Kappa opioid receptor activation in the amygdala disinhibits CRF neurons to generate pain-like behaviors
Copyright © 2021 Elsevier Ltd. All rights reserved..
Recent evidence suggests that kappa opioid receptors (KOR) in limbic brain regions such as the amygdala contribute to pain conditions, but underlying mechanisms remain to be determined. The amygdala is an important player in averse-affective aspects of pain and pain modulation. The central nucleus (CeA) serves output functions through projection neurons that include corticotropin releasing factor (CRF) expressing neurons. The CeA is also rich in KOR. Here we tested the novel hypothesis that KOR activation in the CeA generates pain-like behaviors through a mechanism that involves inhibition of synaptic inhibition (disinhibition) of CRF neurons. Intra-CeA administration of a KOR agonist (U-69,593) increased vocalizations of naïve rats to noxious stimuli, and induced anxiety-like behaviors in the open field test (OFT) and avoidance in the conditioned place preference test, without affecting mechanosensory thresholds. Optogenetic silencing of CeA-CRF neurons blocked the facilitatory effects of systemically applied U-69,593 in naïve rats. Patch-clamp recordings of CRF neurons in rat brain slices found that U-69,593 decreased feedforward inhibitory transmission evoked by optogenetic stimulation of parabrachial afferents, but had no effect on monosynaptic excitatory transmission. U-69,593 decreased frequency, but not amplitude, of inhibitory synaptic currents, suggesting a presynaptic action. Multiphoton imaging of CeA-CRF neurons in rat brain slices showed that U-69,593 increased calcium signals evoked by electrical stimulation of presumed parabrachial input. This study shows for the first time that KOR activation increases activity of amygdala CRF neurons through synaptic disinhibition, resulting in averse-affective pain-like behaviors. Blocking KOR receptors may therefore represent a novel therapeutic strategy.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:185 |
|---|---|
| Enthalten in: |
Neuropharmacology - 185(2021) vom: 01. März, Seite 108456 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Hein, Matthew [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 21.10.2021 Date Revised 30.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.neuropharm.2021.108456 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM320078884 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM320078884 | ||
| 003 | DE-627 | ||
| 005 | 20240330235408.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.neuropharm.2021.108456 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1357.xml |
| 035 | |a (DE-627)NLM320078884 | ||
| 035 | |a (NLM)33444637 | ||
| 035 | |a (PII)S0028-3908(21)00010-1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Hein, Matthew |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Kappa opioid receptor activation in the amygdala disinhibits CRF neurons to generate pain-like behaviors |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 21.10.2021 | ||
| 500 | |a Date Revised 30.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier Ltd. All rights reserved. | ||
| 520 | |a Recent evidence suggests that kappa opioid receptors (KOR) in limbic brain regions such as the amygdala contribute to pain conditions, but underlying mechanisms remain to be determined. The amygdala is an important player in averse-affective aspects of pain and pain modulation. The central nucleus (CeA) serves output functions through projection neurons that include corticotropin releasing factor (CRF) expressing neurons. The CeA is also rich in KOR. Here we tested the novel hypothesis that KOR activation in the CeA generates pain-like behaviors through a mechanism that involves inhibition of synaptic inhibition (disinhibition) of CRF neurons. Intra-CeA administration of a KOR agonist (U-69,593) increased vocalizations of naïve rats to noxious stimuli, and induced anxiety-like behaviors in the open field test (OFT) and avoidance in the conditioned place preference test, without affecting mechanosensory thresholds. Optogenetic silencing of CeA-CRF neurons blocked the facilitatory effects of systemically applied U-69,593 in naïve rats. Patch-clamp recordings of CRF neurons in rat brain slices found that U-69,593 decreased feedforward inhibitory transmission evoked by optogenetic stimulation of parabrachial afferents, but had no effect on monosynaptic excitatory transmission. U-69,593 decreased frequency, but not amplitude, of inhibitory synaptic currents, suggesting a presynaptic action. Multiphoton imaging of CeA-CRF neurons in rat brain slices showed that U-69,593 increased calcium signals evoked by electrical stimulation of presumed parabrachial input. This study shows for the first time that KOR activation increases activity of amygdala CRF neurons through synaptic disinhibition, resulting in averse-affective pain-like behaviors. Blocking KOR receptors may therefore represent a novel therapeutic strategy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Amygdala | |
| 650 | 4 | |a Behavior | |
| 650 | 4 | |a Corticotropin-releasing factor | |
| 650 | 4 | |a Kappa opioid receptor | |
| 650 | 4 | |a Pain | |
| 650 | 4 | |a Patch clamp | |
| 650 | 7 | |a Benzeneacetamides |2 NLM | |
| 650 | 7 | |a Pyrrolidines |2 NLM | |
| 650 | 7 | |a Receptors, Opioid, kappa |2 NLM | |
| 650 | 7 | |a Corticotropin-Releasing Hormone |2 NLM | |
| 650 | 7 | |a 9015-71-8 |2 NLM | |
| 650 | 7 | |a U 69593 |2 NLM | |
| 650 | 7 | |a J5S4K6TKTG |2 NLM | |
| 700 | 1 | |a Ji, Guangchen |e verfasserin |4 aut | |
| 700 | 1 | |a Tidwell, Dalton |e verfasserin |4 aut | |
| 700 | 1 | |a D'Souza, Preston |e verfasserin |4 aut | |
| 700 | 1 | |a Kiritoshi, Takaki |e verfasserin |4 aut | |
| 700 | 1 | |a Yakhnitsa, Vadim |e verfasserin |4 aut | |
| 700 | 1 | |a Navratilova, Edita |e verfasserin |4 aut | |
| 700 | 1 | |a Porreca, Frank |e verfasserin |4 aut | |
| 700 | 1 | |a Neugebauer, Volker |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Neuropharmacology |d 1970 |g 185(2021) vom: 01. März, Seite 108456 |w (DE-627)NLM000008486 |x 1873-7064 |7 nnns |
| 773 | 1 | 8 | |g volume:185 |g year:2021 |g day:01 |g month:03 |g pages:108456 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.neuropharm.2021.108456 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 185 |j 2021 |b 01 |c 03 |h 108456 | ||