Brain Research Bulletin 200 (2023) 110691

Contents lists available at ScienceDirect

Brain Research Bulletin

journal homepage: www.elsevier.com/locate/brainresbull

Review

Role of GABAergic system in the comorbidity of pain and depression

Siqi Yang a, 1, Bingyuan Zhang b, 1, Di Wang a, Suwan Hu a, Wenli Wang a, Cunming Liu a,
Zifeng Wu a, *, Chun Yang a, *
a
Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029. China
b
Department of Anesthesiology, Taizhou People’s Hospital Affiliated to Nanjing Medical University, No. 399 Hailing South Road, Taizhou City 225300, Jiangsu
Province, China

A R T I C L E I N F O A B S T R A C T

Keywords: Patients with chronic pain often suffer with depressive symptoms, and these two conditions can be aggravated by
Chronic pain each other over time, leading to an increase in symptom intensity and duration. The comorbidity of pain and
Depression depression poses a significant challenge to human health and quality of life, as it is often difficult to diagnose
Comorbidity
early and treat effectively. Therefore, exploring the molecular mechanisms underlying the comorbidity of
GABAergic system
Treatment
chronic pain and depression is crucial to identifying new therapeutic targets for treatment. However, under­
standing the pathogenesis of comorbidity requires examining interactions among multiple factors, which calls for
an integrative perspective. While several studies have explored the role of the GABAergic system in pain and
depression, fewer have examined its interactions with other systems involved in their comorbidity. Here, we
review the evidence that the role of GABAergic system in the comorbidity of chronic pain and depression, as well
as the interactions between the GABAergic system and other secondary systems involved in pain and depression
comorbidity, providing a comprehensive understanding of their intricate interplay.

1. Introduction ranging from 5 % to 25 % (Smith, 2014). Unfortunately, the precise

Chronic pain is defined as pain that persists or recurs for more than 3
months, with a global incidence of approximately 20 %− 25 %
(Lopez-Gonzalez et al., 2017). It can manifest in various forms such as
neuropathic, cancer-related and inflammatory pain. Chronic pain not
only limits daily activities but also leads to anxiety, anger, frustration or
depression and even self-harming behaviors, all of which can signifi­
cantly affect the quality of life and hinder socio-economic development.
Currently, the pathogenesis of chronic pain remains elusive. Although a
large number of therapies are emerging in this field, including opioid
and non-steroidal anti-inflammatory drugs (NSAIDs), nerve blocks and
destruction, acupuncture, physiotherapy, and psychotherapy (Cohen
et al., 2021; McCracken et al., 2022), their therapeutic efficacy remains
inadequate. Additionally, many patients are troubled by the side effects
of drug treatment.
Depression mainly manifests as low mood, anhedonia and low en­
ergy levels, cognitive impairment, sleep disturbances and so on. Ac­
cording to the World Health Organization (WHO), approximately 350
million people have suffered from depression with incidence rates
molecular mechanisms underlying depression remain unclear, and
treatment options are often inadequate. In fact, over one-third of pa­
tients with depression fail to achieve symptom remission after treatment
(Rush et al., 2022). Intriguingly, the presence of comorbidities, partic­
ularly somatic symptom disorders with predominant pain, can highly
increase the difficulty in treating depression.
Chronic pain and major depression commonly occur together. Up to
61 % of individuals with chronic pain suffer from depression (Hooten,
2016), while the prevalence of chronic pain is approximately 51.8–59.1
% in patients with depression (Doan et al., 2015). Adjuvant therapy with
antidepressants has been shown to improve the management of re­
fractory chronic pain, based on clinical guidelines and experience. Some
depressed patients often present unexplained pain symptoms that lead to
a higher medical burden. Thus, it is important to explore the molecular
and therapeutic mechanisms underlying the comorbidity of chronic pain
and depression. This will help to develop better treatment strategies for
patients suffering from both conditions.
The GABAergic (gamma-aminobutyric acid) system is a major
inhibitory system in the brain. Its main neurotransmitter, GABA, binds

* Corresponding authors.
E-mail addresses: zifengwu57@126.com (Z. Wu), chunyang@njmu.edu.cn (C. Yang).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.brainresbull.2023.110691
Received 13 April 2023; Received in revised form 23 May 2023; Accepted 16 June 2023
Available online 17 June 2023
0361-9230/© 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
S. Yang et al.
to GABAergic receptors on inhibitory neurons, leading to a decrease in
neural activity and an overall reduction in excitability in the central
nervous system (CNS). With over 20 % of all brain neurons being
GABAergic, the importance of it cannot be overstated (Sahara et al.,
2012). However, disruptions in the GABAergic system can lead to
various diseases, including depression and chronic pain. The comor­
bidity of depression and chronic pain is a complex condition that re­
quires further investigation. While it is known that both conditions
involve changes in the GABAergic system. Moreover, alterations in
GABAergic system may affect other neurotransmitter systems. There­
fore, understanding the interactions between the GABAergic system and
other secondary systems may provide important insights into these
comorbidities, and could ultimately lead to more effective treatments.
2. The comorbidity of chronic pain and depression
2.1. Pre-clinical studies
Animal models are important tools for investigating and mimicking
the co-morbid mechanisms of chronic pain and depression. Numerous
pre-clinical studies have revealed a correlation between chronic pain
and depression. Chronic pain can induce depressive-like behaviors, as
observed in a Complete Freund’s adjuvant (CFA)-induced inflammatory
pain model where rodents showed lower sucrose preference in the su­
crose preference test (SPT) and longer immobility time in the forced
swim test (FST) (Burek et al., 2022). Likewise, depressive-like behaviors
have been observed in animals with neuropathic pain models. Based on
a sciatic nerve ligation (SNL) paradigm, the FST immobility time was
significantly prolonged for 15–30 days following the surgery in mice
(Suzuki et al., 2007). In addition, SNL rats exhibited a decreased
climbing time from 2 to 3 weeks following surgery and a persistently
lower score in SPT from 1 to 5 weeks following surgery (Hu et al., 2017).
In the case of sciatic nerve injury (SNI) model, both rats and mice
exhibited an increased FST immobility time and a reduced score of SPT
(Liu et al., 2022; Wang et al., 2011). In chronic constriction injury (CCI)
model, Li et al. found prolonged FST immobility time in rats (Li et al.,
2019).
Meanwhile, depression can also affect pain-related behaviors.
Increasing evidence suggests that depressive-like symptoms enhance
pain behaviors. It has been reported that chronic restraint stress (CRS)
leads to depressive-like behaviors in both male and female mice,
accompanied by a reduction in mechanical nociception threshold, but
only male mice showed thermal hypersensitivity (Yin et al., 2020). In
addition, chronic social stress-induced anhedonic behavior exacerbated
mechanical allodynia and thermal hyperalgesia in CFA models (Kim
et al., 2012). Moreover, depression enhanced some sensory perceptions
of pain, including cold allodynia, but did not affect the mechanical
threshold in a rat model combining CCI with unpredictable chronic mild
stress (Bravo et al., 2012). Recently, Sun et al. showed that chronic
unpredicted stress delayed postoperative pain recovery with prolonged
hypersensitivity to mechanical and cold stimuli (Sun et al., 2023).
Altogether, these findings suggest that chronic pain and depression
symptoms not only coexist but also interact with each other.
2.2. Clinical studies
Epidemiological studies have reported that an average of 50 % of
pain patients suffer from depressive symptoms(Hooten, 2016). Clinical
studies have demonstrated that among those with chronic pain,
depression is more common than other mental illnesses. Additionally, a
change in depression severity was a powerful predictor of pain severity.
(Kroenke et al., 2011). Another follow-up study also revealed a rela­
tionship between the degree of depression and chronic pain, with in­
dividuals experiencing major depression being four times more likely to
experience neck or low back pain than those with mild depression
(Carroll et al., 2004).
2
Brain Research Bulletin 200 (2023) 110691
Genetic studies have identified common genes associated with both
chronic pain and depression (Humo et al., 2019; Pinheiro et al., 2018).
Polymorphisms in candidate genes involved in 5-hydroxytryptaminergic
and catecholaminergic systems, such as 5-HTTLRR and COMT genes,
have been strongly linked to the occurrence and susceptibility of both
diseases (Horjales-Araujo et al., 2013; Tour et al., 2017; Treister et al.,
2011; Wang et al., 2016; Willeit et al., 2003; Zubieta et al., 2003).
Chronic pain and depression are also regulated by
immune-inflammatory mechanisms, with inflammatory cytokines like
tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6
(IL-6) (Lopes et al., 2020). In addition, abnormal changes in functional
magnetic resonance imaging (fMRI) signals of the anterior cingulate
cortex (ACC) and prefrontal cortex (PFC), which are responsible for
processing emotional and cognitive information, have been observed in
patients with chronic pain (Kummer et al., 2020a; Zheng et al., 2022).
Notably, treatments commonly used to alleviate depression, such as
antidepressants and cognitive-behavioral therapy, have also been found
to be effective in improving pain symptoms (Li et al., 2018a,b;
McCracken et al., 2022). Taken together, the aforementioned clinical
studies support a strong link between chronic pain and depression.
3. The GABAergic system
3.1. GABA
GABA acts as the major inhibitory mediator in the brain, modulating
various local neurotransmitter systems, particularly the glutamatergic
systems. It is synthesized from glutamate through glutamate decarbox­
ylase enzymes (GAD65 and GAD67) and stored in vesicles by the ve­
sicular GABA transporter. The GABAergic signal ceases upon rapid
uptake of GABA into glial cells and presynaptic neurons via plasma
membrane GABA transporters (Fogaça and Duman, 2019).
3.2. GABAergic neurons in the brain
GABAergic neurons comprise both projection neurons and in­
terneurons. GABA neurons are widely distributed throughout the CNS,
especially abundant in the cerebral cortex and spinal cord (Ascoli et al.,
2008). Additionally, they are concentrated in subcortical structures such
as the hippocampus, midbrain, and thalamus (Galarreta and Hestrin,
2001; Koob, 1992; Pelkey et al., 2017). Even though GABAergic in­
terneurons make up a relatively small proportion of the total number of
neurons in the brain, they are critical for generating inhibitory inputs
over other neurons. GABA interneurons can be classified into 20
different subtypes based on different molecular markers, mainly
including parvalbumin (PV), somatostatin (SST), and the 5-hydroxytryp­
tamine 3 A receptor (5HT3AR) interneurons (Engin et al., 2018). In the
cerebral cortex, PV neurons make up approximately 40 % of GABAergic
neurons, while SST neurons represent approximately 30 % of GABAergic
neurons; 5HT3AR neurons account for 30 % of GABAergic neurons
(Rudy et al., 2011).
3.3. GABA receptors in the brain
The responses to GABA are mediated via metabotropic GABAb re­
ceptors (G protein-coupled receptors) and ionotropic GABAa and GABAc
receptors (ligand-gated ion channels). Of these, GABAa receptors
mediate the majority of fast synaptic inhibition. Among the mammalian
ligand-gated ion channels, the GABAa receptor is composed of 5 protein
subunits and at least 19 distinct subunit isoforms (α1–6, β1–3, γ1–3, δ, ε,
θ, π, and ρ1–3), mediating different behavioral and pharmacological
responses. The most abundant and widely distributed GABAa receptor in
the brain consists of two α1 subunits, two β2 subunits, and a single γ2
subunit (Olsen and Sieghart, 2008). GABAc receptors share structural
and functional similarities with GABAa receptors, but little research has
been done on them to date. GABAb receptors are expressed both on the
S. Yang et al.
presynaptic and postsynaptic terminals where they can inhibit neuro­
transmitter release and cause cell membrane hyperpolarization sepa­
rately (Colmers and Bains, 2018). Among them, GABAa receptors are
tightly linked to depression and pain. It has been shown that deleting or
mutating the γ2 subunit of GABAa receptors leads to depressive be­
haviors (Smith and Rudolph, 2012). Similarly, the results of fMRI in rats
revealed that the GABAa agonist reduced the activity levels in brain
regions linked to sensory and associative-emotional aspects of pain,
including the medial thalamus, contralateral primary sensory cortex,
cingulate cortex, frontal association cortex, and limbic system (Knabl
et al., 2008).
3.4. GABA modulators
The GABAa receptor contains binding sites not only for the agonist
(GABA) but also for modulators such as benzodiazepines (BZs), barbi­
turates, neurosteroids and ethanol (Atack et al., 2007). Among those
GABA modulators, the BZs and neurosteroids are contributed to the
development of depression and pain. Previous clinical trials have shown
that the benzodiazepines provide antidepressant effects comparable to
conventional antidepressants in patients with major depressive disor­
ders (Amsterdam et al., 1994; Petty et al., 1995). While the BZs are
generally not regarded as analgesics, a preclinical study showed that
midazolam reduced C-fiber-mediated activity in the SNL rats (Kontinen
and Dickenson, 2000). Another study found that continuous midazolam
infusion prevented thermal hyperalgesia in CCI rats (Shih et al., 2008).
Moreover, allopregnanolone, an endogenous progesterone metabolite,
acts as a potent positive allosteric modulator of synaptic and extra­
synaptic GABAa receptors. Clinical studies have indicated that brex­
anolone, an intravenous formulation of allopregnanolone, is effective in
improving symptoms of postpartum depression (Meltzer-Brody et al.,
2018). In addition, it was shown to be effective in relieving pain and
reducing intravenous morphine consumption in patients orally admin­
istered with alphadolone (Goodchild et al., 2001). Overall, the above
pharmacological studies have further highlighted the role of GABAergic
neurotransmission in depression and pain.
3.5. GABAergic projections in the brain
The GABAergic projections are widely distributed throughout the
CNS. A diversity of GABAergic interneurons can produce GABAergic
inhibition, not only via local pathways, but also through regional net­
works. For instance, most cortical GABAergic neurons target nearby
cells and regulate the activity of local networks. However, a significant
number of cortical GABAergic neurons also project to other brain areas
such as the hippocampus, septum, amygdala and basal ganglia (Trem­
blay et al., 2016). In this review, we focus on GABAergic projections
related to pain and depression. As for local projection pathways,
GABAergic local circuits play a vital role in affective pain processing
within the prefrontal cortex (Kummer et al., 2020b). And increased PV
interneuron excitability and reduced SST interneuron excitability were
found in the mPFC of painful mice (Jones and Sheets, 2020). In addition,
it has been found that chronic stress could affect the function of hip­
pocampal GABAergic networks (Czéh et al., 2015). As for inter-regional
projection pathways, a considerable body of evidence implicates the
importance of inter-regional GABAergic projections in depression and
pain. For example, the central amygdala sends GABAergic projections to
the parafascicular nucleus, which controls comorbid pain in depression
(Zhu et al., 2019). Moreover, our recent study indicates that lateral
septum GABAergic projection to the lateral hypothalamus plays an
important role in pain and anxiety comorbidities (Wang et al., 2023). Of
note, optogenetics and chemogenetics have become the key methods for
testing the cell-specific tracing of connectivity and cell-specific tools for
GABAergic circuits.
In summary, once the GABAergic system in the CNS is disrupted,
pathological states such as chronic pain and depression may occur.
3
Brain Research Bulletin 200 (2023) 110691
Consequently, exploring the role of the GABAergic system in the co­
morbidity of chronic pain and depression is essential to reveal the
pathological linkage between each other, and also provide new strate­
gies and ideas for treatment in clinic.
4. The potential role of GABAergic systems in pain and
depression by interacting with secondary systems
4.1. The 5-hydroxytryptaminergic and noradrenergic systems
The 5-hydroxytryptaminergic system consists of 5-HT (5-hydroxy­
tryptamine), 5-HT receptors and 5-HT neurons. The 5-HT neurons can
synthesize and release the important neurotransmitter 5-HT (Okaty
et al., 2019). Then, the released 5-HT acts on its downstream targets
through multiple 5-HT receptors (5-HTRs). Studies have shown that the
5-HT system plays a critical role in chronic pain and depression. In an
inflammatory pain model, rats exhibited depression-like behavior along
with reduced levels of 5-HT in vivo (Zhang et al., 2016a,b). Similarly, in
another chronic migraine model, rats exhibited depression-like behavior
with decreased levels of 5-HT in the prefrontal cortex (Zhang et al.,
2017). Furthermore, mice lacking central 5-HT neurons have increased
inflammatory pain and an impaired analgesic response to antidepres­
sants (Zhao et al., 2007). The selective 5-HT reuptake inhibitors (SSRIs),
which block 5-HT reuptake transporter and increase 5-HT signaling, are
widely accepted as the first-line treatment for depression. Meanwhile,
5-HT influences endogenous analgesic processes through descending
inhibitory pain pathways in the brain and the spinal cord (Liu et al.,
2020), suggesting that SSRIs may also have therapeutic effects on
chronic pain (Haleem, 2018). Overall, the above studies demonstrate
that the 5-HT system plays a vital role in the comorbidity of chronic pain
and depression.
The interaction between the 5-HT system and the GABAergic system
plays an important role in regulating chronic pain and depression. It has
been shown that the activation of 5-HT3 receptors could increase spinal
GABA release from the spinal dorsal horn and reduce nociceptive
hyperalgesia in SNL rats (Hayashida et al., 2012). In addition, activating
5-HT1A heteroreceptors can inhibit the activity of GABA neurons in the
ventral tegmental area (VTA) to produce anti-depressant effects (Kim
et al., 2021; Wang et al., 2021). The GABAergic system also plays a role
in the antidepressant effects of SSRIs, as knocking out the γ2 subunit of
the GABA receptor in mice led to diminished antidepressant-like effects
of SSRIs (Shen et al., 2010). As mentioned previously, SSRIs have
therapeutic effects both on pain and depression. Fluoxetine, a repre­
sentative antidepressant (SSRIs), attenuates nociceptive hyperalgesia
via the activation of 5-HT2A receptors and GABAa receptors (Dupuis
et al., 2017). Furthermore, a neural circuit study indicated that chronic
pain probably leads to disinhibition of the 5-HT projections from the
DRN to somatostatin (SOM) interneurons in the amygdala (CeA), and
the resulting enhanced activity of lateral habenula (LHb) neurons then
induced depressive symptoms. Activating the 5-HTDRN→SOMCeA
pathway could reduce depression-like behavior in these painful mice
(Zhou et al., 2019). Previous neuroimaging studies have also revealed
the role of 5-HT and GABA in pain and depression (Loggia et al., 2014;
Ritter et al., 2022). Additionally, a clinical neuroimaging study indi­
cated that SSRIs have downstream impacts on GABA neurotransmission
(Spurny et al., 2021). Future studies on neural circuits and neuroimage
could further elucidate the role of the GABAergic system interacting
with 5-HT system in the comorbidity of depression and pain.
The noradrenergic system is also associated with chronic pain and
depression. The functions of norepinephrine (NE) are mediated by α-and
β-adrenergic receptors, which are widely expressed in the central and
peripheral nervous systems. The post-synaptic alpha2-adrenoreceptors
(α2-ARs) have received considerable attention as they mediate the
regulation of sedation, memory, analgesia and neurogenesis.(Bravo
et al., 2019; Langer, 2015; Muguruza et al., 2013). However, the role of
α2-ARs in depression is still controversial (Landau et al., 2015; Wang
S. Yang et al.
et al., 2017; Yu et al., 2019). There is evidence to suggest that chronic
pain can exacerbate changes in LC-noradrenergic transmission associ­
ated with depression (Bravo et al., 2013; Bravo et al., 2014). Impor­
tantly, the selective norepinephrine reuptake inhibitors produce
antinociceptive hyperalgesia and antidepressant-like effects in rodents.
And clinical studies have also demonstrated that
serotonin-norepinephrine reuptake inhibitors can improve symptoms of
chronic pain and depression (Belinskaia et al., 2019; Obata, 2017).
Overall, research suggests that the noradrenergic system may be a po­
tential target for treating co-morbid chronic pain and depression.
The GABAergic system interacts with the noradrenergic system to
regulate chronic pain and depression. Oral administration of GABA has
been found to improve depressive symptoms and restore NE and 5-HT
levels in the hippocampus of rats (Chuang et al., 2011). The GABAer­
gic system may also be related to α2-AR-mediated neuropathic pain in
CNS. It has been reported that NE reduces nociceptive hypersensitivity
through the activation of α2-AR in SNI rats. Correspondingly, GABAa
receptor agonist enhances the inhibitory effect of α2-agonist colistin on
the nociceptive hypersensitivity, while GABAa receptor antagonist at­
tenuates the inhibitory effect of clonidine (Zhu et al., 2013). The NE
induces an increase in spiking in CRH neurons that is greatly dependent
on glutamate receptor activation and restrained by GABAa receptor
activation. Furthermore, the effects of NE on synaptic activity have
different concentration sensitivities. Low concentrations of NE activates
presynaptic α2-AR and inhibit GABA release; high concentrations of NE
also activates α1-AR to stimulate spiking in presynaptic GABA neurons
and increases the spike-dependent GABA release in CRH neurons of the
hypothalamic paraventricular nucleus (PVN) (Chen et al., 2019).
Additionally, α2-AR activation stimulates the release of GABA from as­
trocytes via Giβγ subunit-related signaling pathway (Gaidin et al.,
2020). Therefore, the various effects of NE on chronic pain and
depression are most likely due to the difference in concentration and its
effects on GABA.
In summary, since the GABA system interacts with 5-HT and NE
systems, which play a significant role in the development of chronic pain
and depression, further exploration of common neural circuits and drug
targets of GABAergic and monoaminergic systems may help to
compensate for the limitations of traditional monoamines.
4.2. Glutamate system
Glutamate (Glu) is an excitatory neurotransmitter that mediates
excitatory synaptic transmission in the CNS. Glu triggers signaling
through two classes of receptors: ionotropic and metabotropic glutamate
receptors. This review focuses on the former, including N-Methyl-D-
aspartic (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic
acid (AMPA), and kainate (KA) receptors (Li et al., 2016). Both animal
and human studies have found that reduced Glu concentrations in the
brain are associated with pain and depression (Moriguchi et al., 2019;
Thompson and Neugebauer, 2019). Glutamate modulators, which act on
glutamate receptors, are also associated with dysfunction in brain re­
gions linked to the development and maintenance of chronic pain and
depression. Among them, acetyl L-carnitine (ALCAR) and ketamine are
the most representative. ALCAR regulates glutamate biosynthesis and
release (Wang et al., 2014), which can rapidly relieve chronic neuro­
pathic pain and depression (Freo et al., 2021). Ketamine is a
non-selective NMDA receptor antagonist. A single sub-anesthetic dose of
ketamine (0.5 mg/kg) has been shown to relieve postoperative depres­
sion and pain (Schwenk et al., 2018). Our previous study also found a
significant ameliorative effect of ketamine on chronic pain-related
anhedonia (the core symptom of depression) (Fang et al., 2019). The
above studies corroborate that the glutamatergic system plays a vital
role in chronic pain and depression.
The Glu-Gln-GABA circle between neurons and astrocytes is
responsible for maintaining the homeostasis of excitatory and inhibitory
neurotransmission (Duman et al., 2019). The decrease of GABAergic
4
Brain Research Bulletin 200 (2023) 110691
inhibition may temporarily induce neuronal over-excitation and exci­
totoxicity, which leads to reduced excitatory synaptic structures and Glu
release, as well as hypoplastic dendrites (Workman et al., 2018). It is
well established that an imbalance between excitation and inhibition in
brain networks is one of the mechanisms that lead to chronic pain and
neuropsychiatric disorders (Leonardon et al., 2022; Sohal and Ruben­
stein, 2019; Tatti et al., 2017; Thu Ha and Gardier, 2019). Local
GABAergic activity may contribute to the development of pain and
depression. Currently, the mainstream view is that ketamine exerts an­
tidepressant effects via the inhibition of GABAergic interneurons in the
mPFC is sufficient and necessary for rapid antidepressant responses, and
its antidepressant actions are blocked by GluN2B-NMDAR knockdown
on GABA interneurons (Fogaca et al., 2021; Gerhard et al., 2020).
Likewise, excessive activation of NMDA receptors in the ACC leads to
excitotoxicity and central sensitization, resulting in chronic pain(Zhuo,
2016). It is also implicated that ketamine produces analgesic effects by
blocking NMDA receptors. Another study has indicated (Leonardon
et al., 2022) that the modulation of GABAergic synaptic transmission via
NMDA receptors activation in the dorsal horn of the spinal cord is
involved in the development of neuropathic pain. Moreover, several
neuroimaging studies provide evidence for the altered brain levels of
combined glutamate and glutamine (Glx) and GABA in the cortex are
related to chronic pain and depression (Ritter et al., 2022; Zunhammer
et al., 2016). Furthermore, inter-regional projections between Glu and
GABA are associated with pain and depression. It has been shown that
the pathway from the parafascicular thalamic nucleus (PFGlu) to ACC
GABA-containing neurons to glutamatergic neurons (ACCGABA→Glu)
mediates allodynia associated with depression-like behaviors (Zhu et al.,
2021). In conclusion, disruption of the GABAergic system interferes with
the glutamate system and causes E/I imbalance, finally leading to
chronic pain and depression.
4.3. Neuroplasticity and BDNF
Neuroplasticity is the ability of the brain to adapt to internal and
external stimuli through enhancing or weakening of synapses. Brain-
derived neurotrophic factor (BDNF) is essential for the growth of neu­
rons, synapse formation and synaptic plasticity (Castren and Monteggia,
2021; Notaras and van den Buuse, 2020). Studies have shown that
BDNF-TrkB signaling in the hippocampus and prefrontal cortex is crucial
in the pathogenesis of depression (Infantino et al., 2022; Zhang et al.,
2016a,b). BDNF is also involved in the development of inflammatory
and neuropathic pain and plays a crucial role in the transition from acute
to chronic pain (Sikandar et al., 2018). It is worth noting that BDNF has
distinct roles in pain regulation in different regions. Both BDNF and its
receptors are upregulated in the spinal dorsal horn (SDH) under chronic
pain conditions (Cao et al., 2020). In contrast, hippocampal and pre­
frontal levels of BDNF are decreased in chronic pain, and circuit-specific
upregulation of BDNF in the ventral hippocampal CA1-infralimbic cor­
tex reduces spontaneous pain and promotes the recovery from inflam­
matory pain (Ma et al., 2019). In addition, patients carrying the BDNF
Val66Met allele are associated with a higher risk of postoperative pain
and depressive episodes (Harrisberger et al., 2015; Tian et al., 2018).
The GABAergic system interacts with the BDNF-TrkB signaling
pathway. Endogenous GABA activates GABAb receptors and increases L-
type calcium channel activity, which in turn activates phosphatidyli­
nositol 3-kinases (PI3K) and mTORC1, promoting the translation of
BDNF mRNA and increasing synapse formation (Workman et al., 2015;
Workman et al., 2013). In a model of chronic mild stress-induced
depression-like behavior in susceptible rats, abnormalities in GABA
and Glu release on the presynaptic membrane, together with BDNF
mRNA trafficking in dendrites and dendritic morphology in the hippo­
campus (Tornese et al., 2019). Interestingly, SST interneuron knockout
mice exhibit increased anxiety and depression-like behaviors accom­
panied by reduced BDNF gene expression in the cingulate cortex (Lin
and Sibille, 2015). BDNF knockout or deletion mice produce
S. Yang et al.
depression-like behaviors accompanied by reduced SST interneuron
gene expression in the cingulate cortex (Tripp et al., 2012). As with
previous studies by Guilloux et al., the SST interneurons are closely
related to BDNF. After a peripheral nervous injury (PNI), the synaptic
numbers of GABAa receptors were reduced in the SDH, leading to BDNF
release through the activation of microglia. However, the neural injury
is accompanied by BDNF-TrkB-mediated upregulation of synaptic
GABAa receptors and a shift in GABAa subunit (Lorenzo et al., 2020).
Similarly, the involvement of BDNF-trkB signaling on altered GABAa
receptors after nerve injury has also been demonstrated to be correlated
with neuropathic pain in another study (Chen et al., 2014). In conclu­
sion, GABA interacts with BDNF, a key factor affecting neuroplasticity,
which is involved in the onset and development of chronic pain and
depression.
4.4. Stress and the HPA axis
Chronic pain and depression may be exacerbated by stress (Edwards
et al., 2016). The hypothalamic-pituitary-adrenal (HPA) axis mediates
the neuroendocrine stress response. Chronic social defeat stress (CSDS)
is a well-known pre-clinical paradigm for developing stress-induced
depression models (Gururajan et al., 2019). Chronic stress induces
decreased expression of glucocorticoid receptor (GR) in the mPFC of
mice and elicits depression-like behavior (Lu et al., 2022). GR antago­
nists prevent behavioral despair and cognitive impairment in mice after
chronic stress (Horchar and Wohleb, 2019). The HPA axis is involved in
stress-activated pain pathways leading to chronic hyperalgesia. GR re­
ceptors are widely distributed in nociceptive neurons and fibers, as well
as glial cells. The glucocorticoids can stabilize neuronal cell membranes
through neuromodulation and inhibit abnormal firing of neurons and
nerve fibers. Therefore, systemic or topical glucocorticoid treatment is
commonly used to relieve chronic pain (Conaghan et al., 2019; McEwen
and Kalia, 2010). Moreover, serum levels of adrenocorticotropic hor­
mone (ACTH) and corticosterone are elevated in a SNL model (Bruening
et al., 2015). The above studies suggest the role of stress in chronic pain
and depression co-morbidity through activation of the HPA axis. Of
note, the HPA axis mediating neuroendocrine responses is tightly
regulated by the GABAergic nervous system.
Dysfunction of the GABAergic system causes dysregulation of the
HPA axis, stress response and altered neurosteroid signaling, leading to
chronic pain and depression. Stress or stress hormones are capable of
affecting GABAergic system function. The effects of stress on GABA re­
ceptors may be affected by a variety of factors, including the types of
stressors, intensity and duration of stress exposure (Fogaca and Duman,
2019; Fuchs et al., 2017). Chronic stress reduces the GR of PV neurons
and impairs the ability of glucocorticoids to inhibit PV neurons, leading
to an increase in inhibitory neurotransmission and triggering an E/I
imbalance (McKlveen et al., 2016), which is related to the comorbidity
of chronic pain and depression (as previously described). CRH is asso­
ciated with behavioral and emotional responses to stress, and it is
well-known as a biomarker for depression (Gold, 2015). CRH reduced
inhibitory GABAergic synaptic transmission onto LHb neurons and the
increased activity of the LHb is involved in depression (Authement et al.,
2018). In addition, a neural circuit study suggests that the CeA → lateral
parabrachial (LPB) pathway plays a significant role in chronic pain, and
a population of neurons in this pathway express CRH (Raver et al.,
2020). Moreover, CORT can enter the CNS and be further metabolized to
neuroactive 3α5α-reduced steroids, which specifically enhance
GABAergic synaptic transmission and alleviate hyperalgesia and allo­
dynia (Zell et al., 2015). Recent clinical studies have found that several
neurosteroids acting on GABAa receptors can effectively alleviate
chronic pain and ameliorate depression (Cerne et al., 2022; Naylor et al.,
2020), further supporting the involvement of GABA system in the
regulation of the neuroendocrine and its important role in co-morbid
chronic pain and depression.
5
Brain Research Bulletin 200 (2023) 110691
4.5. Immune-inflammatory pathways
The high comorbidity of chronic pain and depression occurs when
the body is in a chronic state of inflammation, suggesting that immune-
inflammatory pathways are associated with the mechanisms for this
comorbidity. Infection, nerve injury or immunotherapy triggers a cyto­
kine storm that allows the widespread release of pro-inflammatory cy­
tokines, such as TNF-α, IL-1, IL-6, IL-17 and IL-23, which stimulate other
cytokines in pain-related pathways that induce and modulate neuro­
pathic pain by promoting peripheral and central sensitization (Duan
et al., 2022; Gupta et al., 2020; Luo et al., 2019; Luo et al., 2021). Be­
sides, these changes have long-term implications for synaptic plasticity,
which in turn transforms into persistent neuropathic pain (Ellis and
Bennett, 2013). Likewise, pro-inflammatory cytokines are also closely
associated with the development of depression. A growing body of ev­
idence from animal experiments and clinical trials points out that the
high expression of TNF-α, IL-1, IL-6, IL-17 and IL-23, may induce
depression (Cheng et al., 2018; Das et al., 2021; Lee et al., 2021; Li et al.,
2018a,b; Li et al., 2017; Luo et al., 2019). Antidepressants may alleviate
depression-like behaviors induced by inflammatory stress in the pe­
ripheral and central nervous systems (Ramirez and Sheridan, 2016).
Intriguingly, in patients with refractory depression, the adjunction of
anti-inflammatory medications can alleviate depressive symptoms
(Avari et al., 2020). Notably, pro-inflammatory cytokines can reduce the
synthesis and release of 5-HT and NE by activating indoleamine-2,
3-dioxygenase (IDO) (Roman and Irwin, 2020). Consequently, immune
and inflammatory mechanisms not only influence the development of
chronic pain and depression, but also interact with the monoamine
system to participate in the co-morbid mechanisms.
The GABAergic system is involved in the regulation of inflammation
in chronic pain and depression. GABAergic signaling pathways are
affected through the disturbance of chloride homeostasis, which is
involved in the development of neurological and psychiatric disorders.
In pathological conditions, the ratio of NKCC1 to KCC2 returns to an
immature state, thus increasing the excitation of GABAergic trans­
mission and decreasing its inhibitory influence (Medina et al., 2014).
Notably, inflammation can exacerbate this shift, disrupting the
NKCC1/KCC2 ratio (Li et al., 2010). The NKCC1-specific antagonist
bumetanide produces antidepressant-like effects in mice (Goubert et al.,
2019). The sodium-potassium-chloride cotransporter of GABA neurons
is also implicated in the pathogenesis of chronic pain. In a chronic in­
flammatory pain model, peripheral inflammation induces
down-regulation of KCC2 in the medullary dorsal horn (Wu et al., 2009).
Additionally, antagonists of NKCC1 or KCC2 play an important role in
the development of pain (Walker et al., 2014). Taken together, inflam­
mation may affect the GABAergic system by exacerbating the disruption
of the NKCC1/KCC2 ratio, which is involved in pain and depression. A
recent study showed that the shift from acute injury-related pain to
nociplastic pain is initiated by spinal microglia through the process of
neuroinflammation, while GABAergic disinhibition induced by periph­
eral injury plays a crucial role in enabling innocuous stimulation to
activate spinal microglia (McDonough et al., 2023). Indeed, inflamma­
tory indicators are more accessible in the clinic than other biological
indicators. Future studies need to further explore the role of inflam­
matory cytokines in patients suffering from chronic pain combined with
depression. Furthermore, establishing a model based on inflammation
indicators is for the early prediction of depression.
4.6. Oxytocin
In addition to the systems described above, oxytocin (OT) also plays
a significant role in pain and depression. Oxytocin is a nonapeptide
hormone produced primarily in the neurons of the PVN and supraoptic
nuclei of the hypothalamus (Gimpl and Fahrenholz, 2001).
OT-expressing neurons project to various regions of the CNS, including
the spinal cord and amygdala (Knobloch et al., 2012). It has been shown
S. Yang et al. Brain Research Bulletin 200 (2023) 110691

Fig. 1. The possible mechanism of GABAergic system involved in the comorbidity of chronic pain and depression. Abbreviations: α2-AR, α2-adrenoreceptor; Akt,
protein kinase B; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor; ARK, adrenergic receptor kinase; BDNF, brain-derived neurotrophic factor;
eEF2, eukaryotic translation elongation factor 2; ERK, extracellular signal-regulated kinase; E/I imbalance, excitatory and inhibitory imbalance; GABA, γ-amino­
butyric acid; GABAR, γ-aminobutyric acid receptor; Gln, glutamine; Glu, glutamate; IDO, indoleamine-2,3-Dioxygenase; IL-1, interleukin-1; IL-6, interleukin-6; IL-R,
interleukin receptor; KCC2, K+/Cl- cotransporter 2; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; NE, norepinephrine;
NMDAR, N-methyl-D-aspartate receptor; OT, oxytocin; OTR, oxytocin receptor; TNF-α, tumor necrosis factor-α; TNF-R, tumour necrosis factor receptor; TrkB,
tyrosine kinase receptor B; 5-HT, 5-hydroxytryptamine; 5-HTP, 5-hydroxytryptophan; 5-HT1AR, 5-hydroxytryptamine 1A receptor.

6
S. Yang et al.
that oxytocin produces a strong antinociceptive effect during the pro­
cessing of spinal pain (Condés-Lara et al., 2006). The primary molecular
target for OT-induced antinociception consists of GABAa receptor
channels, and acute OT-induced analgesia is associated with a
strengthening of GABA receptor-mediated inhibition in the spinal cord
(Juif et al., 2013). Additionally, Han et al. found that the change of
GABAergic transmission in CeA neurons resulting from oxytocin recepto
(OTR) down-regulation underlies the emergence of the
isolation-induced depression- and anxiety-related behaviors (Han et al.,
2018). Overall, the GABAergic system interacts with oxytocin, which is
involved in pain and depression.
5. Conclusion
In summary, the GABAergic system is involved in the comorbidity of
chronic pain and depression, with intricate mechanisms involving the 5-
hydroxytryptaminergic and noradrenergic systems, glutamatergic sys­
tem, neuroplasticity and BDNF, stress and HPA axis, immune-
inflammatory pathways and oxytocin (Fig. 1.). The GABAergic system
is regarded as an interface between chronic pain combined with
depression and other systems, but the specific underlying mechanisms
need to be further elucidated. Therefore, we need to combine molecular
biology, optogenetics, chemical genetics, and electrophysiology to
explore the potential molecular biological mechanisms and specific
neural circuits of co-morbid chronic pain and depression for targeted
treatment in the future.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Data availability
No data was used for the research described in the article.
Acknowledgments
This study was supported by grants from the National Natural Sci­
ence Foundation of China (81974171 and 82271254 to Chun Yang, and
82201420 to Di Wang), Innovative and Entrepreneurial Team of Jiangsu
Province, China (JSSCTD202144 to Chun Yang), Natural Science
Foundation of Jiangsu Province, China (BK20211382 to Cunming Liu),
and China Postdoctoral Science Foundation, China (2021M701496 to Di
Wang).
Author contribution
All authors contributed to the writing, review, and approval of the
manuscript.
References
Amsterdam, J.D., Hornig-Rohan, M., Maislin, G., 1994. Efficacy of alprazolam in
reducing fluoxetine-induced jitteriness in patients with major depression. J. Clin.
Psychiatry 55 (9), 394–400.
Ascoli, G.A., Alonso-Nanclares, L., Anderson, S.A., Barrionuevo, G., Benavides-
Piccione, R., Burkhalter, A., Buzsáki, G., Cauli, B., Defelipe, J., Fairén, A., et al.,
2008. Petilla terminology: nomenclature of features of GABAergic interneurons of
the cerebral cortex. Nat. Rev. Neurosci. 9 (7), 557–568. https://doi.org/10.1038/
nrn2402.
Atack, J.R., Ohashi, Y., McKernan, R.M., 2007. Characterization of [35S]t-
butylbicyclophosphorothionate ([35S]TBPS) binding to GABAA receptors in
postmortem human brain. Br. J. Pharmacol. 150 (8), 1066–1074.
Authement, M.E., Langlois, L.D., Shepard, R.D., Browne, C.A., Lucki, I., Kassis, H.,
Nugent, F.S., 2018. A role for corticotropin-releasing factor signaling in the lateral
habenula and its modulation by early-life stress. Sci. Signal 11 (520). https://doi.
org/10.1126/scisignal.aan6480.
Avari, J.N., Kanellopoulos, D., Solomonov, N., Oberlin, L., Alexopoulos, G.S., 2020.
Minocycline augmentation in older adults with persistent depression: an open label
7
Brain Research Bulletin 200 (2023) 110691
proof of concept study. Int. Psychogeriatr. 32 (7), 881–884. https://doi.org/
10.1017/s1041610220001313.
Belinskaia, D.A., Belinskaia, M.A., Barygin, O.I., Vanchakova, N.P., Shestakova, N.N.,
2019. Psychotropic drugs for the management of chronic pain and itch.
Pharmaceuticals 12 (2). https://doi.org/10.3390/ph12020099.
Bravo, L., Mico, J.A., Rey-Brea, R., Pérez-Nievas, B., Leza, J.C., Berrocoso, E., 2012.
Depressive-like states heighten the aversion to painful stimuli in a rat model of
comorbid chronic pain and depression. Anesthesiology 117 (3), 613–625.
Bravo, L., Alba-Delgado, C., Torres-Sanchez, S., Mico, J.A., Neto, F.L., Berrocoso, E.,
2013. Social stress exacerbates the aversion to painful experiences in rats exposed to
chronic pain: the role of the locus coeruleus. Pain 154 (10), 2014–2023. https://doi.
org/10.1016/j.pain.2013.06.021.
Bravo, L., Torres-Sanchez, S., Alba-Delgado, C., Mico, J.A., Berrocoso, E., 2014. Pain
exacerbates chronic mild stress-induced changes in noradrenergic transmission in
rats. Eur. Neuropsychopharmacol. 24 (6), 996–1003. https://doi.org/10.1016/j.
euroneuro.2014.01.011.
Bravo, L., Llorca-Torralba, M., Berrocoso, E., Antonio Mico, J., 2019. Monoamines as
drug targets in chronic pain: focusing on neuropathic pain. Front. Neurosci. 13.
https://doi.org/10.3389/fnins.2019.01268.
Bruening, C.A., Martini, F., Soares, S.M., Sampaio, T.B., Gai, B.M., Duarte, M.M.M.F.,
Nogueira, C.W., 2015. m-Trifluoromethyl-diphenyl diselenide, a multi-target
selenium compound, prevented mechanical allodynia and depressive-like behavior
in a mouse comorbid pain and depression model. Prog. Neuro-Psychopharmacol.
Biol. Psychiatry 63, 35–46. https://doi.org/10.1016/j.pnpbp.2015.05.011.
Burek, D.J., Massaly, N., Yoon, H.J., Doering, M., Moron, J.A., 2022. Behavioral
outcomes of complete Freund adjuvant-induced inflammatory pain in the rodent
hind paw: a systematic review and meta-analysis. Pain 163 (5), 809–819. https://
doi.org/10.1097/j.pain.0000000000002467.
Cao, T., Matyas, J.J., Renn, C.L., Faden, A.I., Dorsey, S.G., Wu, J., 2020. Function and
mechanisms of truncated BDNF receptor TrkB.T1 in neuropathic pain. Cells 9 (5).
https://doi.org/10.3390/cells9051194.
Carroll, L.J., Cassidy, J.D., Cote, P., 2004. Depression as a risk factor for onset of an
episode of troublesome neck and low back pain. Pain 107 (1–2), 134–139. https://
doi.org/10.1016/j.pain.2003.10.009.
Castren, E., Monteggia, L.M., 2021. Brain-derived neurotrophic factor signaling in
depression and antidepressant action. Biol. Psychiatry 90 (2), 128–136. https://doi.
org/10.1016/j.biopsych.2021.05.008.
Cerne, R., Lippa, A., Poe, M.M., Smith, J.L., Jin, X., Ping, X., Golani, L.K., Cook, J.M.,
Witkin, J.M., 2022. GABAkines - advances in the discovery, development, and
commercialization of positive allosteric modulators of GABA receptors. Pharmacol.
Ther. 234, 108035 https://doi.org/10.1016/j.pharmthera.2021.108035.
Chen, C., Jiang, Z., Fu, X., Yu, D., Huang, H., Tasker, J.G., 2019. Astrocytes amplify
neuronal dendritic volume transmission stimulated by norepinephrine. Cell Rep. 29
(13), 4349–4434. https://doi.org/10.1016/j.celrep.2019.11.092.
Chen, J.T.-c, Guo, D., Campanelli, D., Frattini, F., Mayer, F., Zhou, L., Kuner, R.,
Heppenstall, P.A., Knipper, M., Hu, J., 2014. Presynaptic GABAergic inhibition
regulated by BDNF contributes to neuropathic pain induction. Nat. Commun. 5,
5331. https://doi.org/10.1038/ncomms6331.
Cheng, Y., Desse, S., Martinez, A., Worthen, R.J., Jope, R.S., Beurel, E., 2018. TNFα
disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior
in mice. Brain Behav. Immun. 69, 556–567. https://doi.org/10.1016/j.
bbi.2018.02.003.
Chuang, C.-Y., Shi, Y.-C., You, H.-P., Lo, Y.-H., Pan, T.-M., 2011. Antidepressant effect of
GABA-rich monascus-fermented product on forced swimming rat model. J. Agric.
Food Chem. 59 (7), 3027–3034. https://doi.org/10.1021/jf104239m.
Cohen, S.P., Vase, L., Hooten, W.M., 2021. Chronic pain: an update on burden, best
practices, and new advances. Lancet (Lond., Engl.) 397 (10289), 2082–2097.
https://doi.org/10.1016/S0140-6736(21)00393-7.
Colmers, P.L.W., Bains, J.S., 2018. Balancing tonic and phasic inhibition in hypothalamic
corticotropin-releasing hormone neurons. J. Physiol. -Lond. 596 (10), 1919–1929.
https://doi.org/10.1113/jp275588.
Conaghan, P.G., Cook, A.D., Hamilton, J.A., Tak, P.P., 2019. Therapeutic options for
targeting inflammatory osteoarthritis pain. Nat. Rev. Rheumatol. 15 (6), 355–363.
https://doi.org/10.1038/s41584-019-0221-y.
Condés-Lara, M., Rojas-Piloni, G., Martínez-Lorenzana, G., Rodríguez-Jiménez, J., López
Hidalgo, M., Freund-Mercier, M.J., 2006. Paraventricular hypothalamic influences
on spinal nociceptive processing. Brain Res. 1081 (1), 126–137.
Czéh, B., Varga, Z.K.K., Henningsen, K., Kovács, G.L., Miseta, A., Wiborg, O., 2015.
Chronic stress reduces the number of GABAergic interneurons in the adult rat
hippocampus, dorsal-ventral and region-specific differences. Hippocampus 25 (3),
393–405. https://doi.org/10.1002/hipo.22382.
Das, R., Emon, M.P.Z., Shahriar, M., Nahar, Z., Islam, S.M.A., Bhuiyan, M.A., Islam, S.N.,
Islam, M.R., 2021. Higher levels of serum IL-1 beta and TNF-alpha are associated
with an increased probability of major depressive disorder. Psychiatry Res. 295.
https://doi.org/10.1016/j.psychres.2020.113568.
Doan, L., Manders, T., Wang, J., 2015. Neuroplasticity underlying the comorbidity of
pain and depression. Neural Plast. 2015, 504691 https://doi.org/10.1155/2015/
504691.
Duan, Y.-W., Chen, S.-X., Li, Q.-Y., Zang, Y., 2022. Neuroimmune mechanisms
underlying neuropathic pain: the potential role of TNF-alpha-necroptosis pathway.
Int. J. Mol. Sci. 23 (13) https://doi.org/10.3390/ijms23137191.
Duman, R.S., Sanacora, G., Krystal, J.H., 2019. Altered connectivity in depression: GABA
and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron
102 (1), 75–90. https://doi.org/10.1016/j.neuron.2019.03.013.
Dupuis, A., Wattiez, A.-S., Pinguet, J., Richard, D., Libert, F., Chalus, M., Aissouni, Y.,
Sion, B., Ardid, D., Marin, P., et al., 2017. Increasing spinal 5-HT2A receptor
S. Yang et al.
responsiveness mediates anti-allodynic effect and potentiates fluoxetine efficacy in
neuropathic rats. Evidence for GABA release. Pharmacol. Res. 118, 93–103. https://
doi.org/10.1016/j.phrs.2016.09.021.
Edwards, R.R., Dworkin, R.H., Sullivan, M.D., Turk, D.C., Wasan, A.D., 2016. The role of
psychosocial processes in the development and maintenance of chronic pain. J. Pain.
17 (9), T70–T92. https://doi.org/10.1016/j.jpain.2016.01.001.
Ellis, A., Bennett, D.L.H., 2013. Neuroinflammation and the generation of neuropathic
pain. Br. J. Anaesth. 111 (1), 26–37. https://doi.org/10.1093/bja/aet128.
Engin, E., Benham, R.S., Rudolph, U., 2018. An emerging circuit pharmacology of GABA
(A) receptors. Trends Pharmacol. Sci. 39 (8), 710–732. https://doi.org/10.1016/j.
tips.2018.04.003.
Fang, X., Zhan, G., Zhang, J., Xu, H., Zhu, B., Hu, Y., Yang, C., Luo, A., 2019.
Abnormalities in inflammatory cytokines confer susceptible to chronic neuropathic
pain-related anhedonia in a rat model of spared nerve injury. Clin.
Psychopharmacol. Neurosci. 17 (2), 189–199. https://doi.org/10.9758/
cpn.2019.17.2.189.
Fogaca, M.V., Duman, R.S., 2019. Cortical GABAergic dysfunction in stress and
depression: new insights for therapeutic interventions. Front. Cell. Neurosci. 13.
https://doi.org/10.3389/fncel.2019.00087.
Fogaca, M.V., Wu, M., Li, C., Li, X.-Y., Picciotto, M.R., Duman, R.S., 2021. Inhibition of
GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant
responses. Mol. Psychiatry 26 (7), 3277–3291. https://doi.org/10.1038/s41380-
020-00916-y.
Fogaça, M.V., Duman, R.S., 2019. Cortical GABAergic dysfunction in stress and
depression: new insights for therapeutic interventions. Front. Cell. Neurosci. 13, 87.
https://doi.org/10.3389/fncel.2019.00087.
Freo, U., Brugnatelli, V., Turco, F., Zanette, G., 2021. Analgesic and antidepressant
effects of the clinical glutamate modulators acetyl-L-carnitine and ketamine. Front.
Neurosci. 15. https://doi.org/10.3389/fnins.2021.584649.
Fuchs, T., Jefferson, S.J., Hooper, A., Yee, P.H.P., Maguire, J., Luscher, B., 2017.
Disinhibition of somatostatin-positive GABAergic interneurons results in an
anxiolytic and antidepressant-like brain state. Mol. Psychiatry 22 (6), 920–930.
https://doi.org/10.1038/mp.2016.188.
Gaidin, S.G., Zinchenko, V.P., Sergeev, A.I., Teplov, I.Y., Mal’tseva, V.N., Kosenkov, A.
M., 2020. Activation of alpha-2 adrenergic receptors stimulates GABA release by
astrocytes. Glia 68 (6), 1114–1130. https://doi.org/10.1002/glia.23763.
Galarreta, M., Hestrin, S., 2001. Electrical synapses between GABA-releasing
interneurons. Nat. Rev. Neurosci. 2 (6), 425–433.
Gerhard, D.M., Pothula, S., Liu, R.-J., Wu, M., Li, X.-Y., Girgenti, M.J., Taylor, S.R.,
Duman, C.H., Delpire, E., Picciotto, M., et al., 2020. GABA interneurons are the
cellular trigger for ketamine’s rapid antidepressant actions. J. Clin. Investig. 130 (3),
1336–1349. https://doi.org/10.1172/jci130808.
Gimpl, G., Fahrenholz, F., 2001. The oxytocin receptor system: structure, function, and
regulation. Physiol. Rev. 81 (2), 629–683.
Gold, P.W., 2015. The organization of the stress system and its dysregulation in
depressive illness. Mol. Psychiatry 20 (1), 32–47. https://doi.org/10.1038/
mp.2014.163.
Goodchild, C.S., Robinson, A., Nadeson, R., 2001. Antinociceptive properties of
neurosteroids IV: pilot study demonstrating the analgesic effects of alphadolone
administered orally to humans. Br. J. Anaesth. 86 (4), 528–534.
Goubert, E., Altvater, M., Rovira, M.-N., Khalilov, I., Mazzarino, M., Sebastiani, A.,
Schaefer, M.K.E., Rivera, C., Pellegrino, C., 2019. Bumetanide prevents brain
trauma-induced depressive-like behavior. Front. Mol. Neurosci. 12. https://doi.org/
10.3389/fnmol.2019.00012.
Gupta, K.K., Khan, M.A., Singh, S.K., 2020. Constitutive inflammatory cytokine storm: a
major threat to human health. J. Interferon Cytokine Res. 40 (1), 19–23. https://doi.
org/10.1089/jir.2019.0085.
Gururajan, A., Reif, A., Cryan, J.F., Slattery, D.A., 2019. The future of rodent models in
depression research. Nat. Rev. Neurosci. 20 (11), 686–701. https://doi.org/
10.1038/s41583-019-0221-6.
Haleem, D.J., 2018. Serotonin-1A receptor dependent modulation of pain and reward for
improving therapy of chronic pain. Pharmacol. Res. 134, 212–219. https://doi.org/
10.1016/j.phrs.2018.06.030.
Han, R.T., Kim, Y.-B., Park, E.-H., Kim, J.Y., Ryu, C., Kim, H.Y., Lee, J., Pahk, K.,
Shanyu, C., Kim, H., et al., 2018. Long-term isolation elicits depression and anxiety-
related behaviors by reducing oxytocin-induced GABAergic transmission in central
amygdala. Front. Mol. Neurosci. 11, 246. https://doi.org/10.3389/
fnmol.2018.00246.
Harrisberger, F., Smieskova, R., Schmidt, A., Lenz, C., Walter, A., Wittfeld, K., Grabe, H.
J., Lang, U.E., Fusar-Poli, P., Borgwardt, S., 2015. BDNF Val66Met polymorphism
and hippocampal volume in neuropsychiatric disorders: a systematic review and
meta-analysis. Neurosci. Biobehav. Rev. 55, 107–118. https://doi.org/10.1016/j.
neubiorev.2015.04.017.
Hayashida, K.-i, Kimura, M., Yoshizumi, M., Hobo, S., Obata, H., Eisenach, J.C., 2012.
Ondansetron reverses antihypersensitivity from clonidine in rats after peripheral
nerve injury role of gamma-aminobutyric acid in alpha 2-adrenoceptor and 5-HT3
serotonin receptor analgesia. Anesthesiology 117 (2), 389–398. https://doi.org/
10.1097/ALN.0b013e318260d381.
Hooten, W.M., 2016. Chronic pain and mental health disorders: shared neural
mechanisms, epidemiology, and treatment. Mayo Clin. Proc. 91 (7), 955–970.
https://doi.org/10.1016/j.mayocp.2016.04.029.
Horchar, M.J., Wohleb, E.S., 2019. Glucocorticoid receptor antagonism prevents
microglia-mediated neuronal remodeling and behavioral despair following chronic
unpredictable stress. Brain Behav. Immun. 81, 329–340. https://doi.org/10.1016/j.
bbi.2019.06.030.
8
Brain Research Bulletin 200 (2023) 110691
Horjales-Araujo, E., Demontis, D., Lund, E.K., Vase, L., Finnerup, N.B., Borglum, A.D.,
Jensen, T.S., Svensson, P., 2013. Emotional modulation of muscle pain is associated
with polymorphisms in the serotonin transporter gene. Pain 154 (8), 1469–1476.
https://doi.org/10.1016/j.pain.2013.05.011.
Hu, X., Dong, Y., Jin, X., Zhang, C., Zhang, T., Zhao, J., Shi, J., Li, J., 2017. The novel and
potent anti-depressive action of triptolide and its influences on hippocampal
neuroinflammation in a rat model of depression comorbidity of chronic pain. Brain
Behav. Immun. 64, 180–194. https://doi.org/10.1016/j.bbi.2017.03.005.
Humo, M., Lu, H., Yalcin, I., 2019. The molecular neurobiology of chronic pain-induced
depression. Cell Tissue Res. 377 (1), 21–43. https://doi.org/10.1007/s00441-019-
03003-z.
Infantino, R., Schiano, C., Luongo, L., Paino, S., Mansueto, G., Boccella, S., Guida, F.,
Ricciardi, F., Iannotta, M., Belardo, C., et al., 2022. MED1/BDNF/TrkB pathway is
involved in thalamic hemorrhage-induced pain and depression by regulating
microglia. Neurobiol. Dis. 164. https://doi.org/10.1016/j.nbd.2022.105611.
Jones, A.F., Sheets, P.L., 2020. Sex-specific disruption of distinct mPFC inhibitory
neurons in spared-nerve injury model of neuropathic pain. Cell Rep. 31 (10), 107729
https://doi.org/10.1016/j.celrep.2020.107729.
Juif, P.-E., Breton, J.-D., Rajalu, M., Charlet, A., Goumon, Y., Poisbeau, P., 2013. Long-
lasting spinal oxytocin analgesia is ensured by the stimulation of allopregnanolone
synthesis which potentiates GABA(A) receptor-mediated synaptic inhibition.
J. Neurosci. 33 (42), 16617–16626. https://doi.org/10.1523/JNEUROSCI.3084-
12.2013.
Kim, H., Chen, L., Lim, G., Sung, B., Wang, S., McCabe, M.F., Rusanescu, G., Yang, L.,
Tian, Y., Mao, J., 2012. Brain indoleamine 2,3-dioxygenase contributes to the
comorbidity of pain and depression. J. Clin. Invest 122 (8), 2940–2954. https://doi.
org/10.1172/JCI61884.
Kim, J.-K., Han, S.-K., Joo, M.-K., Kim, D.-H., 2021. Buspirone alleviates anxiety,
depression, and colitis; and modulates gut microbiota in mice. Sci. Rep. 11 (1), 6094.
https://doi.org/10.1038/s41598-021-85681-w.
Knabl, J., Witschi, R., Hösl, K., Reinold, H., Zeilhofer, U.B., Ahmadi, S., Brockhaus, J.,
Sergejeva, M., Hess, A., Brune, K., et al., 2008. Reversal of pathological pain through
specific spinal GABAA receptor subtypes. Nature 451 (7176), 330–334. https://doi.
org/10.1038/nature06493.
Knobloch, H.S., Charlet, A., Hoffmann, L.C., Eliava, M., Khrulev, S., Cetin, A.H.,
Osten, P., Schwarz, M.K., Seeburg, P.H., Stoop, R., et al., 2012. Evoked axonal
oxytocin release in the central amygdala attenuates fear response. Neuron 73 (3),
553–566. https://doi.org/10.1016/j.neuron.2011.11.030.
Kontinen, V.K., Dickenson, A.H., 2000. Effects of midazolam in the spinal nerve ligation
model of neuropathic pain in rats. Pain 85 (3), 425–431. https://doi.org/10.1016/
S0304-3959(99)00298-5.
Koob, G.F., 1992. Drugs of abuse: anatomy, pharmacology and function of reward
pathways. Trends Pharmacol. Sci. 13 (5), 177–184.
Kroenke, K., Wu, J., Bair, M.J., Krebs, E.E., Damush, T.M., Tu, W., 2011. Reciprocal
relationship between pain and depression: a 12-month longitudinal analysis in
primary care. J. Pain. 12 (9), 964–973. https://doi.org/10.1016/j.
jpain.2011.03.003.
Kummer, K.K., Mitric, M., Kalpachidou, T., Kress, M., 2020a. The medial prefrontal
cortex as a central hub for mental comorbidities associated with chronic pain. Int. J.
Mol. Sci. 21 (10) https://doi.org/10.3390/ijms21103440.
Kummer, K.K., Mitrić, M., Kalpachidou, T., Kress, M., 2020b. The medial prefrontal
cortex as a central hub for mental comorbidities associated with chronic pain. Int. J.
Mol. Sci. 21 (10) https://doi.org/10.3390/ijms21103440.
Landau, A.M., Phan, J.-A., Iversen, P., Lillethorup, T.P., Simonsen, M., Wegener, G.,
Jakobsen, S., Doudet, D.J., 2015. Decreased in vivo alpha 2 adrenoceptor binding in
the Flinders Sensitive Line rat model of depression. Neuropharmacology 91, 97–102.
https://doi.org/10.1016/j.neuropharm.2014.12.025.
Langer, S.Z., 2015. alpha(2)-Adrenoceptors in the treatment of major neuropsychiatric
disorders. Trends Pharmacol. Sci. 36 (4), 196–202. https://doi.org/10.1016/j.
tips.2015.02.006.
Lee, S., Lee, K.H., Park, K.M., Park, S.J., Kim, W.J., Lee, J., Kronbichler, A., Smith, L.,
Solmi, M., Stubbs, B., et al., 2021. Impact of data extraction errors in meta-analyses
on the association between depression and peripheral inflammatory biomarkers: an
umbrella review. Psychol. Med. https://doi.org/10.1017/s0033291721003767.
Leonardon, B., Cathenaut, L., Vial-Markiewicz, L., Hugel, S., Schlichter, R.,
Inquimbert, P., 2022. Modulation of GABAergic synaptic transmission by NMDA
receptors in the dorsal horn of the spinal cord. Front. Mol. Neurosci. 15, 903087
https://doi.org/10.3389/fnmol.2022.903087.
Li, D.-D., Xie, H., Du, Y.-F., Long, Y., Reed, M.N., Hu, M., Suppiramaniam, V., Hong, H.,
Tang, S.-S., 2018a. Antidepressant-like effect of zileuton is accompanied by
hippocampal neuroinflammation reduction and CREB/BDNF upregulation in
lipopolysaccharide-challenged mice. J. Affect. Disord. 227, 672–680. https://doi.
org/10.1016/j.jad.2017.11.047.
Li, J.-M., Zhang, Y., Su, W.-J., Liu, L.-L., Gong, H., Peng, W., Jiang, C.-L., 2018b.
Cognitive behavioral therapy for treatment-resistant depression: A systematic review
and meta-analysis. Psychiatry Res. 268, 243–250. https://doi.org/10.1016/j.
psychres.2018.07.020.
Li, M., Li, C., Yu, H., Cai, X., Shen, X., Sun, X., Wang, J., Zhang, Y., Wang, C., 2017.
Lentivirus-mediated interleukin-1 beta (IL-1 beta) knock-down in the hippocampus
alleviates lipopolysaccharide (LPS)-induced memory deficits and anxiety-and
depression-like behaviors in mice. J. Neuroinflamm. 14. https://doi.org/10.1186/
s12974-017-0964-9.
Li, Y., Dharkar, P., Han, T.-H., Serpe, M., Lee, C.-H., Mayer, M.L., 2016. Novel functional
properties of drosophila CNS glutamate receptors. Neuron 92 (5), 1036–1048.
https://doi.org/10.1016/j.neuron.2016.10.058.
S. Yang et al.
Li, Y., Chen, C., Li, S., Jiang, C., 2019. Ginsenoside Rf relieves mechanical
hypersensitivity, depression-like behavior, and inflammatory reactions in chronic
constriction injury rats. Phytother. Res. 33 (4), 1095–1103. https://doi.org/
10.1002/ptr.6303.
Li, Y.-Q., Li, H., Wei, J., Qu, L., Wu, L.-a, 2010. Expression changes of K+-Cl- co-
transporter 2 and Na+-K+-Cl- co-transporter1 in mouse trigeminal subnucleus
caudalis following pulpal inflammation. Brain Res. Bull. 81 (6), 561–564. https://
doi.org/10.1016/j.brainresbull.2010.01.002.
Lin, L.C., Sibille, E., 2015. Somatostatin, neuronal vulnerability and behavioral
emotionality. Mol. Psychiatry 20 (3), 377–387. https://doi.org/10.1038/
mp.2014.184.
Liu, L., Dai, L., Xu, D., Wang, Y., Bai, L., Chen, X., Li, M., Yang, S., Tang, Y., 2022.
Astrocyte secretes IL-6 to modulate PSD-95 palmitoylation in basolateral amygdala
and depression-like behaviors induced by peripheral nerve injury. Brain Behav.
Immun. 104, 139–154. https://doi.org/10.1016/j.bbi.2022.05.014.
Liu, Q.Q., Yao, X.X., Gao, S.H., Li, R., Li, B.J., Yang, W., Cui, R.J., 2020. Role of 5-HT
receptors in neuropathic pain: potential therapeutic implications. Pharmacol. Res.
159. https://doi.org/10.1016/j.phrs.2020.104949.
Loggia, M.L., Berna, C., Kim, J., Cahalan, C.M., Gollub, R.L., Wasan, A.D., Harris, R.E.,
Edwards, R.R., Napadow, V., 2014. Disrupted brain circuitry for pain-related
reward/punishment in fibromyalgia. Arthritis Rheuma 66 (1), 203–212. https://doi.
org/10.1002/art.38191.
Lopes, F., Vicentini, F.A., Cluny, N.L., Mathews, A.J., Lee, B.H., Almishri, W.A.,
Griffin, L., Goncalves, W., Pinho, V., McKay, D.M., et al., 2020. Brain TNF drives
post-inflammation depression-like behavior and persistent pain in experimental
arthritis. Brain Behav. Immun. 89, 224–232. https://doi.org/10.1016/j.
bbi.2020.06.023.
Lopez-Gonzalez, M.J., Landry, M., Favereaux, A., 2017. MicroRNA and chronic pain:
From mechanisms to therapeutic potential. Pharmacol. Ther. 180, 1–15. https://doi.
org/10.1016/j.pharmthera.2017.06.001.
Lorenzo, L.-E., Godin, A.G., Ferrini, F., Bachand, K., Plasencia-Fernandez, I.,
Labrecque, S., Girard, A.A., Boudreau, D., Kianicka, I., Gagnon, M., et al., 2020.
Enhancing neuronal chloride extrusion rescues α2/α3 GABA-mediated analgesia in
neuropathic pain. Nat. Commun. 11 (1), 869. https://doi.org/10.1038/s41467-019-
14154-6.
Lu, C.-L., Ren, J., Mo, J.-W., Fan, J., Guo, F., Chen, L.-Y., Wen, Y.-L., Li, S.-J., Fang, Y.-Y.,
Wu, Z.-F., et al., 2022. Glucocorticoid receptor-dependent astrocytes mediate stress
vulnerability. Biol. Psychiatry 92 (3), 204–215. https://doi.org/10.1016/j.
biopsych.2021.11.022.
Luo, H., Liu, H.-Z., Zhang, W.-W., Matsuda, M., Lv, N., Chen, G., Xu, Z.-Z., Zhang, Y.-Q.,
2019. Interleukin-17 regulates neuron-glial communications, synaptic transmission,
and neuropathic pain after chemotherapy. Cell Rep. 29 (8) https://doi.org/10.1016/
j.celrep.2019.10.085.
Luo, X., Chen, O., Wang, Z., Bang, S., Ji, J., Lee, S.H., Huh, Y., Furutani, K., He, Q.,
Tao, X., et al., 2021. IL-23/IL-17A/TRPV1 axis produces mechanical pain via
macrophage-sensory neuron crosstalk in female mice. Neuron 109 (17). https://doi.
org/10.1016/j.neuron.2021.06.015.
Ma, L., Yue, L., Zhang, Y., Wang, Y., Han, B., Cui, S., Liu, F.-Y., Wan, Y., Yi, M., 2019.
Spontaneous pain disrupts ventral hippocampal CA1-infralimbic cortex connectivity
and modulates pain progression in rats with peripheral inflammation, 1579-157 Cell
Rep. 29 (6). https://doi.org/10.1016/j.celrep.2019.10.002.
McCracken, L., Yu, L., Vowles, K.J.B. (2022). New generation psychological treatments in
chronic pain. 376, e057212. https://doi.org/10.1136/bmj-2021–057212.
McDonough, K.E., Hammond, R., Wang, J., Tierney, J., Hankerd, K., Chung, J.M., La, J.-
H., 2023. Spinal GABAergic disinhibition allows microglial activation mediating the
development of nociplastic pain in male mice. Brain Behav. Immun. 107, 215–224.
https://doi.org/10.1016/j.bbi.2022.10.013.
McEwen, B.S., Kalia, M., 2010. The role of corticosteroids and stress in chronic pain
conditions. Metab. -Clin. Exp. 59 (10), S9–S15. https://doi.org/10.1016/j.
metabol.2010.07.012.
McKlveen, J.M., Morano, R.L., Fitzgerald, M., Zoubovsky, S., Cassella, S.N.,
Scheimann, J.R., Ghosal, S., Mahbod, P., Packard, B.A., Myers, B., et al., 2016.
Chronic stress increases prefrontal inhibition: a mechanism for stress-induced
prefrontal dysfunction. Biol. Psychiatry 80 (10), 754–764. https://doi.org/10.1016/
j.biopsych.2016.03.2101.
Medina, I., Friedel, P., Rivera, C., Kahle, K.T., Kourdougli, N., Uvarov, P., Pellegrino, C.,
2014. Current view on the functional regulation of the neuronal K+-Cl-
cotransporter KCC2. Front. Cell. Neurosci. 8. https://doi.org/10.3389/
fncel.2014.00027.
Meltzer-Brody, S., Colquhoun, H., Riesenberg, R., Epperson, C.N., Deligiannidis, K.M.,
Rubinow, D.R., Li, H., Sankoh, A.J., Clemson, C., Schacterle, A., et al., 2018.
Brexanolone injection in post-partum depression: two multicentre, double-blind,
randomised, placebo-controlled, phase 3 trials. Lancet (Lond., Engl.) 392 (10152),
1058–1070. https://doi.org/10.1016/S0140-6736(18)31551-4.
Moriguchi, S., Takamiya, A., Noda, Y., Horita, N., Wada, M., Tsugawa, S., Plitman, E.,
Sano, Y., Tarumi, R., ElSalhy, M., et al., 2019. Glutamatergic neurometabolite levels
in major depressive disorder: a systematic review and meta-analysis of proton
magnetic resonance spectroscopy studies. Mol. Psychiatry 24 (7), 952–964. https://
doi.org/10.1038/s41380-018-0252-9.
Muguruza, C., Rodriguez, F., Rozas, I., Javier Meana, J., Urigueen, L., Callado, L.F., 2013.
Antidepressant-like properties of three new alpha 2-adrenoceptor antagonists.
Neuropharmacology 65, 13–19. https://doi.org/10.1016/j.
neuropharm.2012.09.003.
Naylor, J.C., Kilts, J.D., Shampine, L.J., Parke, G.J., Wagner, H.R., Szabo, S.T., Smith, K.
D., Allen, T.B., Telford-Marx, E.G., Dunn, C.E., et al., 2020. Effect of pregnenolone vs
placebo on self-reported chronic low back pain among US Military Veterans: a
9
Brain Research Bulletin 200 (2023) 110691
randomized clinical trial. JAMA Netw. Open 3 (3), e200287. https://doi.org/
10.1001/jamanetworkopen.2020.0287.
Notaras, M., van den Buuse, M., 2020. Neurobiology of BDNF in fear memory, sensitivity
to stress, and stress-related disorders. Mol. Psychiatry 25 (10), 2251–2274. https://
doi.org/10.1038/s41380-019-0639-2.
Obata, H., 2017. Analgesic mechanisms of antidepressants for neuropathic pain. Int. J.
Mol. Sci. 18 (11) https://doi.org/10.3390/ijms18112483.
Okaty, B.W., Commons, K.G., Dymecki, S.M., 2019. Embracing diversity in the 5-HT
neuronal system. Nat. Rev. Neurosci. 20 (7), 397–424. https://doi.org/10.1038/
s41583-019-0151-3.
Olsen, R.W., Sieghart, W., 2008. International union of pharmacology. LXX. Subtypes of
gamma-aminobutyric Acid(A) receptors: Classification on the basis of subunit
composition, pharmacology, and function. Update. Pharmacol. Rev. 60 (3),
243–260. https://doi.org/10.1124/pr.108.00505.
Pelkey, K.A., Chittajallu, R., Craig, M.T., Tricoire, L., Wester, J.C., McBain, C.J., 2017.
Hippocampal GABAergic inhibitory interneurons. Physiol. Rev. 97 (4), 1619–1747.
https://doi.org/10.1152/physrev.00007.2017.
Petty, F., Trivedi, M.H., Fulton, M., Rush, A.J., 1995. Benzodiazepines as antidepressants:
does GABA play a role in depression? Biol. Psychiatry 38 (9), 578–591.
Pinheiro, M.B., Morosoli, J.J., Colodro-Conde, L., Ferreira, P.H., Ordonana, J.R., 2018.
Genetic and environmental influences to low back pain and symptoms of depression
and anxiety: a population-based twin study. J. Psychosom. Res. 105, 92–98. https://
doi.org/10.1016/j.jpsychores.2017.12.007.
Ramirez, K., Sheridan, J.F., 2016. Antidepressant imipramine diminishes stress-induced
inflammation in the periphery and central nervous system and related anxiety- and
depressive- like behaviors. Brain Behav. Immun. 57, 293–303. https://doi.org/
10.1016/j.bbi.2016.05.008.
Raver, C., Uddin, O., Ji, Y., Li, Y., Cramer, N., Jenne, C., Morales, M., Masri, R., Keller, A.,
2020. An amygdalo-parabrachial pathway regulates pain perception and chronic
pain. J. Neurosci. 40 (17), 3424–3442. https://doi.org/10.1523/JNEUROSCI.0075-
20.2020.
Ritter, C., Buchmann, A., Müller, S.T., Volleberg, M., Haynes, M., Ghisleni, C.,
Noeske, R., Tuura, R., Hasler, G., 2022. Evaluation of prefrontal γ-aminobutyric acid
and glutamate levels in individuals with major depressive disorder using proton
magnetic resonance spectroscopy. JAMA Psychiatry 79 (12), 1209–1216. https://
doi.org/10.1001/jamapsychiatry.2022.3384.
Roman, M., Irwin, M.R., 2020. Novel neuroimmunologic therapeutics in depression: a
clinical perspective on what we know so far. Brain Behav. Immun. 83. https://doi.
org/10.1016/j.bbi.2019.09.016.
Rudy, B., Fishell, G., Lee, S., Hjerling-Leffler, J., 2011. Three groups of interneurons
account for nearly 100% of neocortical GABAergic neurons. Dev. Neurobiol. 71 (1),
45–61. https://doi.org/10.1002/dneu.20853.
Rush, A.J., Sackeim, H.A., Conway, C.R., Bunker, M.T., Hollon, S.D., Demyttenaere, K.,
Young, A.H., Aaronson, S.T., Dibué, M., Thase, M.E., et al., 2022. Clinical research
challenges posed by difficult-to-treat depression. Psychol. Med. 52 (3), 419–432.
https://doi.org/10.1017/S0033291721004943.
Sahara, S., Yanagawa, Y., O’Leary, D.D.M., Stevens, C.F., 2012. The fraction of cortical
GABAergic neurons is constant from near the start of cortical neurogenesis to
adulthood. J. Neurosci. 32 (14), 4755–4761. https://doi.org/10.1523/
JNEUROSCI.6412-11.2012.
Schwenk, E.S., Viscusi, E.R., Buvanendran, A., Hurley, R.W., Wasan, A.D., Narouze, S.,
Bhatia, A., Davis, F.N., Hooten, W.M., Cohen, S.P., 2018. Consensus Guidelines on
the Use of Intravenous Ketamine Infusions for Acute Pain Management From the
American Society of Regional Anesthesia and Pain Medicine, the American Academy
of Pain Medicine, and the American Society of Anesthesiologists. Reg. Anesth. Pain.
Med. 43 (5), 456–466. https://doi.org/10.1097/aap.0000000000000806.
Shen, Q., Lal, R., Luellen, B.A., Earnheart, J.C., Andrews, A.M., Luscher, B., 2010.
gamma-Aminobutyric Acid-Type A Receptor Deficits Cause Hypothalamic-Pituitary-
Adrenal Axis Hyperactivity and Antidepressant Drug Sensitivity Reminiscent of
Melancholic Forms of Depression. Biol. Psychiatry 68 (6), 512–520. https://doi.org/
10.1016/j.biopsych.2010.04.024.
Shih, A., Miletic, V., Miletic, G., Smith, L.J., 2008. Midazolam administration reverses
thermal hyperalgesia and prevents gamma-aminobutyric acid transporter loss in a
rodent model of neuropathic pain. Anesth. Analg. 106 (4) https://doi.org/10.1213/
ane.0b013e318164f1e9.
Sikandar, S., Minett, M.S., Millet, Q., Santana-Varela, S., Lau, J., Wood, J.N., Zhao, J.,
2018. Brain-derived neurotrophic factor derived from sensory neurons plays a
critical role in chronic pain. Brain 141, 1028–1039. https://doi.org/10.1093/brain/
awy009.
Smith, K., 2014. Mental health: a world of depression, 181-181 Nature 515 (7526).
https://doi.org/10.1038/515180a.
Smith, K.S., Rudolph, U., 2012. Anxiety and depression: mouse genetics and
pharmacological approaches to the role of GABA(A) receptor subtypes.
Neuropharmacology 62 (1), 54–62. https://doi.org/10.1016/j.
neuropharm.2011.07.026.
Sohal, V.S., Rubenstein, J.L.R., 2019. Excitation-inhibition balance as a framework for
investigating mechanisms in neuropsychiatric disorders. Mol. Psychiatry 24 (9),
1248–1257. https://doi.org/10.1038/s41380-019-0426-0.
Spurny, B., Vanicek, T., Seiger, R., Reed, M.B., Klöbl, M., Ritter, V., Unterholzner, J.,
Godbersen, G.M., Silberbauer, L.R., Pacher, D., et al., 2021. Effects of SSRI treatment
on GABA and glutamate levels in an associative relearning paradigm. Neuroimage
232, 117913. https://doi.org/10.1016/j.neuroimage.2021.117913.
Sun, J., Xu, W., Ye, H., Tang, D., Jiang, Y., Kang, Y., Pan, J., Zhu, J., Zhou, M., Chen, L.,
2023. Stress induces prolonged pain recovery after surgery: involvement of
glucocorticoid-related pathway. Int J. Neuropsychopharmacol. 26 (4), 268–279.
https://doi.org/10.1093/ijnp/pyad010.
S. Yang et al.
Suzuki, T., Amata, M., Sakaue, G., Nishimura, S., Inoue, T., Shibata, M., Mashimo, T.,
2007. Experimental neuropathy in mice is associated with delayed behavioral
changes related to anxiety and depression. Anesth. Analg. 104 (6).
Tatti, R., Haley, M.S., Swanson, O.K., Tselha, T., Maffei, A., 2017. Neurophysiology and
regulation of the balance between excitation and inhibition in neocortical circuits.
Biol. Psychiatry 81 (10), 821–831. https://doi.org/10.1016/j.
biopsych.2016.09.017.
Thompson, J.M., Neugebauer, V., 2019. Cortico-limbic pain mechanisms. Neurosci. Lett.
702, 15–23. https://doi.org/10.1016/j.neulet.2018.11.037.
Thu Ha, P., Gardier, A.M., 2019. Fast-acting antidepressant activity of ketamine:
highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical
studies. Pharmacol. Ther. 199, 58–90. https://doi.org/10.1016/j.
pharmthera.2019.02.017.
Tian, Y., Liu, X., Jia, M., Yu, H., Lichtner, P., Shi, Y., Meng, Z., Kou, S., Ho, I.H.T., Jia, B.,
et al., 2018. Targeted genotyping identifies susceptibility locus in brain-derived
neurotrophic factor gene for chronic postsurgical pain, 1049-1049 Anesthesiology
128 (5). https://doi.org/10.1097/aln.0000000000002200.
Tornese, P., Sala, N., Bonini, D., Bonifacino, T., La Via, L., Milanese, M., Treccani, G.,
Seguini, M., Ieraci, A., Mingardi, J., et al., 2019. Chronic mild stress induces
anhedonic behavior and changes in glutamate release, BDNF trafficking and dendrite
morphology only in stress vulnerable rats. The rapid restorative action of ketamine.
Neurobiol. Stress 10. https://doi.org/10.1016/j.ynstr.2019.100160.
Tour, J., Lofgren, M., Mannerkorpi, K., Gerdle, B., Larsson, A., Palstam, A., Bileviciute-
Ljungar, I., Bjersing, J., Martin, I., Ernberg, M., et al., 2017. Gene-to-gene
interactions regulate endogenous pain modulation in fibromyalgia patients and
healthy controls-antagonistic effects between opioid and serotonin-related genes.
Pain 158 (7), 1194–1203. https://doi.org/10.1097/j.pain.0000000000000896.
Treister, R., Pud, D., Ebstein, R.P., Laiba, E., Raz, Y., Gershon, E., Haddad, M.,
Eisenberg, E., 2011. Association between polymorphisms in serotonin and
dopamine-related genes and endogenous pain modulation. J. Pain. 12 (8), 875–883.
https://doi.org/10.1016/j.jpain.2011.02.348.
Tremblay, R., Lee, S., Rudy, B., 2016. GABAergic interneurons in the neocortex: from
cellular properties to circuits. Neuron 91 (2), 260–292. https://doi.org/10.1016/j.
neuron.2016.06.033.
Tripp, A., Oh, H., Guilloux, J.-P., Martinowich, K., Lewis, D.A., Sibille, E., 2012. Brain-
derived neurotrophic factor signaling and subgenual anterior cingulate cortex
dysfunction in major depressive disorder. Am. J. Psychiatry 169 (11), 1194–1202.
https://doi.org/10.1176/appi.ajp.2012.12020248.
Walker, A.K., Kavelaars, A., Heijnen, C.J., Dantzer, R., 2014. Neuroinflammation and
comorbidity of pain and depression. Pharmacol. Rev. 66 (1), 80–101. https://doi.
org/10.1124/pr.113.008144.
Wang, B., Wang, Y., Wu, Q., Huang, H.-p, Li, S., 2017. Effects of alpha 2A adrenoceptors
on norepinephrine secretion from the locus coeruleus during chronic stress-induced
depression. Front. Neurosci. 11. https://doi.org/10.3389/fnins.2017.00243.
Wang, D., Pan, X., Zhou, Y., Wu, Z., Ren, K., Liu, H., Huang, C., Yu, Y., He, T., Zhang, X.,
et al., 2023. Lateral septum-lateral hypothalamus circuit dysfunction in comorbid
pain and anxiety. Mol. Psychiatry 28 (3), 1090–1100. https://doi.org/10.1038/
s41380-022-01922-y.
Wang, H.-Q., Wang, Z.-Z., Chen, N.-H., 2021. The receptor hypothesis and the
pathogenesis of depression: genetic bases and biological correlates. Pharmacol. Res.
167. https://doi.org/10.1016/j.phrs.2021.105542.
Wang, J., Goffer, Y., Xu, D., Tukey, D.S., Shamir, D.B., Eberle, S.E., Zou, A.H., Blanck, T.
J.J., Ziff, E.B., 2011. A single subanesthetic dose of ketamine relieves depression-like
behaviors induced by neuropathic pain in rats. Anesthesiology 115 (4), 812–821.
https://doi.org/10.1097/ALN.0b013e31822f16ae.
Wang, M., Ma, Y., Yuan, W., Su, K., Li, M.D., 2016. Meta-analysis of the COMT
Val158Met polymorphism in major depressive disorder: effect of ethnicity.
J. Neuroimmune Pharmacol. 11 (3), 434–445. https://doi.org/10.1007/s11481-016-
9651-3.
Wang, S.-M., Han, C., Lee, S.-J., Patkar, A.A., Masand, P.S., Pae, C.-U., 2014. A review of
current evidence for acetyl-L-carnitine in the treatment of depression. J. Psychiatr.
Res. 53, 30–37. https://doi.org/10.1016/j.jpsychires.2014.02.005.
Willeit, M., Praschak-Rieder, N., Neumeister, A., Zill, P., Leisch, F., Stastny, J., Hilger, E.,
Thierry, N., Konstantinidis, A., Winkler, D., et al., 2003. A polymorphism (5-
HTTLPR) in the serotonin transporter promoter gene is associated with DSM-IV
depression subtypes in seasonal affective disorder. Mol. Psychiatry 8 (11), 942–946.
https://doi.org/10.1038/sj.mp.4001392.
Workman, E.R., Niere, F., Raab-Graham, K.F., 2013. mTORC1-dependent protein
synthesis underlying rapid antidepressant effect requires GABA(B)R signaling.
Neuropharmacology 73, 192–203. https://doi.org/10.1016/j.
neuropharm.2013.05.037.
10
Brain Research Bulletin 200 (2023) 110691
Workman, E.R., Haddick, P.C.G., Bush, K., Dilly, G.A., Niere, F., Zemelman, B.V., Raab-
Graham, K.F., 2015. Rapid antidepressants stimulate the decoupling of GABA(B)
receptors from GIRK/Kir3 channels through increased protein stability of 14-3-3 eta.
Mol. Psychiatry 20 (3), 298–310. https://doi.org/10.1038/mp.2014.165.
Workman, E.R., Niere, F., Raab-Graham, K.F., 2018. Engaging homeostatic plasticity to
treat depression. Mol. Psychiatry 23 (1), 26–35. https://doi.org/10.1038/
mp.2017.225.
Wu, L.-A., Huang, J., Wang, W., Wang, W., Wang, X.-J., Wu, S.-X., 2009. Down-
regulation of K+-Cl- co-transporter 2 in mouse medullary dorsal horn contributes to
the formalin-induced inflammatory orofacial pain. Neurosci. Lett. 457 (1), 36–40.
https://doi.org/10.1016/j.neulet.2009.03.107.
Yin, W., Mei, L., Sun, T., Wang, Y., Li, J., Chen, C., Farzinpour, Z., Mao, Y., Tao, W., Li, J.,
et al., 2020. A central amygdala-ventrolateral periaqueductal gray matter pathway
for pain in a mouse model of depression-like behavior. Anesthesiology 132 (5),
1175–1196. https://doi.org/10.1097/aln.0000000000003133.
Yu, H.-Y., Wang, S.-Y., Quan, C.-X., Fang, C., Luo, S.-C., Li, D.-Y., Zhen, S.-S., Ma, J.-H.,
Duan, K.-M., 2019. Dexmedetomidine alleviates postpartum depressive symptoms
following cesarean section in Chinese women: a randomized placebo-controlled
study. Pharmacotherapy 39 (10), 994–1004. https://doi.org/10.1002/phar.2320.
Zell, V., Juif, P.-É., Hanesch, U., Poisbeau, P., Anton, F., Darbon, P., 2015. Corticosterone
analgesia is mediated by the spinal production of neuroactive metabolites that
enhance GABAergic inhibitory transmission on dorsal horn rat neurons. Eur. J.
Neurosci. 41 (3), 390–397. https://doi.org/10.1111/ejn.12796.
Zhang, G.-F., Wang, J., Han, J.-F., Guo, J., Xie, Z.-M., Pan, W., Yang, J.-J., Sun, K.-J.,
2016a. Acute single dose of ketamine relieves mechanical allodynia and consequent
depression-like behaviors in a rat model. Neurosci. Lett. 631, 7–12. https://doi.org/
10.1016/j.neulet.2016.08.006.
Zhang, J.-c, Yao, W., Hashimoto, K., 2016b. Brain-derived neurotrophic factor (BDNF)-
TrkB signaling in inflammation-related depression and potential therapeutic targets.
Curr. Neuropharmacol. 14 (7), 721–731. https://doi.org/10.2174/
1570159x14666160119094646.
Zhang, M., Liu, Y., Zhao, M., Tang, W., Wang, X., Dong, Z., Yu, S., 2017. Depression and
anxiety behaviour in a rat model of chronic migraine. J. Headache Pain. 18. https://
doi.org/10.1186/s10194-017-0736-z.
Zhao, Z.-Q., Chiechio, S., Sun, Y.-G., Zhang, K.-H., Zhao, C.-S., Scott, M., Johnson, R.L.,
Deneris, E.S., Renner, K.J., Gereau, R.W., et al., 2007. Mice lacking central
serotonergic neurons show enhanced inflammatory pain and an impaired analgesic
response to antidepressant drugs. J. Neurosci. 27 (22), 6045–6053. https://doi.org/
10.1523/jneurosci.1623-07.2007.
Zheng, C.J., Van Drunen, S., Egorova-Brumley, N., 2022. Neural correlates of co-
occurring pain and depression: an activation-likelihood estimation (ALE) meta-
analysis and systematic review. Transl. Psychiatry 12 (1). https://doi.org/10.1038/
s41398-022-01949-3.
Zhou, W., Jin, Y., Meng, Q., Zhu, X., Bai, T., Tian, Y., Mao, Y., Wang, L., Xie, W.,
Zhong, H., et al., 2019. A neural circuit for comorbid depressive symptoms in
chronic pain. Nat. Neurosci. 22 (10), 1649. https://doi.org/10.1038/s41593-019-
0468-2.
Zhu, J.-X., Xu, F.-Y., Xu, W.-J., Zhao, Y., Qu, C.-L., Tang, J.-S., Barry, D.M., Du, J.-Q.,
Huo, F.-Q., 2013. The role of alpha(2) adrenoceptor in mediating noradrenaline
action in the ventrolateral orbital cortex on allodynia following spared nerve injury.
Exp. Neurol. 248, 381–386. https://doi.org/10.1016/j.expneurol.2013.07.004.
Zhu, X., Zhou, W., Jin, Y., Tang, H., Cao, P., Mao, Y., Xie, W., Zhang, X., Zhao, F.,
Luo, M.-H., et al., 2019. A central amygdala input to the parafascicular nucleus
controls comorbid pain in depression. Cell Rep. 29 (12) https://doi.org/10.1016/j.
celrep.2019.11.003.
Zhu, X., Tang, H.-D., Dong, W.-Y., Kang, F., Liu, A., Mao, Y., Xie, W., Zhang, X., Cao, P.,
Zhou, W., et al., 2021. Distinct thalamocortical circuits underlie allodynia induced
by tissue injury and by depression-like states. Nat. Neurosci. 24 (4), 542–553.
https://doi.org/10.1038/s41593-021-00811-x.
Zhuo, M., 2016. Neural mechanisms underlying anxiety-chronic pain interactions.
Trends Neurosci. 39 (3), 136–145. https://doi.org/10.1016/j.tins.2016.01.006.
Zubieta, J.K., Heitzeg, M.M., Smith, Y.R., Bueller, J.A., Xu, K., Xu, Y.J., Koeppe, R.A.,
Stohler, C.S., Goldman, D., 2003. COMT val(158)met genotype affects mu-opioid
neurotransmitter responses to a pain stressor. Science 299 (5610), 1240–1243.
https://doi.org/10.1126/science.1078546.
Zunhammer, M., Schweizer, L.M., Witte, V., Harris, R.E., Bingel, U., Schmidt-Wilcke, T.,
2016. Combined glutamate and glutamine levels in pain-processing brain regions are
associated with individual pain sensitivity. Pain 157 (10), 2248–2256. https://doi.
org/10.1097/j.pain.0000000000000634.