agonists in Opioid Relapse Prevention
Amanda K. Fakira, Lakshmi A. Devi, and Pamela J. Kennedy
For centuries, the most effective treatment for pain has been
opioids, such as morphine, codeine and hydrocodone, which
bind to mu opioid receptors (MORs) in the brain and spinal
cord to produce their pain-relieving effects. Unfortunately,
there are several side effects of long-term treatment with
opioids, including respiratory depression, constipation,
dependence, tolerance, and addiction, which limit their use.
Historically, clinicians prescribed these pain treatments
cautiously because of these adverse side effects. However, in
the early 1990s pharmaceutical companies began promoting
the use of newly formulated slow-release opioids, such as
oxycodone, claiming that they were less addictive, and as a
result these opioid medications became increasingly pre-
scribed. However, patients still became dependent and
addicted. When prescriptions could no longer be obtained or
afforded, many sought the illegal opioid heroin, which is often
mixed with fentanyl, another potent synthetic opioid (www.
drugabuse.gov). As a result, over the past 2 decades there
has been an increase in prescription opioid and heroin abuse
escalating the number of opioid-induced overdoses.
It is well known that binding of opioids to MORs activates
multiple signaling cascades including the G protein and b-
arrestin pathways. It is generally thought that internalization
and resensitization of MORs, which underlies tolerance, is
produced by the phosphorylation of the active receptor by
kinases followed by the interaction with b-arrestins. More than
2 decades ago, a pivotal study by Bohn et al. (1) identified that
morphine analgesia was both enhanced and prolonged in male
mice lacking the b-arrestin 2 gene (1). Subsequently, these
investigators discovered that lack of b-arrestin 2 also pre-
vented morphine-induced antinociceptive tolerance, con-
stipation, and respiratory depression (2,3). This led to the
notion that if agonists for MORs that activated the G protein–
signaling pathway over the b-arrestin 2 pathway could be
identified, these therapeutics would enhance pain relief out-
comes while minimizing unwanted side effects, such as res-
piratory depression, tolerance, and constipation. This concept
became known as “biased agonism.” Over the past decade a
few compounds have been identified to have G protein bias at
the MOR, including TRV130 (oliceridine), which was identified
and characterized by Trevena, Inc. (Chesterbrook, PA) (4).
TRV130 was shown to exhibit G protein coupling efficiency
comparable to morphine with an increased potency while
having minimal coupling to b-arrestin 2. When administered
in vivo, this compound produced rapid analgesia without the
unwanted side effects of respiratory depression, tolerance,
and constipation. Further studies in humans have demon-
strated that TRV130 has a similar analgesic profile as morphine
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896 ª 2020 Society of Biological Psychiatry.
Biological Psychiatry December 15, 2020; 88:896–897 www.sobp.org/journal
in the treatment of postoperative pain with reduced side ef-
fects including reduced respiratory effects [for review, see (2)].
In the current issue of Biological Psychiatry, Bossert et al. (5)
take into account the available data on TRV130 as an analgesic
with improved efficacy and reduced potential for side effects to
directly test its application as a maintenance medication in a
rodent model of oxycodone addiction. Relapse prevention is a
major focus in the treatment of opioid addiction. Current
therapies involve the use of maintenance medications such as
methadone (a MOR agonist) or buprenorphine (a partial MOR
agonist and kappa opioid receptor [KOR] antagonist). The
success of these treatment regimens is often thwarted by
undesirable and dangerous side effects, supporting the need
for novel and safer opioid addiction therapeutics. Bossert et al.
(5) trained male and female rats to self-administer oxycodone
on a long-access protocol (6 hours/day for 14 days). Animals
were then implanted with slow-release osmotic minipumps to
provide continuous doses of either buprenorphine (3, 6, or 9
mg/kg/day for males and 9 mg/kg/day for females) or TRV130
(3, 6, or 9 mg/kg/day for both males and females). Beginning 3
to 4 days after the start of maintenance treatment, rats were
subjected to a range of tests to investigate relapse potential.
To further determine whether any behavioral effects of
buprenorphine were mediated through its actions on MORs
versus KORs, the authors included a separate group of male
and female rats that received a single injection (20 mg/kg) of
the long-acting KOR antagonist norbinaltorphimine after oxy-
codone self-administration and before behavioral testing.
Rapid and significant decreases in nucleus accumbens oxygen
levels have been reported following intravenous heroin, fen-
tanyl, morphine, and oxycodone (6). Given the potential for
reduced respiratory depression after TRV130 administration,
the authors further tested whether TRV130 maintenance
treatment (9 mg/kg/day for 12 days) could prevent acute
oxycodone-induced decreases in nucleus accumbens oxygen
levels.
Several preclinical models for the study of drug addiction
have been developed, each with certain advantages and limi-
tations (7). For their experimental goals, Bossert et al. (5)
assessed 3 measures of drug-seeking and -taking behavior
during maintenance treatment: 1) extinction responding to
discrete drug-paired cues; 2) context-induced reinstatement
after extinction; and 3) reacquisition of oxycodone self-
administration. Male and female rats showed similar patterns
of oxycodone self-administration. In male rats, buprenorphine
and TRV130 maintenance treatment decreased extinction
responding and reacquisition of oxycodone self-administration
with minimal effects on context-induced reinstatement. In
https://doi.org/10.1016/j.biopsych.2020.09.006
ISSN: 0006-3223

Commentary
female rats, buprenorphine maintenance treatment decreased
all 3 measures of drug seeking and taking, while TRV130 only
decreased extinction responding. In contrast, maintenance
treatment with norbinaltorphimine did not affect any of the
measures of relapse in either males or females, suggesting that
the reported buprenorphine effects are likely mediated through
its action on MORs as opposed to KORs.
The experiments reported by Bossert et al. (5) are a tour de
force effort combining understudied but emerging animal
models of oxycodone addiction with sex differences and novel
maintenance therapeutics. Of particular note in the reported
data are the similar effects of buprenorphine and TRV130
maintenance treatment on drug-seeking and -taking behaviors
in male rats contrasted with the differential effects of these
treatments in female rats. While the abuse and misuse of
prescription opioids has risen in both men and women during
the opioid crisis, there is an alarming trend indicating that
women are being affected in a larger proportion. Although no
difference in the pharmacokinetics and dynamics of opioids
between males and females has been reported, evidence
suggests that women not only show a greater incidence of
opioid abuse than men but also have stronger cravings and
withdrawal symptoms [for review, see (8)]. Further research
suggests that women are more likely to misuse prescription
opioid medications to self-medicate for anxiety and depres-
sion. Withdrawal, negative affect, and stress are potent drivers
of opioid relapse, and these symptoms are in part mediated
through the corticotropin-releasing factor receptor 1 (CRF1R)
(9). Like MORs, CRF1 activates multiple signaling cascades
including the G protein and b-arrestin pathways. Stress in-
creases CRF1R–b-arrestin 2 association in males, contributing
to desensitization and internalization of the receptor. This is
not reported in females, resulting in a different cellular signaling
cascade engaged by ligand–receptor interaction. This biologic,
sex-biased CRF1R signaling profile is thought to contribute to
heightened responsivity to acute stressors and less adapt-
ability to chronic stressors in females than in males (10). Taken
together with the findings reported by the authors, novel MOR
agonist maintenance therapeutics with a G protein bias may
minimize unwanted side effects, such as respiratory depres-
sion, in both males and females but may be more effective for
relapse prevention in males. In females, relapse prevention
may be better supported with maintenance drugs that also
activate the b-arrestin 2 signaling pathway (e.g., buprenor-
phine) to mitigate negative affect and anxiety associated with
withdrawal. Follow-up studies comparing buprenorphine and
TRV130 maintenance treatments on measures of anxiety and
stress-induced reinstatement of oxycodone seeking and tak-
ing in males and females may be a first step to understanding
the interesting sex differences reported by Bossert et al. (5).
Drug addiction is a complex disease with numerous asso-
ciated behavioral and brain pathologies. Different stages of the
addiction cycle are known to impact overlapping but distinct
brain circuits and neurotransmitter systems (9). Preclinical
models of drug addiction and relapse capture and isolate
Biological Psychiatry December 15, 2020; 88:896–897 www.sobp.org/journal
Biological
Psychiatry
addiction-associated behavioral pathologies that likely involve
drug-induced adaptations in different neural pathways. The
importance of investigating sex differences and similarities on
multiple measures of drug relapse potential has been high-
lighted by the work of Bossert et al. (5). The novel behavioral
data calls for follow-up consideration with more detailed ana-
lyses in specific brain regions to understand the neurobiolog-
ical effects of the contrasting maintenance programs studied.
Acknowledgments and Disclosures
This work was supported by National Institute on Drug Abuse Grant Nos.
DA005010 (to PJK) and DA008863 (to LAD) and National Institute of
Neurological Disorders and Stroke Grant No. NS026880 (to LAD).
The authors report no biomedical financial interests or potential conflicts
of interest.
Article Information
From the Department of Biomedical Sciences (AKF), Cooper Medical School
of Rowan University, Camden, New Jersey; Department of Pharmacological
Sciences (LAD), Icahn School of Medicine at Mount Sinai, New York, New
York; and the Department of Psychology and Brain Research Institute (PJK),
University of California, Los Angeles, California.
Address correspondence to Lakshmi A. Devi, Ph.D., at lakshmi.devi@
mssm.edu.
Received Sep 3, 2020; accepted Sep 4, 2020.
References
1. Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT
(1999): Enhanced morphine analgesia in mice lacking beta-arrestin 2.
Science 286:2495–2498.
2. Grim TW, Acevedo-Canabal A, Bohn LM (2020): Toward directing
opioid receptor signaling to refine opioid therapeutics. Biol Psychiatry
87:15–21.
3. Raehal KM, Walker JK, Bohn LM (2005): Morphine side effects in beta-
arrestin 2 knockout mice. J Pharmacol Exp Ther 314:1195–1201.
4. DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL,
Graczyk TM, et al. (2013): A G protein-biased ligand at the mu-opioid
receptor is potently analgesic with reduced gastrointestinal and res-
piratory dysfunction compared with morphine. J Pharmacol Exp Ther
344:708–717.
5. Bossert JM, Kiyatkin EA, Korah H, Hoots JK, Afzal A, Perekopskiy D,
et al. (2020): In a rat model of opioid maintenance, the G protein–
biased mu opioid receptor agonist TRV130 decreases relapse to
oxycodone seeking and taking and prevents oxycodone-induced brain
hypoxia. Biol Psychiatry 88:935–944.
6. Kiyatkin EA (2019): Respiratory depression and brain hypoxia induced
by opioid drugs: Morphine, oxycodone, heroin, and fentanyl. Neuro-
pharmacology 151:219–226.
7. Kuhn BN, Kalivas PW, Bobadilla AC (2019): Understanding addiction
using animal models. Front Behav Neurosci 13:262.
8. Serdarevic M, Striley CW, Gurka KK, Leeman RF, Cottler LB (2019):
Sex differences in prescription opioid use patterns assessed through a
community engagement program in Florida. Drug Alcohol Depend
204:107568.
9. Koob GF, Volkow ND (2016): Neurobiology of addiction: A neuro-
circuitry analysis. Lancet Psychiatry 3:760–773.
10. Valentino RJ, Bangasser D, Van Bockstaele EJ (2013): Sex-biased
stress signaling: The corticotropin-releasing factor receptor as a
model. Mol Pharmacol 83:737–745.
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