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INRC
INRC Program Book 2020 • Back to schedule
International
Narcotics
Research
Conference
july 22–24
2020 Valencia ES Program Book
1
INRC Program Book 2020
Photo credits: Brian Ruyle - Morón Lab
2
INRC Program Book 2020
Table of Content
Welcome to INRC 2020 4
Code of conduct 5
Schedule 7
Day 1 • July 22nd 9
Abstracts 11
Day 2 • July 23rd 19
Abstracts 21
Day 3 • July 24th 28
Abstracts 30
Sponsors 38
INRC 2020 Committees 39
INRC in 2021... 40
3INRC Program Book 2020
Welcome
to INRC 2020
Welcome to International ⚠ Rules for the Conference:
Narcotics Research Conference • NO RECORDING. All talks will be recorded and
– INRC – conference in 2020! available on our website for a limited amount of
time after the conference. It is very important to
Thank you for attending our very first abide by these rules to encourage open commu-
online conference. We are very pleased to nication and trust within our community.
be able to hold our yearly meeting and wel- • Please do not distribute the links to the con-
come you to attend this amazing science ference. We are trying our best to avoid being
content despite the current challenges. ‘zoom-bombed’ by not distributing them widely.
This year will honor our fantastic under- Anyone who wants to attend can register here
graduate, graduate students and postdoc- for $5. If it’s an issue of money, please email us at
toral researchers and give them the voice internationalnarcoticsresearch@gmail.com and
they deserve to present their latest results. we are happy to provide a code to waive the fee.
Let’s enjoy some science. • Please be respectful in all comments and inter-
actions. The INRC Committee will not allow any
form of disrespect or discrimination at our con-
ferences. Any issues can be reported to interna-
tionalnarcoticsresearch@gmail.com. Please see
our Code of Conduct for further details.
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4INRC Program Book 2020
Code of conduct
INRC upholds a strong code Recording Restrictions
of conduct to protect and Presentations will be recorded by the INRC for
encourage scientists to rebroadcast with permission from presenters and
share their work. The Code of posted on the INRC website with restricted access
(password protected) for attendees who can not
Conduct aims to outline this and participate during the live session. Unauthorized
increase the conversations and recordings by attendees will not be allowed. Prior
collaborations around scientific to quoting or publishing any information pre-
sented at a conference in any publication, written
topics. This Code applies to all
or electronic, written approval of the contributing
platforms hosted by the INRC. member must first be obtained.
Without previous written consent of the contrib-
uting member, the audio or video recording of
oral presentations and discussions, the photog-
raphy/screen-shooting of slides, and printed or
electronic quotes from papers, during the con-
ference is strictly prohibited.
These restrictions apply to each attendee and are
intended to cover social networks, blogs, tweets
or any other publication, distribution, communi-
cation or sharing of information presented or dis-
cussed at the conference.
Each attendee acknowledges and agrees to these
restrictions when registration is accepted and as
a condition of being permitted to attend.
Each attendee assumes sole responsibility for
the protection and preservation of any intellectual
property rights in such member’s contributions to
a conference. If you become aware of someone
making unauthorized recordings, please immedi-
ately email this information to:
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5INRC Program Book 2020
Unauthorized Sharing of Conference that demean another person by reason of his or
her gender, gender identity or expression, race,
Links
religion, ethnicity, age or disability or that are
Our attendance is limited to license constraints. unwelcome or offensive to other members of the
To ensure that all attendees can access the meet- community or their guests. Any allegations of any
ing access to the conference must be limited to such behavior will be considered and analyzed
paid registration. Sharing the access links with by the INRC committee on a case by case basis,
anyone is thus prohibited. Individuals must reg- and violations will result in immediate removal
ister individually and can ask for a fee waiver if from the conference. Please report inappropriate
necessary. behavior to:
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Virtual Conference Best Practices
If any member of the INRC board becomes aware
To avoid unwanted disruptions (i.e. “zoom-bomb- of illegal or inappropriate behavior, the member
ing”) attendees should not share any links to the will report this to the rest of the INRC board.
virtual conference rooms. Attendees, unless pre- Immediate reporting is important to allow the
senting, will turn their microphones/cameras off. INRC the opportunity to properly assess the sit-
Any questions addressed to the speaker should be uation and fashion an appropriate response that
typed in the chat window. Moderators will select addresses the problem while being sensitive to
questions within this chat window and share them the concerns of all who are affected. Those who
with the speaker according to the time remaining violate this policy will be removed from partici-
within the time allotted. Cameras may be on or off pating in the conference to the best of the INRC
depending on personal choice, although keeping board’s capability.
your camera on may foster a better experience for
the speaker as they deliver their talk to the audi- Privacy Policy
ence. A virtual background will be shared with the
speakers if they decide to use it. The INRC is committed to protecting the privacy
of its website visitors and conference attendees.
Inappropriate Behavior Policy Attendee information will not be shared unless
given explicit permission.
The INRC has always been encouraging open and
honest intellectual debate as part of a welcoming
and inclusive atmosphere. The INRC will foster
rigorous analysis of all science presented or dis-
cussed in a manner respectful to all attendees. To
help maintain an open and respectful community
of scientists, the INRC does not tolerate illegal,
disrespectful or inappropriate behavior, includ-
ing harassment of any kind. The INRC condemns
inappropriate or suggestive acts or comments
6INRC Program Book 2020
Schedule
https://wustl-hipaa.zoom.us/j/91468020593?
pwd=MGtIenlsWUJNZjZGck93T0ZHaGJ4UT09
Password: 009991
22 23 24
J U LY J U LY J U LY
Eastern
Time WED THU FRI
11:00am
Iqira Saeed Manish K. Madasu
11:10am INRC Welcome Reception
Anna Gutridge Michelle Morochnik
11:20am
Sam Groom Arryn Blaine Alexander French
11:30am
Sweta Adhikary Samuel Singleton Sarah C. Simmons
11:40am
Jade Degrandmaison Farhana Sakloth Susan Ahmedyar
11:50am
Julia K. Brynildsen Javier Cuitavi Dani Cao
12:00pm
Besma Benredjem Eden Anderson Moriah L. Jacobson
12:10pm
Zoë Dworsky-Fried Gregory Grecco Valentina Martinez Damonte
12:20pm
Sineadh M. Conway Lani Tieu Courtney A. Bouchet
12:30pm
Kaitlin C. Reeves David Reiner Bryan Sears
12:40pm
Crystal Lemchi Darrell Eacret Zachariah Bertels
12:50pm
Devan Gomez Marwa Mikati Evan F. Fullerton
1:00pm
Lauren C. Smith Benjamin M. Clements
1:10pm
Ethan M. Anderson Sarah Palumbo
1:20pm
Matthew S. Scarnati Tamara Markovic
Round Table (1hour)
1:30pm
Academic and Industry Career
Hannah Frye Kylie B. McPherson
1:40pm
Shijia Liu Virtual INRC Closure
1:50pm
Jacob A. Beierle Valencia Announcement
2:00pm
INRC Welcome | Goodbye, Opioid Signaling, Reward—Addiction, Pain–Analgesia, Kappa, Round Table
7INRC Program Book 2020
22 23 24
J U LY J U LY J U LY
Eastern
Time WED THU FRI
11:00am
11:10am Talk: Larry Toll
11:20am Moderators:
Gregory Corder
11:30am Tuan Trang
Moderators:
11:40am Ream Al-Hasani
Lee-Yuan Liu-Chen
11:50am Moderators:
Larry Toll
12:00pm Maritxell Canals
12:10pm
12:20pm Moderators:
Thomas Kash
12:30pm Lucia Hipolito
12:40pm
12:50pm
Moderators:
1:00pm Catherine Cahill
Nicolas Massaly
1:10pm Moderators:
Emily Jutkiewicz
1:20pm Jose Moron-Concepcion
Round Table (1hour)
1:30pm
Academic and Industry Career
1:40pm
Virtual INRC Closure
1:50pm
Valencia Announcement
2:00pm
INRC Welcome | Goodbye, Opioid Signaling, Reward—Addiction, Pain–Analgesia, Kappa, Round Table
8INRC Program Book 2020 • Back to schedule
Day 1 • July 22nd
Introduction 12 : 0 0 p m – 12 :10 p m
Besma Benredjem
11: 0 0 a m – 11: 2 0 a m In vitro signaling profiles of opioid ligands allow to infer
Larry Toll their clinical responses
12 :10 p m – 12 : 2 0 p m
Zoë Dworsky-Fried
Talks session #1 Central amygdala inflammation drives pain hypersensi-
tivity and impaired opioid signalling in a mouse model of
multiple sclerosis
11: 2 0 a m – 12 : 3 0 p m
Opioid Signaling 12 : 2 0 p m – 12 : 3 0 p m
Sineadh M. Conway
Developing a novel approach for in vivo electrochemical
Moderators: detection of opioid peptides
Larry Toll
Meritxell Canals
Talk session #2
Speakers: 12 : 3 0 p m – 2 : 0 0 p m
Reward – Addiction
11: 2 0 a m – 11: 3 0 a m
Sam Groom
A novel G protein-biased agonist at the μ opioid receptor Moderators:
induces substantial receptor desensitization through GRK Emily Jutkiewicz
11: 3 0 a m – 11: 4 0 a m Jose Moron-Concepcion
Sweta Adhikary
Mu opioid receptors regulate adenosine tone in stratal Speakers:
Synapses
12 : 3 0 p m – 12 : 4 0 p m
11: 4 0 a m – 11: 5 0 a m
Kaitlin C. Reeves
Jade Degrandmaison Mu opioid receptors on vGluT2-expressing glutamatergic
In vivo mapping of the delta-opioid receptor interactome neurons modulate opioid reward
using knock-in mice
12 : 4 0 p m – 12 : 5 0 p m
11: 5 0 a m – 12 : 0 0 p m
Crystal Lemchi
Julia K. Brynildsen Development of a Novel Neonatal Opioid Exposure Model
Gene coexpression patterns predict opiate-induced brain in Mice
state transitions
9INRC Program Book 2020 • Back to schedule
12 : 5 0 p m – 1: 0 0 p m
Devan Gomez
Mesolimbic subcicruit-specific adaptations following
protracted morphine withdrawal and altered motivated
behavior
1: 0 0 p m – 1:10 p m
Lauren C. Smith
Validation of a nicotine vapor self-administration model in
rats with relevance to electronic cigarette use
1:10 p m – 1: 2 0 p m
Ethan M. Anderson
HDAC5 in the rat nucleus accumbens suppresses cued
and drug-primed reinstatement of heroin seeking in a D1
vs D2 cell type-specific manner
1: 2 0 p m – 1: 3 0 p m
Matthew S. Scarnati
Differential sensitivity of human neurons carrying μ opi-
oid receptor (MOR) N40D variants in response to ethanol
1: 3 0 p m – 1: 4 0 p m
Hannah Frye
Sex Differences in the Role of Cornichon Homolog-3 on
Opioid Use Disorder Risk and Spatial Memory
1: 4 0 p m – 1: 5 0 p m
Shijia Liu
Neural basis of opioid-induced respiratory depression
and its rescue
1: 5 0 p m – 2 : 0 0 p m
Jacob A. Beierle
Differences in oxycodone state dependent learning
between nearly isogenic BALB/cJ and BALB/cByJ mouse
substrains map to chromosomes 14 and 6
10INRC Program Book 2020 • Back to schedule
Sam Groom Sweta Adhikary
Ph.D. Student Graduate Student
Sam Groom*, Nina Kathleen Blum, Alex Conibear, Sweta Adhikary*, John T. Williams, & William T.
Alex Disney, Stephen Husbands, Yangmei Li, Birdsong
Lawrence Toll, Stefan Schluz, Graeme Henderson,
Eamonn Kelly, Chris Bailey Mu opioid receptors regulate adenos-
ine tone in stratal Synapses
A novel G protein-biased agonist
at the μ opioid receptor induces Activation of mu opioid receptors inhibits ade-
substantial receptor desensitization nosine tone in striatal synapses through a cAMP
mediated pathway. Selectively knocking-out mu
through GRK opioid receptors from pre or post synaptic com-
partments does not augment adenosine tone in
My recent work has determined that the cyclic
the presence of morphine, but a global mu knock
endomorphin analogue Tyr-c[D-Lys-Phe-Tyr-Gly]
out does. Additionally, adenosine is regulated
(Compound 1) is a novel G protein-biased agonist
by postsynaptic medium spiny neurons in the
at the μ opioid receptor. Surprisingly, we found
striatum.
that Compound 1 induces considerable desensi-
tization of the μ opioid receptor in rat locus coe-
ruleus neurons. Compound 1-induced receptor
desensitization occurred through GRK in spite of
its G protein-biased pharmacology. Our findings
cast doubt on the assumption that G protein-bi-
ased agonists will categorically evade receptor
desensitization and tolerance.
Day 1 • July 22nd Day 1 • July 22nd
Session #1, Talk #1 Session #1, Talk #2
Opioid Signaling Opioid Signaling
11: 2 0 a m – 11: 3 0 a m 11: 3 0 a m – 11: 4 0 a m
11INRC Program Book 2020 • Back to schedule
Jade Degrandmaison Julia K. Brynildsen
Ph.D. Candidate Ph.D. Candidate
Jade Degrandmaison*, Khaled Abdallah, Julia K. Brynildsen*, Kyla D. Mace, Eli J. Cornblath,
Véronique Blais, Samuel Génier, Marie-Pier Carmen Weidler, Fabio Pasqualetti, Danielle S.
Lalumière, Francis Bergeron, Catherine M. Cahill, Bassett, and Julie A. Blen
Jim Boulter, Christine L. Lavoie, Jean-Luc Parent
and Louis Gendron Gene coexpression patterns predict
opiate-induced brain state transitions
In vivo mapping of the delta-opioid
receptor interactome using knock-in Reconfiguration of neuronal connectivity may
mice explain heightened opioid abuse liability in indi-
viduals with a history of chronic drug exposure.
Despite its significant potential as a therapeutic To characterize network-level changes in neuronal
target for chronic pain management, our under- activity induced by chronic opiate exposure, we
standing of the molecular and cellular mecha- constructed network models from FOS expres-
nisms regulating the trafficking and signaling of sion data in mice that are morphine-naïve, mor-
the delta-opioid receptor (DOPr) remains frag- phine-dependent, or have undergone 4 weeks
mentary. Using brain homogenates from our of withdrawal from chronic morphine exposure.
newly generated FLAG-DOPr-KO (knock-out) and We demonstrate that basal gene expression pat-
FLAG-DOPr-KI (knock-in) mouse models, we iden- terns are predictive of changes in FOS correla-
tified several novel endogenous DOPr interactors tion networks in the morphine-dependent state
involved in protein folding, trafficking, and signal and identify key brain regions that are particu-
transduction, as well as other proteins belong- larly influential in driving transitions between opi-
ing to the receptors/channels/transporters family. ate-naïve and opiate-dependent brain states.
We also describe the generation of a conditional
KI FLAG-DOPr mouse line, an invaluable tool to
investigate DOPr functions in specific neuron pop-
ulations and circuits.
Day 1 • July 22nd Day 1 • July 22nd
Session #1, Talk #3 Session #1, Talk #4
Opioid Signaling Opioid Signaling
11: 4 0 a m – 11: 5 0 a m 11: 5 0 a m – 12 : 0 0 p m
12INRC Program Book 2020 • Back to schedule
Besma Benredjem Zoë Dworsky-Fried
Ph.D. Student M.S.c Student
Besma Benredjem*, Jonathan Gallion, Dennis Zoë Dworsky-Fried*, Bradley J Kerr, Anna MW
Pelletier, Paul Dallaire, Johanie Charbonneau, Taylor
Darren Cawkill, Karim Nagi, Mark Gosink, Viktoryia
Lukashova, Stephen Jenkinson, Yong Ren, Central amygdala inflammation
Christopher Somps, Brigitte Murat, Emma Van Der
Westhuizen, Christian Le Gouill, Olivier Lichtarge,
drives pain hypersensitivity and
Anne Schmidt, Michel Bouvier, Graciela Pineyro impaired opioid signalling in a mouse
model of multiple sclerosis
In vitro signaling profiles of opioid
Chronic pain is one of the most frequent and
ligands allow to infer their clinical
debilitating symptoms associated with the auto-
responses immune disorder multiple sclerosis (MS). In this
study, we use a mouse model of MS to show that
We have developed a method that uses preclini- inflammation within the central amygdala alters
cal responses of well-known prescription opioids anti-nociceptive signalling leading to blunted opi-
and of novel molecules to classify them accord- oid analgesia. Our data identify a novel mecha-
ing to similarities in their signaling profiles. We nism for impaired pain control in autoimmune
have found that the categories that result from disorders and highlight potential strategies, such
this classification are associated with different as targeting inflammation, to improve analgesic
degrees of clinically reported side effects (such efficacy in MS.
as respiratory depression). This method could
help to identify better drug candidates, allowing
to advance to clinical testing only those with less
side effects potential.
Day 1 • July 22nd Day 1 • July 22nd
Session #1, Talk #5 Session #1, Talk #6
Opioid Signaling Opioid Signaling
12 : 0 0 p m – 12 :10 p m 12 :10 p m – 12 : 2 0 p m
13INRC Program Book 2020 • Back to schedule
Sineadh M. Conway Kaitlin C. Reeves
Postdoctoral Researcher Ph.D. Candidate
Sineadh M. Conway*, Graydon B. Gereau, Loc Kaitlin C. Reeves*, Megan J. Kube, Gregory G.
V. Thang, John R. Cirrito, Carla M. Yuede, Ream Grecco, Brandon M. Fritz, Braulio Muñoz, Fuqin
Al-Hasani Yin, Yong Gao, David L. Haggerty, Hunter J.
Hoffman, Brady K. Atwood
Developing a novel approach for in
vivo electrochemical detection of Mu opioid receptors on vGluT2-ex-
opioid peptides pressing glutamatergic neurons
modulate opioid reward
The endogenous opioid peptide systems are criti-
cal for analgesia, reward processing, and negative The role of mu opioid receptor (MOR)-mediated
affect, however research on their in vivo function regulation of GABA transmission in opioid reward
in modulation of these behaviors has been chal- is well established, but much less is known about
lenging due to an inability to reliably and consis- MOR-mediated regulation of glutamate transmis-
tently detect dynamic changes in opioid peptides. sion and how this relates to drug reward; therefore,
To fill this gap, we have developed microimmuno- we created a transgenic mouse that lacks MORs in
electrodes (MIEs) for rapid and sensitive detection vGluT2-expressing neurons (MORflox-vGluT2cre).
of opioid peptides. Using square wave voltamme- Compared to wild-type littermate controls, these
try, we show that dynorphin antibody-coated MIEs MORflox-vGluT2cre mice have disrupted opioid
are sensitive and selective to increasing concen- reward, consume less oxycodone, lack oxyco-
trations of dynorphin in the fmol range, and we done-induced locomotor stimulation, and dis-
are currently working to demonstrate the utility play baseline withdrawal-like responses following
of these MIEs both in vitro via brain slice prepa- the development of oxycodone dependence.
ration and in vivo for real-time, rapid detection of However, other MOR-mediated behaviors, includ-
endogenous opioid peptide release in awake and ing oxycodone-induced analgesia, are unaffected,
behaving animals. suggesting that MOR-mediated regulation of glu-
tamate transmission plays a specific role in opioid
reward and withdrawal.
Day 1 • July 22nd Day 1 • July 22nd
Session #1, Talk #7 Session #2, Talk #1
Opioid Signaling Reward – Addiction
12 : 2 0 p m – 12 : 3 0 p m 12 : 3 0 p m – 12 : 4 0 p m
14INRC Program Book 2020 • Back to schedule
Crystal Lemchi Devan Gomez
Ph.D. Candidate Graduate Student
Crystal Lemchi*, Amelia Dunn, Juliet Mengaziol, Devan Gomez*, Matthew Hearing
Shivon Robinson and Julie A. Blendy
Mesolimbic subcircuit-specific
Development of a Novel Neonatal adaptations following protracted
Opioid Exposure Model in Mice morphine withdrawal and altered
The long-term effects of chronic opioid exposure
motivated behavior
during early life are not well characterized due
Our lab has found that protracted withdrawal
to many confounding factors in human studies
from a dependence-inducing regimen of mor-
and lack of consistency in animal models. Our
phine reduces excitation and increases GABAAR-
lab has created a novel mouse model of opioid
mediated inhibition within a subpopulation
exposure [spanning both in utero and PND 1-14],
of lateral VTA dopamine neurons projecting to
which encompasses the human equivalent of
the lateral NAc shell. These adaptations align
“three-trimester” opioid exposure and recapitu-
with preliminary findings suggesting that prior
lates characteristic phenotypes associated with
induction of dependence increases subsequent
NOWS during both development and withdrawal.
motivation for intravenously available morphine
Despite this robust withdrawal, preliminary results
at this protracted withdrawal time point. These
suggest few long-term behavioral consequences
data underscore the significance of distinguishing
(CPP, LH,TST) of this NOWS model.
functional differences between dopaminergic cir-
cuitry and their potential to separately contribute
to neurobehavioral alterations related to opioid
withdrawal, relapse and shifts in motivated states
that drive drug-seeking.
Day 1 • July 22nd Day 1 • July 22nd
Session #2, Talk #2 Session #2, Talk #3
Reward – Addiction Reward – Addiction
12 : 4 0 p m – 12 : 5 0 p m 12 : 5 0 p m – 1: 0 0 p m
15INRC Program Book 2020 • Back to schedule
Lauren C. Smith Ethan M. Anderson
Graduate Student Research Assistant Professor
Lauren C. Smith*, Marsida Kallupi, Lani Tieu, Kokila Ethan M. Anderson*, Evgeny Tsvetkov, Allison
Shankar, Abigail Jaquish, Jamie Barr, Yujuan Su, Galante, Makoto Taniguchi, and Christopher W.
Nathan Velarde, Sharona Sedighim, Lieselot L. Cowan
G. Carrette, Mike Klodnicki, Xin Sun, Giordano de
Guglielmo, Olivier George HDAC5 in the rat nucleus accumbens
suppresses cued and drug-primed
Validation of a nicotine vapor self-ad-
reinstatement of heroin seeking in a
ministration model in rats with rele-
D1 vs D2 cell type-specific manner
vance to electronic cigarette use
Histone deacetylase 5 (HDAC5) is an epigene-
There is currently no rodent model of nicotine tic regulator that shuttles between the nucleus
vapor self-administration, so we developed a and cytoplasm following drug exposure and
novel model of voluntary electronic cigarette alters intrinsic excitability of medium spiny neu-
use in rats using operant behavior. We found rons (MSNs) in the nucleus accumbens (NAc).
that rats voluntarily exposed themselves to nico- Here, using overexpression and knockdown
tine vapor to the point of reaching blood nicotine manipulations of HDAC5 in the rat NAc, I show
levels that are similar to humans. Moreover, nic- bi-directional effects of HDAC5 on 3 types of her-
otine vapor self-administration resulted in addic- oin-seeking behavior following several weeks of
tion-like behaviors, including somatic signs of heroin self-administration. Finally, I show that
withdrawal, allodynia, anxiety-like behavior, and overexpression of HDAC5 reduces cue-induced
relapse-like behavior after 3 weeks of abstinence. reinstatement when selectively expressed in
These findings validate a novel animal model of D1-MSNs and this same HDAC5 overexpression
nicotine vapor self-administration in rodents in D2-MSNs reduces heroin-primed reinstatement
with relevance to electronic cigarette use in selectively; importantly, these results suggest that
humans and demonstrate the addictive proper- the current dogma concerning opposing roles of
ties and harmful effects of chronic nicotine vapor D1 vs D2-MSNs on drug-seeking behavior may
self-administration. be incomplete and these separable MSNs may
instead have complimentary roles in drug-seek-
ing behavior.
Day 1 • July 22nd Day 1 • July 22nd
Session #2, Talk #4 Session #2, Talk #5
Reward – Addiction Reward – Addiction
1: 0 0 p m – 1:10 p m 1:10 p m – 1: 2 0 p m
16INRC Program Book 2020 • Back to schedule
Matthew S. Scarnati Hannah Frye
Postdoctoral Researcher Graduate Student
Matthew S. Scarnati*, Andrew J.,Boreland, Marisa Hannah E. Frye*, Yukitoshi Izumi, Min-Yu Sun,
Joel, Ronald P. Hart, Zhiping P. Pang Sidney B. Williams, Christopher R. Trousdale,
Alexis N. Harris, Andrew D. Sauerbeck, Terrance T.
Differential sensitivity of human Kummer, Steven Mennerick, Charles F. Zorumski,
Elliot C. Nelson, Joseph D. Dougherty, Jose A.
neurons carrying μ opioid receptor Morón
(MOR) N40D variants in response to
ethanol Sex Differences in the Role of Cor-
nichon Homolog-3 on Opioid Use
There is a limited understanding of the precise
cellular and molecular mechanisms underlying Disorder Risk and Spatial Memory
AUD in humans. A functional polymorphism of
the mu-opioid receptor (MOR) N40D may alter the Single nucleotide polymorphisms (SNPs)
risk of developing AUD. iPS and induced neuronal in CNIH3, the gene which encodes for the AMPA
(iN) cell technology provide unique opportunities receptor (AMPAR) auxiliary protein cornichon
to model AUD in a human context. Alcohol appli- homolog-3 (CNIH3), are correlated with reduced
cation reveals that the MOR genotype confers risk of opioid use disorder in humans. New data
differential sensitivity to synaptic output which suggest this correlation is stronger in women, and
depends on ethanol exposure time and concen- in mouse studies CNIH3 only affects spatial mem-
tration for AD-iNs and may help explain alcohol ory, hippocampal synaptic plasticity, and synaptic
dependence in individuals who carry the MOR density in females during the metestrus stage of
D40 SNP. the estrous cycle. Our study defines a sex-spe-
cific role for CNIH3 in spatial memory formation
and synaptic plasticity, which are highly involved
in opioid use disorder and relapse.
Day 1 • July 22nd Day 1 • July 22nd
Session #2, Talk #6 Session #2, Talk #7
Reward – Addiction Reward – Addiction
1: 2 0 p m – 1: 3 0 p m 1: 3 0 p m – 1: 4 0 p m
17INRC Program Book 2020 • Back to schedule
Shijia Liu Jacob A. Beierle
Ph.D. Candidate Graduate Student
Shijia Liu*, Dongil Kim, Tae Gyu Oh, Gerald Pao, Jacob A. Beierle*, Emily Yao, Julia Scotellaro, Gary
Jonghyun Kim, Richard D. Palmiter, Ronald M. Peltz, Camron D. Bryant
Evans, Sung Han.
Differences in oxycodone state
Neural basis of opioid-induced respi- dependent learning between nearly
ratory depression and its rescue isogenic BALB/cJ and BALB/cByJ
Opioid-induced respiratory depression (OIRD)
mouse substrains map to chromo-
is the direct cause of the rapidly evolving opioid somes 14 and 6
crisis, yet its underlying neurobiological mecha-
nisms are not well understood. We identify that Variation in subjective sensitivity to the rewarding
a genetically defined neuronal population in the effects of opioids is heritable and can influence
lateral parabrachial nucleus expressing µ-opioid addiction liability. In inbred BALB/c substrains we
receptors (PBLOprm1 neurons) are involved in reg- identified robust differences in state-dependent
ulating breathing rhythm and OIRD pathogenesis. retrieval of oxycodone conditioned reward, but
In addition, we find that activating PBLOprm1 neu- not drug-free reward as measured via conditioned
rons via artificial and endogenous G-protein cou- place preference. Because these substrains are
pled receptor signaling pathways rescues OIRD, over 99% isogenic, identification of the genetic
thereby providing insights on novel therapeutic factors influencing this trait is greatly facilitated
interventions of OIRD in humans. compared to traditional F2 crosses. I will discuss
identification of 2 major-effect QTLs influencing
state dependent learning/retrieval of oxycodone
reward on proximal chromosome 14, and a female
specific locus on chromosome 6 as well as the
limited number of candidate genes that lie under-
neath these loci.
Day 1 • July 22nd Day 1 • July 22nd
Session #2, Talk #8 Session #2, Talk #9
Reward – Addiction Reward – Addiction
1: 4 0 p m – 1: 5 0 p m 1: 5 0 p m – 2 : 0 0 p m
18INRC Program Book 2020 • Back to schedule
Day 2 • July 23rd
Talks session #3 Talks session #4
11: 0 0 a m – 11: 5 0 a m 11: 5 0 a m – 1: 0 0 p m
Pain – Analgesia Reward – Addiction
Moderators: Moderators:
Gregory Corder Thomas Kash
Tuan Trang Lucia Hipolito
Speakers: Speakers:
11: 0 0 a m – 11:10 a m 11: 5 0 a m – 12 : 0 0 p m
Iqira Saeed Javier Cuitavi
Can opioid exposure alter cancer incidence? Microglia-mediated Mu Opioid Receptor alterations? A
new insight into pain-induced alcohol relapse in female
11:10 a m – 11: 2 0 a m rats
Anna Gutridge 12 : 0 0 p m – 12 :10 p m
Pharmacological Characterization of Natural and
Synthetic Akuamma Alkaloids for Pain Therapeutics Eden Anderson
Opioid self-administration induced sex-specific medial
11: 2 0 a m – 11: 3 0 a m prefrontal cortex plasticity and deficits in cognitive
Arryn Blaine flexibility
Investigating the Cellular and Behavioral Effects of δ-Opi- 12 :10 p m – 12 : 2 0 p m
oid Receptor Mediated β-arrestin 1 Signaling
Gregory Grecco
11: 3 0 a m – 11: 4 0 a m Prenatal Methadone Exposure Disrupts Neurobehavioral
Samuel Singleton Development
TRV130 partial agonism and capacity to produce analge- 12 : 2 0 p m – 12 : 3 0 p m
sic tolerance revealed through reducing available mu opi-
oid receptor number Lani Tieu
Identification of Individual Differences in Response to
11: 4 0 a m – 11: 5 0 a m Methadone, Buprenorphine, and Naltrexone in an Animal
Farhana Sakloth Model of Opioid Use Disorder
In Vivo Evidence that Positive Allosteric Modulators of the 12 : 3 0 p m – 12 : 4 0 p m
μ-Opioid Receptor Enhance the Antinociceptive Efficacy
of Clinically Used Opioids, but not the Adverse Effects David Reiner
Associated with their Repeated Administration Role of projections between piriform and orbitofrontal
cortex in relapse to fentanyl seeking after food choice-in-
duced voluntary abstinence
19INRC Program Book 2020 • Back to schedule
12 : 4 0 p m – 12 : 5 0 p m
Darrell Eacret
Investigations into the behavioral and molecular conse-
quences of chronic opioids and the relationship to dis-
rupted sleep
12 : 5 0 p m – 1: 0 0 p m
Marwa Mikati
In vivo detection of endogenous opioid peptides and their
role in opioid withdrawal syndrome
Round Table
1: 0 0 p m – 2 : 0 0 p m
Moderators:
Andrea Bedini
Assistant professor, University of Bologna
Lucia Hipolito
Associate professor, University of Valencia
Ream Al-Hasani
Assistant professor, St Louis College of Pharmacy
Jose Moron-Concepcion
Professor, Washington University in St. Louis
Amynah Pradhan
Associate Professor, University of Illinois in Chicago
John Streicher
Assistant professor, University of Arizona
Katherine Martucci
Assistant professor, Duke University
20INRC Program Book 2020 • Back to schedule
Iqira Saeed Anna Gutridge
Ph.D. Student Graduate Student
Can opioid exposure alter cancer Gutridge AM*, Hennessy MR, Argade MD, Rhoda
ES, Royer QH, Riley AP, van Rijn RM
incidence?
There is considerable controversy regarding Pharmacological Characterization
whether opioids influence cancer-related out- of Natural and Synthetic Akuamma
comes in patients with pre-existing cancer. Less Alkaloids for Pain Therapeutics
work has explored whether opioid exposure
increases the risk of cancer-related outcomes in Picralima nitida, commonly known as akuamma,
opioid users who were initially free from cancer. is a tree that produces opioidergic alkaloids
We report a systematic review which examines (Menzies et al., Eur. J. Pharmacol.1998) and is
the relationship between opioid exposure and used most generally for its analgesic and anti-in-
cancer outcomes in populations of individuals flammatory properties (Erharuyi et al., Asian Pac.
who were cancer-free prior to opioid exposure. J. Trop. Med. 2014). Due to their ability to ago-
nize the µ-opioid receptor (Menzies et al., Eur. J.
Pharmacol. 1998), I hypothesized these alkaloids
can be used in the treatment of pain. Six akua-
mma alkaloids were pharmacologically charac-
terized at the µ-, δ- and κ- opioid receptors (µOR,
δOR, κOR) for binding affinity and biased signaling
activity, and the compounds with the highest µOR
potency were then tested for analgesic properties
in nociception paradigms.
Day 2 • July 23rd Day 2 • July 23rd
Session #3, Talk #1 Session #3, Talk #2
Pain – Analgesia Pain – Analgesia
11: 0 0 a m – 11:10 a m 11:10 a m – 11: 2 0 a m
21INRC Program Book 2020 • Back to schedule
Arryn Blaine Samuel Singleton
Graduate Student Ph.D. Student
Arryn Blaine*, Dr. Richard van Rijn, Rebecca Liu Samuel Singleton*, Daniel Baptista-Hon, Emily
Edelston, Kirsty McCaughey, Ewan Camplisson,
Investigating the Cellular and Behav- Tim G Hales
ioral Effects of δ-Opioid Receptor
TRV130 partial agonism and capac-
Mediated β-arrestin 1 Signaling
ity to produce analgesic tolerance
Opioids targeting the delta opioid receptor have revealed through reducing available
been investigated as alternative analgesic strat- mu opioid receptor number
egy to avoid adverse effects observed with mu
opioids. Unfortunately, delta opioids have a ten- The possibility that β-arrestin2 recruitment to mu
dency to induce seizures, a severe side effect receptors may contribute to opioid side effects led
linked to arrestin signaling. Here I investigated to the development of TRV130, a biased agonist in
seizure severity and ERK signaling by delta opi- favour of G-protein signalling. However, apparent
oids with different arrestin efficacy in male and bias may be confounded by receptor overexpres-
female wild-type, beta-arrestin 1 and beta-arres- sion. We examined the efficacies and apparent
tin 2 KO mice. potencies of mu agonists with full and partial recep-
tor availability following exposure to the irreversible
mu antagonist β-FNA. In vivo, we also assessed
whether receptor number influenced the develop-
ment of analgesic tolerance using heterozygous
mice expressing 50% fewer mu receptors. TRV130
was a very weak partial agonist in vitro even without
prior exposure to β-FNA. TRV130 was highly potent
and caused no analgesic tolerance in wild type mice.
In heterozygous mice, TRV130 was equally effica-
cious but caused profound tolerance after only 4
days. These findings emphasise the need for con-
sideration of receptor reserve when characterising
new opioid agonists. Furthermore, they suggest the
beneficial side effect profile of reportedly biased
agonists may be a result of partial agonism.
Day 2 • July 23rd Day 2 • July 23rd
Session #3, Talk #3 Session #3, Talk #4
Pain – Analgesia Pain – Analgesia
11: 2 0 a m – 11: 3 0 a m 11: 3 0 a m – 11: 4 0 a m
22INRC Program Book 2020 • Back to schedule
Farhana Sakloth Javier Cuitavi
Postdoctoral Researcher Ph.D. Student
Farhana Sakloth*, Kerri Pryce, Hye Jin Kang, Javier Cuitavi*, Jesús David Lorente, Yolanda
Abhijeet Kapoor, Tao Che, Lihuai Qin, Feodora Campos-Jurado, Natalia Landsberg and Lucía
Bertherat, H. Ümit Kaniskan, Jian Jin, Bryan Roth, Hipólito
Venetia Zachariou, and Marta Filizola
Microglia-mediated Mu Opioid
In Vivo Evidence that Positive Receptor alterations? A new insight
Allosteric Modulators of the μ-Opioid into pain-induced alcohol relapse in
Receptor Enhance the Antinoci- female rats
ceptive Efficacy of Clinically Used
Opioids, but not the Adverse Effects Microglia play a role in pain and addictive pro-
cesses and proinflammatory cytokines regulate
Associated with their Repeated Mu Opioid Receptor (MOR) expression. We show
Administration how microglial activation, neuroinflammation and
MORs levels variates during the abstinence and
We report two small molecules from a chemical the relapse phases in female rats and we assess
series of Positive allosteric modulators (PAMs) of the role that pain plays on it.
the µ-opioid receptor (MOR) exhibiting: (a) oppo-
site biased signaling in vitro; (b) a differential
enhancement of the antinociceptive efficacy of
oxycodone, morphine, and methadone in mouse
models of pain, and (c) a lack of potentiation of
an unwanted side effect resulting from excessive
opioid administration. This series of MOR PAMs
holds promise for the development of adjuncts to
opioid therapy to mitigate against overdose and
opioid use disorders.
Day 2 • July 23rd Day 2 • July 23rd
Session #3, Talk #5 Session #4, Talk #1
Pain – Analgesia Reward – Addiction
11: 4 0 a m – 11: 5 0 a m 11: 5 0 a m – 12 : 0 0 p m
23INRC Program Book 2020 • Back to schedule
Eden Anderson Gregory Grecco
Postdoctoral Researcher M.D-Ph.D. Student
Eden Anderson*, Annabel Engelhardt, Skyler Gregory G. Grecco*, Briana Mork, David L.
Demis, Elissa Porath, Matthew Hearing Haggerty, Kaitlin C. Reeves, Yong Gao, Hunter
Hoffman, Andrea R. Masters, Bryan K. Yamamoto,
Opioid self-administration induced Patrick L. Sheets, Brady K. Atwood.
sex-specific medial prefrontal cortex
Prenatal Methadone Exposure Dis-
plasticity and deficits in cognitive
rupts Neurobehavioral Development
flexibility
We have recently developed and characterized a
Women transition to addiction faster and expe-
translational mouse model of prenatal methadone
rience greater difficulties remaining abstinent,
exposure (PME) that resembles the typical pat-
however what drives this is unknown. We show
tern of opioid use in a pregnant woman who is first
that self-administration of the opioid, remifen-
dependent on oxycodone prior to gestation, then
tanil, causes a long-lasting decrease in ex vivo
enters a methadone maintenance therapy pro-
excitability but augments firing capacity of pyra-
gram, and subsequently becomes pregnant while
midal neurons in the prelimbic cortex of mice.
maintained on methadone. Using this model, the
This phenomenon occurs faster in females, mani-
impact of PME on behavioral development and
fests from sex-specific changes in excitatory and
neuronal properties using brain slice electrophys-
inhibitory synaptic regulation and aligns with a
iological measures was investigated in offspring.
significant impairment in cognitive flexibility that
Methadone was found to accumulate in the fetal
can be induced and rescued using chemogenetic
compartment relative to maternal concentra-
manipulations.
tions. In addition to high methadone concentra-
tions in the fetal brain, PME produces substantial
impairments in behavioral development specifi-
cally in sensorimotor and locomotor performance
which was associated with alterations in motor
cortical neuron intrinsic properties and synaptic
connectivity.
Day 2 • July 23rd Day 2 • July 23rd
Session #4, Talk #2 Session #4, Talk #3
Reward – Addiction Reward – Addiction
12 : 0 0 p m – 12 :10 p m 12 :10 p m – 12 : 2 0 p m
24INRC Program Book 2020 • Back to schedule
Lani Tieu David Reiner
Research Assistant Postdoctoral Researcher
Lani Tieu*, Lauren Smith, Giordano de Guglielmo, David J Reiner*, Olivia M Lofaro, Sarah V Applebey,
Marsida Kallupi, Olivier George Hannah Korah, Marco Venniro, Carlo Cifani,
Jennifer M Bossert, Yavin Shaham
Identification of Individual Differ-
ences in Response to Methadone, Role of projections between piriform
Buprenorphine, and Naltrexone in an and orbitofrontal cortex in relapse to
Animal Model of Opioid Use Disorder fentanyl seeking after food choice-in-
duced voluntary abstinence
The current medications for opioid use disorder
(buprenorphine, methadone, and naltrexone) sig- There are few preclinical studies of fentanyl
nificantly reduce craving but there are substan- relapse, and these studies have used experi-
tial individual differences in response to these menter-imposed (forced) abstinence procedures,
treatments, and the reason for such difference is despite that in humans, abstinence is often vol-
poorly known. Here, we tested the hypothesis that untary, with drug available in the drug environ-
similar individual differences may be observed in ment but forgone in favor of non-drug alternative
a large population of heterogeneous stock rats, rewards. Using immunohistochemistry, anatom-
that have been bred to maximize genetic diversity, ical tracing, and classical pharmacology, I identi-
using a behavioral paradigm relevant to opioid use fied a critical role of projections between piriform
disorder. We found that ~65% of rats decreased and orbitofrontal cortices in relapse to fentanyl
their motivation to take oxycodone with at least seeking after food choice-induced voluntary
one treatment and observed large individual dif- abstinence in both male and female rats. These
ference for each treatment. To unveil the genetic, data revealed a surprising finding, that the piri-
cellular, and molecular basis of these differences, form cortex which is traditionally thought of as an
we created the Oxycodone Biobank (www.oxyco- olfaction-related region and not previously stud-
donebiobank.org), from which investigators can ied in the context of drug reinstatement/relapse,
request biological samples, including blood, urine, is critical for relapse to fentanyl seeking.
feces, brain, liver, kidney, and other organs.
Day 2 • July 23rd Day 2 • July 23rd
Session #4, Talk #4 Session #4, Talk #5
Reward – Addiction Reward – Addiction
12 : 2 0 p m – 12 : 3 0 p m 12 : 3 0 p m – 12 : 4 0 p m
25INRC Program Book 2020 • Back to schedule
Darrell Eacret Marwa Mikati
Research Assistant Ph.D. Candidate
Darrell Eacret*, Polina Fenik, Guanxia Zhan, Sigrid Marwa Mikati*, Kia Barclay, Petra Erdmann-
C. Veasey, and Julie A. Blendy Gilmore, Robert Sprung, Reid Townsend, Ream
Al-Hasani
Investigations into the behavioral and
molecular consequences of chronic In vivo detection of endogenous opi-
opioids and the relationship to dis- oid peptides and their role in opioid
rupted sleep withdrawal syndrome
Disrupted sleep is a side effect of opioid use and The withdrawal syndrome associated with absti-
withdrawal. We used an oral morphine adminis- nence from opioids often results in relapse, is
tration paradigm and found significant alterations sometimes fatal and prevents long-term absti-
in sleep parameters during morphine exposure nence. Studies have shown that increased expres-
and withdrawal. Increases in wakefulness during sion of dynorphin mRNA, the endogenous kappa
morphine accompanied a cortical gene expres- opioid receptor ligand, increases in the nucleus
sion profile that is reminiscent of an inflamma- accumbens during withdrawal. However, there is
tory sleep deprivation state. Ongoing studies are not a reliable method to directly measure in vivo
focused on identifying molecular mechanisms changes in opioid peptides. Here, we propose a
underlying these changes and how to intervene novel mouse model of precipitated withdrawal
with treatments during withdrawal to improve from chronic fentanyl exposure. We also describe
sleep disturbances and reduce withdrawal a method coupling microdialysis and nano-liquid
symptoms. chromatography/mass spectrometry to allow
detection of endogenous opioid peptides in vivo.
Day 2 • July 23rd Day 2 • July 23rd
Session #4, Talk #6 Session #4, Talk #7
Reward – Addiction Reward – Addiction
12 : 4 0 p m – 12 : 5 0 p m 12 : 5 0 p m – 1: 0 0 p m
26INRC Program Book 2020 • Back to schedule
Round Table
Academic and Industry Career
Moderators:
Andrea Bedini
Assistant professor, University of Bologna
Lucia Hipolito
Associate professor, University of Valencia
Ream Al-Hasani
Assistant professor, St Louis College of Pharmacy
Jose Moron-Concepcion
Professor, Washington University in St. Louis
Amynah Pradhan
Associate Professor, University of Illinois in Chicago
John Streicher
Assistant professor, University of Arizona
Katherine Martucci
Assistant professor, Duke University
Day 2 • July 23rd
–
Round Table
1: 0 0 p m – 2 : 0 0 p m
27INRC Program Book 2020 • Back to schedule
Day 3 • July 24th
Talks Session #5 receptors (KOR)-inducible Cre recombinase (KOR-iCre),
a better tool for precise localization of KOR-expressing
neurons
11: 0 0 a m – 12 : 2 0 p m
Kappa 12 : 0 0 p m – 12 :10 p m
Moriah L. Jacobson
Kappa Opioid Receptor Desensitization is Required for the
Moderators: Protracted Antidepressant Effects of Ketamine
Ream Al-Hasani
12 :10 p m – 12 : 2 0 p m
Lee-Yuan Liu-Chen
Valentina Martinez Damonte
kORs in the VTA modulate GABAergic synaptic plasticity
Speakers:
11: 0 0 a m – 11:10 a m
Manish K. Madasu
Talks Session #6
Activation of kappa opioid receptor potentiates cold 12 : 2 0 p m – 1: 4 0 p m
sensation Pain
11:10 a m – 11: 2 0 a m
Michelle Morochnick Moderators:
Modulation of cocaine administration by kappa agonists: Catherine Cahill
nalfurafine and novel pyranopiperazines
Nicolas Massaly
11: 2 0 a m – 11: 3 0 a m
Alexander French
Effects of biased agonism at the kappa opioid receptor
Speakers:
on alcohol consumption in mice 12 : 2 0 p m – 12 : 3 0 p m
11: 3 0 a m – 11: 4 0 a m Courtney A. Bouchet
Sarah C. Simmons Differential effects of persistent inflammation on the pre-
synaptic opioid and cannabinoid receptors within the ven-
Early life stress dysregulates kappa opioid receptor sig- trolateral periaqueductal gray
naling within the lateral habenula
12 : 3 0 p m – 12 : 4 0 p m
11: 4 0 a m – 11: 5 0 a m
Bryan Sears
Susan Ahmedyar
Potential Involvement of Peripheral Opioid Receptors In
The role of dynorphin/kappa-opioid receptor (DYN-KOR) The Development Of Tolerance To Morphine
system in stress-mediated affective disorders and alco-
hol self-administration in mice 12 : 4 0 p m – 12 : 5 0 p m
11: 5 0 a m – 12 : 0 0 p m Zachariah Bertels
Danni Cao A translationally significant model of migraine facilitation
through chronic morphine is attenuated by PAC1 receptor
Characterization of knockin mice harboring kappa opioid antagonism
28INRC Program Book 2020 • Back to schedule
12 : 5 0 p m – 1: 0 0 p m
Evan F. Fullerton
The impact of advanced age on Mu Opioid Receptor sig-
naling in the midbrain periaqueductal gray: implications
on analgesia
1: 0 0 p m – 1:10 p m
Benjamin M. Clements
Influence of Strategically Substituted Agmatines on
Opioid-Induced Neuroplasticity
1:10 p m – 1: 2 0 p m
Sarah Palumbo
Assessment of probable opioid use disorder using elec-
tronic health record documentation
1: 2 0 p m – 1: 3 0 p m
Tamara Markovic
Pain induces somatic adaptations in Ventral Tegmental
Area Dopamine neurons to drive anhedonia-like behavior
1: 3 0 p m – 1: 4 0 p m
Kylie B. McPherson
Changes in intrinsic properties of vlPAG neuron subtype
after persistent inflammatory pain
Conclusion and Valencia
Meeting presentation
1: 4 0 p m – 2 : 0 0 p m
Speakers :
Larry Toll
Nicolas Massaly
Lucia Hipolito
29INRC Program Book 2020 • Back to schedule
Manish K. Madasu Michelle Morochnik
Postdoctoral Researcher Research Assistant
Manish K. Madasu*, Loc V. Thang, Priyanka Michelle Morochnik*, Kyle Windisch, Amelia Dunn,
Chilukuri, Sasha Singh, Tayler D. Sheahan, Jordan Philip Pikus, Ariel Ben-Ezra, Brian Reed, Mary
G. McCall, Ream Al-Hasani Jeanne Kreek
Activation of kappa opioid receptor Modulation of cocaine administration
potentiates cold sensation by kappa agonists: nalfurafine and
novel pyranopiperazines
Noxious cold sensation is commonly associated
with peripheral neuropathies, however there has In progressive ratio studies in C57BL/6 mice nal-
been limited progress in understanding the mech- furafine causes an increase in progressive ratio
anism of cold pain. Here we investigate the role breakpoint during cocaine self-administration.
of kappa opioid receptor (KOR) in mediating cold In two novel kappa opioid receptor agonists, we
sensation. Wildtype mice (WT) injected with found one had no effect and the other had a trend
U50,488 (U50) (KOR agonist, 5mg/kg i.p) show toward reduction of progressive ratio breakpoint.
significant potentiation in the number of jumps
on the cold plate compared to controls at 3ºC
and NorBNI (KOR antagonist) blocked the U50-
induced nocifensive responses. Peripheral novel
agonist CR845 had a similar effect to U50 on the
cold plate. U50 or CR845 had no effect on rectal
body temperature vs control, suggesting no role
of central thermoregulation. Together, these find-
ings identify a novel role for the peripheral kappa
opioid receptor system in the potentiation of cold
sensation.
Day 3 • July 24th Day 3 • July 24th
Session #5, Talk #1 Session #5, Talk #2
Kappa Kappa
11: 0 0 a m – 11:10 a m 11:10 a m – 11: 2 0 a m
30INRC Program Book 2020 • Back to schedule
Alexander French Sarah C. Simmons
Postdoctoral Researcher Postdoctoral Researcher
Alexander R. French*, Q. Hawk Royer, Anna M. Sarah C. Simmons*, Ryan D. Shepard, Shawn
Gutridge and Richard M. van Rijn Gouty, Ludovic D. Langlois, Brian M. Cox and
Fereshteh S. Nugent
Effects of biased agonism at the
kappa opioid receptor on alcohol Early life stress dysregulates kappa
consumption in mice opioid receptor signaling within the
lateral habenula
The roles of kappa opioid receptor (KOR) signal-
ing in regulating stress and reward make it an While there is evidence for direct dynorphin/
attractive target for treating alcohol use disorder kappa opioid receptor (DYN/KOR) regulation
(AUD), but this approach is limited by the dys- of the mesocorticolimbic system, to date there
phoric and sedative side effects of KOR activa- has been little study on KOR regulation of other
tion. Different signaling pathways downstream important stress/mood-related regions such as
of the KOR have been associated with different the lateral habenula (LHb). Here we provide sig-
physiological outcomes, driving the develop- nificant evidence for the presence of a functional
ment of “biased” agonists that preferentially sig- DYN/KOR modulation of LHb activity through both
nal through one pathway or another. This study intrinsic properties and synaptic modulation in
examines the potential of biased agonism to treat discrete populations of LHb neurons identified by
AUD by correlating the pharmacological bias of the presence of the hyperpolarization-activated
different KOR-specific ligands with their effects current (Ih). Secondly, we found that severe early
on voluntary ethanol consumption in mice using life stress dysregulated DYN/KOR signaling down-
a two bottle choice drinking paradigm. stream from receptor signaling which resulted in
blunted responses of LHb neurons to acute KOR
stimulation. To our knowledge, this is the first
study directly assessing the effects of DYN/KOR
signaling on LHb neuronal excitability, and pro-
viding evidence for DYN/KOR dysregulation in the
LHb following severe early life stress.
Day 3 • July 24th Day 3 • July 24th
Session #5, Talk #3 Session #5, Talk #4
Kappa Kappa
11: 2 0 a m – 11: 3 0 a m 11: 3 0 a m – 11: 4 0 a m
31INRC Program Book 2020 • Back to schedule
Susan Ahmedyar Danni Cao
M.S. Candidate Postdoctoral Researcher
Susan Ahmedyar*, Kabirullah Lutfy Chongguang Chen, Danni Cao*, Lan Hsuan Melody
Huang, Lee-Yuan Liu-Chen
The role of dynorphin/kappa-opioid
receptor (DYN-KOR) system in Characterization of knockin mice
stress-mediated affective disorders harboring kappa opioid receptors
and alcohol self-administration in (KOR)-inducible Cre recombinase
mice (KOR-iCre), a better tool for precise
localization of KOR-expressing neu-
In a preliminary study, we evaluated the impact of rons
age and the role of DYN-KOR system in the devel-
opment of negative affective states that occur fol- We generated a knockin mouse line expressing an
lowing repeated variable stress exposure as well inducible Cre in the oprk1 gene (KOR-iCre), cross-
as in alcohol self-administration in female mice. bred with Ai6 mice and induced with tamoxifen
Preprodynorphin null mice and their littermates/ in adulthood to enable expression of ZsGreen in
controls underwent a 10-day repeated variable cytosol of KOR cells. Three-dimensional images of
stress exposure followed by alcohol self-admin- CLARITY-cleared brains will be presented, which
istration in the home cage. Our results revealed display high density of KOR-expressing cells
that endogenous dynorphin plays a significant in the claustrum, dorsal endopiriform nucleus,
role in the development of depression-like behav- basolateral amygdala, prefrontal cortex, nucleus
ior and alcohol self-administration in an age-re- accumbens, substantia innominata and nucleus
lated manner. reunion, similar to distribution of KOR mRNA. The
mouse line also facilitates precise identification
of KOR-expressing cells at the cellular level. This
KOR-iCre line is different from the previous KOR-
Cre mouse line of S. Ross’ lab., in which Cre is
expressed constitutively in KOR cells and thus in
all KOR-lineage cells, not just those expressing
KOR in adulthood. This mouse line will be a valu-
able tool for investigation of KOR.
Day 3 • July 24th Day 3 • July 24th
Session #5, Talk #5 Session #5, Talk #6
Kappa Kappa
11: 4 0 a m – 11: 5 0 a m 11: 5 0 a m – 12 : 0 0 p m
32INRC Program Book 2020 • Back to schedule
Moriah L. Jacobson Valentina Martinez Damonte
Postdoctoral Researcher Postdoctoral Researcher
Moriah L. Jacobson*, Sarah C. Simmons, Valentina Martinez Damonte*, Julie Kauer
Hildegard A. Wulf, Fereshteh S. Nugent, Caroline
A. Browne, Irwin Lucki kORs in the VTA modulate GABAer-
gic synaptic plasticity
Kappa Opioid Receptor Desensitiza-
tion is Required for the Protracted We have previously identified kORs as key players
Antidepressant Effects of Ketamine in stress-induced alterations in VTA synaptic plas-
ticity since a single acute exposure to cold-water
We hypothesized that the kappa opioid recep- swim stress blocks a form of potentiation of inhib-
tor (KOR) system is necessary for ketamine to itory postsynaptic currents (LTPGABA) on VTA
exert its rapid and sustained antidepressant dopaminergic cells due to a persistent, ligand-in-
activity. Our data demonstrate that 1) ketamine dependent constitutive activation of kappa opioid
pretreatment prevents behavioral and electro- receptors.
physiological responses caused by subsequent Both dopaminergic and non-dopaminergic cells in
KOR activation, and 2) these responses in mice the VTA receive dynorphin inputs from different
are prevented by prior KOR blockade. These stud- brain regions. Here, using a conditional knock out
ies provide evidence that ketamine reduces KOR approach we selectively deleted kORs in dopami-
signaling which may contribute to the protracted nergic neurons and found that this deletion did
clinical antidepressant effects of ketamine. not prevent stress-induced block of LTPGABA. We
have also begun to identify the specific GABAergic
pathways to the VTA that exhibit this form of
LTPGABA using optogenetics.
Our work contributes to the understanding of the
effects of endogenous opioids within the VTA as
well as the relevance of GABAergic modulation
of the reward pathways.
Day 3 • July 24th Day 3 • July 24th
Session #5, Talk #7 Session #5, Talk #8
Kappa Kappa
12 : 0 0 p m – 12 :10 p m 12 :10 p m – 12 : 2 0 p m
33INRC Program Book 2020 • Back to schedule
Courtney A. Bouchet Bryan Sears
Graduate Student Graduate Student
Courtney A. Bouchet*, Katherine L. Suchland, Bryan Sears*, Emily Jutkiewicz
Susan L. Ingram
Differential effects of persistent Potential Involvement of Peripheral
inflammation on the presynaptic opi- Opioid Receptors In The Develop-
oid and cannabinoid receptors within ment Of Tolerance To Morphine
the ventrolateral periaqueductal gray Tolerance plagues the use of opioid analgesics
but the mechanisms of tolerance are not fully
Opioids and cannabinoids are both used to treat understood. Here, we show the activation of opioid
pain; however, it is not well understand whether receptors in the peripheral nervous system is suf-
these systems function differently after pain. In ficient for inducing tolerance to the antinocicep-
these experiments, we use slice electrophysiol- tive effects of morphine. Further, antagonism of
ogy to determine functional changes in the pre- peripheral opioid receptors with naloxone-methio-
synaptic opioid and cannabinoid systems in the dide attenuates the development of tolerance,
ventrolateral periaqueductal gray, a region of the suggesting the involvement of peripheral opioid
descending pain modulatory pathway, after per- receptors in tolerance development.
sistent inflammation in male and female Sprague
Dawley rats. We find that persistent inflammation
does not appear to effect the function of the pre-
synaptic mu opioid receptor but induces plasticity
in the cannabinoid system, reducing the function
of the cannabinoid 1 receptor.
Day 3 • July 24th Day 3 • July 24th
Session #6, Talk #1 Session #6, Talk #2
Pain Pain
12 : 2 0 p m – 12 : 3 0 p m 12 : 3 0 p m – 12 : 4 0 p m
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