Neurobiology of Disease,
Год журнала:
2024,
Номер
unknown, С. 106758 - 106758
Опубликована: Дек. 1, 2024
Irritable
bowel
syndrome
(IBS)
is
a
functional
disorder
defined
by
recurrent
abdominal
pain,
coupled
with
irregular
habits
and
alterations
in
the
frequency
as
well
consistency
of
stool.
At
present,
IBS
considered
disease
gut-brain
interaction,
an
increasing
number
studies
are
focusing
on
brain-gut
axis.
However,
brain
regions
associated
have
not
been
fully
studied
yet.
In
this
study,
we
utilized
chronic
restraint
stress
(CRS)
model
to
evoke
IBS-like
symptoms
mice,
which
were
accompanied
anxiety-like
behaviors
hyperalgesia.
Through
cFOS
staining,
observed
activation
lateral
periaqueductal
gray
(LPAG)
mice
after
CRS.
By
inhibiting
activity
LPAG
through
tetanus
toxin
or
chemogenetics,
found
that
could
be
relieved,
whereas
chemogenetic
induced
symptoms.
Finally,
classic
analgesic
drug
sufentanil
it
alleviate
CRS-induced
Pharmacological Research,
Год журнала:
2023,
Номер
197, С. 106961 - 106961
Опубликована: Окт. 14, 2023
Drugs
acting
at
the
opioid
receptor
family
are
clinically
used
to
treat
chronic
and
acute
pain,
though
they
represent
second
line
of
treatment
behind
GABA
analogs,
antidepressants
SSRI's.
Within
mu
kappa
commonly
targeted.
However,
activation
has
side
effects
constipation,
tolerance,
dependence,
euphoria,
respiratory
depression;
leads
dysphoria
sedation.
The
have
led
drugs
being
widely
abused
with
great
overdose
risk.
For
these
reasons,
newer
safer
analgesics
in
high
demand.
many
years
a
focus
within
field
was
finding
that
activated
G
protein
pathway
receptor,
without
activating
β-arrestin
pathway,
known
as
biased
agonism.
Recent
advances
shown
this
may
not
be
way
forward
develop
there
is
still
some
promise
receptor.
Here
we
discuss
recent
novel
approaches
including
efficacy
vs
bias
fine-tuning
by
targeting
sub-pockets
orthosteric
site,
explore
works
on
structural
basis
bias,
put
suggestion
Gα
subtype
selectivity
an
exciting
new
area
interest.
British Journal of Pharmacology,
Год журнала:
2023,
Номер
180(18), С. 2341 - 2360
Опубликована: Апрель 3, 2023
Abstract
Background
and
Purpose
The
illicit
use
of
fentanyl‐like
drugs
(fentanyls),
which
are
μ
opioid
receptor
agonists,
the
many
overdose
deaths
that
result,
has
become
a
major
problem.
Fentanyls
very
potent
in
vivo,
leading
to
respiratory
depression
death.
However,
efficacy
possible
signalling
bias
different
fentanyls
is
not
clearly
known.
Here,
we
compared
relative
series
fentanyls.
Experimental
Approach
For
agonist
measurements,
Bioluminescence
Resonance
Energy
Transfer
experiments
were
undertaken
HEK293T
cells
transiently
transfected
with
receptors,
assess
Gi
protein
activation
β‐arrestin
2
recruitment.
Agonist‐induced
cell
surface
loss
was
assessed
using
an
enzyme‐linked
immunosorbent
assay,
whilst
agonist‐induced
G
protein‐coupled
inwardly
rectifying
potassium
channel
current
measured
electrophysiologically
from
rat
locus
coeruleus
slices.
Ligand
poses
determined
silico
molecular
dynamics
simulations.
Key
Results
Relative
reference
ligand
DAMGO,
carfentanil
β‐arrestin‐biased,
whereas
fentanyl,
sufentanil
alfentanil
did
display
bias.
Carfentanil
induced
extensive
loss,
marked
desensitisation
currents
continued
presence
neurones
prevented
by
GRK2/3
inhibitor.
Molecular
simulations
suggested
unique
interactions
orthosteric
site
could
underlie
Conclusions
Implications
β‐arrestin‐biased
drug
at
receptor.
It
uncertain
how
such
influences
vivo
effects
other
British Journal of Pharmacology,
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 11, 2024
Class
A
G
protein‐coupled
receptors
(GPCRs)
continue
to
garner
interest
for
their
essential
roles
in
cell
signalling
and
importance
as
drug
targets.
Although
numerous
drugs
the
clinic
target
these
receptors,
over
60%
GPCRs
remain
unexploited.
Moreover,
adverse
effects
triggered
by
available
unbiased
GPCR
modulators,
limit
use
therapeutic
value.
In
this
context,
elucidation
of
biased
has
opened
up
new
pharmacological
avenues
holding
promise
safer
therapeutics.
Functionally
selective
ligands
favour
receptor
conformations
facilitating
recruitment
specific
effectors
modulation
associated
pathways.
This
review
surveys
current
discovery
landscape
GPCR‐biased
modulators
with
a
focus
on
recent
advances.
Understanding
biological
preferential
coupling
is
at
different
stages
depending
family.
Therefore,
individual
families,
we
present
compilation
functionally
reported
past
few
years.
doing
so,
dissect
relevance,
molecular
determinants
potential
clinical
applications.
Frontiers in Pharmacology,
Год журнала:
2023,
Номер
14
Опубликована: Ноя. 23, 2023
Introduction:
Deaths
due
to
overdose
of
fentanyls
result
primarily
from
depression
respiration.
These
potent
opioids
can
also
produce
muscle
rigidity
in
the
diaphragm
and
chest
muscles,
a
phenomenon
known
as
Wooden
Chest
Syndrome,
which
further
limits
ventilation.
Methods:
We
have
compared
ventilation
by
fentanyl
morphine
directly
measuring
their
ability
induce
using
EMG
recording
external
internal
intercostal
rat
working
heart-brainstem
preparation.
Results:
At
equipotent
bradypnea-inducing
concentrations
produced
greater
increase
expiratory
amplitude
than
all
three
muscles
examined.
In
order
understand
whether
this
effect
was
unique
property
phenylpiperidine
chemical
structure,
or
fentanyl’s
high
agonist
intrinsic
efficacy
its
lipophilicity,
we
variety
agonists
with
different
properties
at
that
were
producing
bradypnea.
carfentanil
alfentanil
(phenylpiperidines
relatively
medium
respectively),
norbuprenorphine
(orvinolmorphinan
lipophilicity)
levorphanol
(morphinan
low
lipophilicity).
Discussion:
observed
that,
higher
more
likely
(i.e.,
rigidity)
lower
efficacy.
Whereas
lipophilicity
structure
did
not
appear
correlate
rigidity.
Journal of Neurophysiology,
Год журнала:
2024,
Номер
132(3), С. 1056 - 1073
Опубликована: Авг. 7, 2024
Acute
fentanyl
exposure
attenuated
the
activity
of
striatal
medium
spiny
neurons
(MSNs)
in
vitro
and
dopamine
D2,
but
not
D1,
receptor-expressing
MSNs
ex
vivo
slices.
By
contrast,
sustained
suppressed
spontaneous
cocultured
with
glia
through
a
nonopioid
receptor-dependent
mechanism
modulated,
part,
by
α
1
-adrenoceptors.
Fentanyl
can
affect
function
via
receptor
action
that
appears
mediated
-adrenoreceptor-expressing
and/or
astroglia.
Current Opinion in Pharmacology,
Год журнала:
2024,
Номер
76, С. 102465 - 102465
Опубликована: Июнь 1, 2024
Ligand
bias
offers
a
novel
means
to
improve
the
therapeutic
profile
of
drugs.
With
regard
G
protein-coupled
receptors
involved
in
analgesia,
it
could
be
advantageous
develop
such
drugs
if
analgesic
effect
is
mediated
by
different
cellular
signalling
pathway
than
adverse
effects
associated
with
drug.
Whilst
this
has
been
explored
over
number
years
for
μ
receptor,
remains
unclear
whether
approach
significant
benefit
treatment
pain.
Nevertheless,
development
biased
ligands
at
other
CNS
does
offer
some
promise
future.
Here
we
summarise
and
discuss
recent
evidence
support
this.
