Contribution of Corticotropin-Releasing Factor Receptor 1 (CRF1) to Serotonin Receptor 5-HT2CR Function in Amygdala Neurons in a Neuropathic Pain Model

Ji, Guangchen; Neugebauer, Volker

doi:10.3390/ijms20184380

Cited by 19 publications

(9 citation statements)

References 93 publications

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“…Extracellular single-unit recordings were made from neurons in the lateral-capsular division of the CeA in the right hemisphere as described previously [ 14 , 32 , 42 , 43 ]. Rats were anesthetized with isoflurane (3–4% induction, 2% maintenance; precision vaporizer, Harvard Apparatus, Holliston, MA).…”

Section: Methodsmentioning

confidence: 99%

Kappa opioid receptors in the central amygdala modulate spinal nociceptive processing through an action on amygdala CRF neurons

Neugebauer

2020

Mol Brain

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The amygdala plays an important role in the emotional-affective aspects of behaviors and pain, but can also modulate sensory aspect of pain (“nociception”), likely through coupling to descending modulatory systems. Here we explored the functional coupling of the amygdala to spinal nociception. We found that pharmacological activation of neurons in the central nucleus of the amygdala (CeA) increased the activity of spinal dorsal horn neurons; and this effect was blocked by optogenetic silencing of corticotropin releasing factor (CRF) positive CeA neurons. A kappa opioid receptor (KOR) agonist (U-69,593) was administered into the CeA by microdialysis. KOR was targeted because of their role in averse-affective behaviors through actions in limbic brain regions. Extracellular single-unit recordings were made of CeA neurons or spinal dorsal horn neurons in anesthetized transgenic Crh-Cre rats. Neurons responded more strongly to noxious than innocuous stimuli. U-69,593 increased the responses of CeA and spinal neurons to innocuous and noxious mechanical stimulation of peripheral tissues. The facilitatory effect of the agonist was blocked by optical silencing of CRF-CeA neurons though light activation of halorhodopsin expressed in these neurons by viral-vector. The CRF system in the amygdala has been implicated in aversiveness and pain modulation. The results suggest that the amygdala can modulate spinal nociceptive processing in a positive direction through CRF-CeA neurons and that KOR activation in the amygdala (CeA) has pro-nociceptive effects.

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Section: Methodsmentioning

confidence: 99%

Kappa opioid receptors in the central amygdala modulate spinal nociceptive processing through an action on amygdala CRF neurons

Neugebauer

2020

Mol Brain

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“…The synaptic and cellular mechanisms of KOR signaling in CeA are not well understood, and we addressed this knowledge gap here. Electrophysiological studies in anesthetized animals have reported increased activity of individual CeA neurons evoked by innocuous and noxious stimulation in a model of arthritic pain ( Neugebauer and Li, 2003 ; Li and Neugebauer, 2004 ; Ji and Neugebauer, 2007 ; Ji and Neugebauer, 2009 ) and in a neuropathic pain model ( Goncalves and Dickenson, 2012 ; Ji et al, 2017 ; Ji and Neugebauer, 2019 ). So-called “multireceptive” CeA neurons are characterized by their stronger activation by noxious than innocuous stimulation; they may serve the integration and evaluation of sensory-affective processing in the context of pain ( Neugebauer et al, 2004 ).…”

Section: Discussionmentioning

confidence: 99%

“…These distinct neuronal populations differentially modulate diverse behaviors, including fear and pain-related behaviors ( Haubensak et al, 2010 ; Wilson et al, 2019 ; Neugebauer et al, 2020 ). The amygdala CRF system has been implicated in stress, fear, anxiety, and depression ( Gafford and Ressler, 2016 ; Pomrenze et al, 2019a ; Pliota et al, 2020 ) and is also recognized as an important player in pain-related plasticity and behavior ( Fu and Neugebauer, 2008 ; Neugebauer, 2015 ; Ji and Neugebauer, 2019 ; Mazzitelli et al, 2021 ). Upregulation of CRF expression levels in the CeA produced mechanical and visceral hypersensitivity, which was blocked by CRF knockdown ( Johnson et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Kappa Opioid Receptor Blockade in the Amygdala Mitigates Pain Like-Behaviors by Inhibiting Corticotropin Releasing Factor Neurons in a Rat Model of Functional Pain

Yakhnitsa

Hein

et al. 2022

Front. Pharmacol.

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Functional pain syndromes (FPS) occur in the absence of identifiable tissue injury or noxious events and include conditions such as migraine, fibromyalgia, and others. Stressors are very common triggers of pain attacks in various FPS conditions. It has been recently demonstrated that kappa opioid receptors (KOR) in the central nucleus of amygdala (CeA) contribute to FPS conditions, but underlying mechanisms remain unclear. The CeA is rich in KOR and encompasses major output pathways involving extra-amygdalar projections of corticotropin releasing factor (CRF) expressing neurons. Here we tested the hypothesis that KOR blockade in the CeA in a rat model of FPS reduces pain-like and nocifensive behaviors by restoring inhibition of CeA-CRF neurons. Intra-CeA administration of a KOR antagonist (nor-BNI) decreased mechanical hypersensitivity and affective and anxiety-like behaviors in a stress-induced FPS model. In systems electrophysiology experiments in anesthetized rats, intra-CeA application of nor-BNI reduced spontaneous firing and responsiveness of CeA neurons to peripheral stimulation. In brain slice whole-cell patch-clamp recordings, nor-BNI increased feedforward inhibitory transmission evoked by optogenetic and electrical stimulation of parabrachial afferents, but had no effect on monosynaptic excitatory transmission. Nor-BNI decreased frequency, but not amplitude, of spontaneous inhibitory synaptic currents, suggesting a presynaptic action. Blocking KOR receptors in stress-induced FPS conditions may therefore represent a novel therapeutic strategy.

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“…The excitability of CeA neurons is increased, c-fos and extracellular signal-regulated kinase are activated in visceral pain ( 55 , 56 ). The increased excitability of CeA in neuropathic pain is accompanied by an increase in expression of corticotrophin-releasing factor and glucocorticoid receptors ( 57 , 58 ). In our experiment, we observed that some CaMKII-positive neurons were activated in CeA.…”

Section: Discussionmentioning

confidence: 99%

Glutamatergic Neurons in the Amygdala Are Involved in Paclitaxel-Induced Pain and Anxiety

Liu

Huang

et al. 2022

Front. Psychiatry

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Paclitaxel is widely used as a first-line chemotherapy agent to treat malignant tumors. However, paclitaxel causes peripheral nerve fiber damage and neuropathic pain in some patients. In addition, patients received paclitaxel chemotherapy are often accompanied by negative emotions such as anxiety. The amygdala is critically involved in regulating pain signals, as well as anxiety. The purpose of this study is to clarify the role of Ca2+/calmodulin-dependent protein kinase II (CaMKII)-positive glutamatergic neurons in the amygdala in paclitaxel-induced pain and negative affective symptoms. Intraperitoneal injection of paclitaxel into mice caused mechanical and thermal allodynia, as measured by Von Frey test and Hargreaves test, and anxiety, as measured by open field test and elevated plus maze test. Immunofluorescence staining revealed that c-fos-positive neurons were significantly more in the basolateral amygdala (BLA) and central amygdala (CeA) in paclitaxel-treated mice than untreated mice. Furthermore, part of c-fos-positive neurons in the BLA were immunoreactive of CaMKII. Engineered Designer receptors exclusively activated by designer drugs (DREADD) receptor hM4Di or hM3Dq was selectively expressed on CaMKII neurons by injection of adeno-associated virus (AAV) vectors containing CaMKII and hM4Di or hM3Dq. Administration of DREADD agonist CNO to selectively inhibit the CaMKII neurons in the BLA significantly increased the paw withdrawal thresholds and paw withdrawal latencies. In addition, selectively inhibition of CaMKII neurons in the BLA alleviated anxiety behavior without affecting the motor activity. In summary, our findings suggest that CaMKII neurons in the amygdala are critical for neuropathic pain and anxiety behaviors induced by paclitaxel chemotherapy.

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Contribution of Corticotropin-Releasing Factor Receptor 1 (CRF1) to Serotonin Receptor 5-HT2CR Function in Amygdala Neurons in a Neuropathic Pain Model

Cited by 19 publications

References 93 publications

Kappa opioid receptors in the central amygdala modulate spinal nociceptive processing through an action on amygdala CRF neurons

Kappa opioid receptors in the central amygdala modulate spinal nociceptive processing through an action on amygdala CRF neurons

Kappa Opioid Receptor Blockade in the Amygdala Mitigates Pain Like-Behaviors by Inhibiting Corticotropin Releasing Factor Neurons in a Rat Model of Functional Pain

Glutamatergic Neurons in the Amygdala Are Involved in Paclitaxel-Induced Pain and Anxiety

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