GluA1 in central amygdala increases pain but inhibits opioid withdrawal-induced aversion

Cai, Yuanheng; Hou, Yuan Yuan; Pan, Zhizhong Z.

doi:10.1177/1744806920911543

Cited by 8 publications

(5 citation statements)

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“…Studies have found that GluA1-mediated synaptic plasticity plays an important role in the early development of Alzheimer’s disease [ 30 , 31 ]. In addition, drug addiction also increases GluA1 protein expression to promote the rewarding effects of drugs, such as opioid analgesics [ 32 ]. Nowadays, pain and its associated diseases remain a problem that plagues human society.…”

Section: Discussionmentioning

confidence: 99%

Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches

Zhu

et al. 2022

Molecules

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Chlorogenic acid (CGA), an important metabolite in natural plant medicines such as honeysuckle and eucommia, has been shown to have potent antinociceptive effects. Nevertheless, the mechanism by which CGA relieves chronic pain remains unclear. α-amino-3-hydroxy-5-methyl-4-isooxazolpropionic acid receptor (AMPAR) is a major ionotropic glutamate receptor that mediates rapid excitatory synaptic transmission and its glutamate ionotropic receptor AMPA type subunit 1 (GluA1) plays a key role in nociceptive transmission. In this study, we used Western blot, surface plasmon resonance (SPR) assay, and the molecular simulation technologies to investigate the mechanism of interaction between CGA and AMPAR to relieve chronic pain. Our results indicate that the protein expression level of GluA1 showed a dependent decrease as the concentration of CGA increased (0, 50, 100, and 200 μM). The SPR assay demonstrates that CGA can directly bind to GluA1 (KD = 496 μM). Furthermore, CGA forms a stable binding interaction with GluA1, which is validated by molecular dynamics (MD) simulation. The binding free energy between CGA and GluA1 is −39.803 ± 14.772 kJ/mol, where van der Waals interaction and electrostatic interaction are the major contributors to the GluA1–CGA binding, and the key residues are identified (Val-32, Glu-33, Ala-36, Glu-37, Leu-48), which play a crucial role in the binding interaction. This study first reveals the structural basis of the stable interaction between CGA and GluA1 to form a binding complex for the relief of chronic pain. The research provides the structural basis to understand the treatment of chronic pain and is valuable to the design of novel drug molecules in the future.

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Section: Discussionmentioning

confidence: 99%

Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches

Zhu

et al. 2022

Molecules

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“…Rats receiving a control vector exhibited significant CPA behavior during naloxone-precipitated morphine withdrawal, while AAV-GluA1-infused rats showed reductions in aversive CPA behavior. These findings suggest that the neuroadaptive activation of GluA1 receptors in the CeA inhibits the aversive effects of opioid withdrawal (Cai et al, 2020).…”

Section: Role Of Neuroplasticity In the Central Nucleus Of The Amygda...mentioning

confidence: 75%

“…Changes in AMPA number, composition, phosphorylation state can modify synaptic strength and support cellular forms of learning (Chater and Goda, 2014). There are neuroadaptations of AMPA GluA1 receptor in the CeA and this change is associated with the conditioned aversive effects of opioid withdrawal (Cai et al, 2020). Additionally, glutamatergic plasticity in the CeA involves NMDA receptor mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Changes in glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits (or GluA) were found to regulate opioid withdrawal-related behaviors (Cai et al, 2020). This study utilized adeno-associated virus (AAV) vectors to achieve GluA1 overexpression (AAV-GluA1) in the CeA.…”

Section: Role Of Neuroplasticity In the Central Nucleus Of The Amygda...mentioning

confidence: 99%

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Neuroplasticity of the extended amygdala in opioid withdrawal and prolonged opioid abstinence

Kaplan,

Thompson

2023

Front. Pharmacol.

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Opioid use disorder is characterized by excessive use of opioids, inability to control its use, a withdrawal syndrome upon discontinuation of opioids, and long-term likelihood of relapse. The behavioral stages of opioid addiction correspond with affective experiences that characterize the opponent process view of motivation. In this framework, active involvement is accompanied by positive affective experiences which gives rise to “reward craving,” whereas the opponent process, abstinence, is associated with the negative affective experiences that produce “relief craving.” Relief craving develops along with a hypersensitization to the negatively reinforcing aspects of withdrawal during abstinence from opioids. These negative affective experiences are hypothesized to stem from neuroadaptations to a network of affective processing called the “extended amygdala.” This negative valence network includes the three core structures of the central nucleus of the amygdala (CeA), the bed nucleus of the stria terminalis (BNST), and the nucleus accumbens shell (NAc shell), in addition to major inputs from the basolateral amygdala (BLA). To better understand the major components of this system, we have reviewed their functions, inputs and outputs, along with the associated neural plasticity in animal models of opioid withdrawal. These models demonstrate the somatic, motivational, affective, and learning related models of opioid withdrawal and abstinence. Neuroadaptations in these stress and motivational systems are accompanied by negative affective and aversive experiences that commonly give rise to relapse. CeA neuroplasticity accounts for many of the aversive and fear-related effects of opioid withdrawal via glutamatergic plasticity and changes to corticotrophin-releasing factor (CRF)-containing neurons. Neuroadaptations in BNST pre-and post-synaptic GABA-containing neurons, as well as their noradrenergic modulation, may be responsible for a variety of aversive affective experiences and maladaptive behaviors. Opioid withdrawal yields a hypodopaminergic and amotivational state and results in neuroadaptive increases in excitability of the NAc shell, both of which are associated with increased vulnerability to relapse. Finally, BLA transmission to hippocampal and cortical regions impacts the perception of conditioned aversive effects of opioid withdrawal by higher executive systems. The prevention or reversal of these varied neuroadaptations in the extended amygdala during opioid withdrawal could lead to promising new interventions for this life-threatening condition.

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“…This notion is in line with our previous study showing an increased expression of GluA1 subunits of AMPARs in CeA neurons under CFA-induced persistent pain ( Hou et al, 2015 ). AMPARs are especially crucial for emotional events of learning and memory through activity-dependent synaptic strengthening via re-composition of GluA1 and GluA2 subunits ( Malinow and Malenka, 2002 ; Maren, 2005 ; Shepherd and Huganir, 2007 ; Bowers et al, 2010 ; Clem and Huganir, 2010 ; Krugers et al, 2010 ; McCool et al, 2010 ; Cole et al, 2012 ; Cai et al, 2013 , 2020 ). This AMPAR strengthening is achieved by switching from low conductance, GluA2-containing AMPARs to high conductance, homomeric GluA1 AMPARs ( Geiger et al, 1995 ; Isaac et al, 2007 ; Kauer and Malenka, 2007 ; Shepherd and Huganir, 2007 ; Polgar et al, 2008 ; Bowers et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Synaptic plasticity in two cell types of central amygdala for regulation of emotion and pain

Cai²,

Pan³

2022

Front. Cell. Neurosci.

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The amygdala is a critical brain site for regulation of emotion-associated behaviors such as pain and anxiety. Recent studies suggest that differential cell types and synaptic circuits within the amygdala complex mediate interacting and opposing effects on emotion and pain. However, the underlying cellular and circuit mechanisms are poorly understood at present. Here we used optogenetics combined with electrophysiological analysis of synaptic inputs to investigate pain-induced synaptic plasticity within the amygdala circuits in rats. We found that 50% of the cell population in the lateral division of the central nucleus of the amygdala (CeAl) received glutamate inputs from both basolateral amygdala (BLA) and from the parabrachial nucleus (PBN), and 39% of the remaining CeAl cells received glutamate inputs only from PBN. Inflammatory pain lasting 3 days, which induced anxiety, produced sensitization in synaptic activities of the BLA–CeAl–medial division of CeA (CeAm) pathway primarily through a postsynaptic mechanism. Moreover, in CeAl cells receiving only PBN inputs, pain significantly augmented the synaptic strength of the PBN inputs. In contrast, in CeAl cells receiving both BLA and PBN inputs, pain selectively increased the synaptic strength of BLA inputs, but not the PBN inputs. Electrophysiological analysis of synaptic currents showed that the increased synaptic strength in both cases involved a postsynaptic mechanism. These findings reveal two main populations of CeAl cells that have differential profiles of synaptic inputs and show distinct plasticity in their inputs in response to anxiety-associated pain, suggesting that the specific input plasticity in the two populations of CeAl cells may encode a different role in amygdala regulation of pain and emotion.

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GluA1 in central amygdala increases pain but inhibits opioid withdrawal-induced aversion

Cited by 8 publications

References 54 publications

Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches

Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches

Neuroplasticity of the extended amygdala in opioid withdrawal and prolonged opioid abstinence

Synaptic plasticity in two cell types of central amygdala for regulation of emotion and pain

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