Kappa opioid receptor activation in the amygdala disinhibits CRF neurons to generate pain-like behaviors.
Amygdala
/ drug effects
Animals
Benzeneacetamides
/ administration & dosage
Corticotropin-Releasing Hormone
/ antagonists & inhibitors
Male
Pain
/ metabolism
Pain Measurement
/ drug effects
Pyrrolidines
/ administration & dosage
Rats
Rats, Transgenic
Rats, Wistar
Receptors, Opioid, kappa
/ metabolism
Stereotaxic Techniques
Vocalization, Animal
/ drug effects
Amygdala
Behavior
Corticotropin-releasing factor
Kappa opioid receptor
Pain
Patch clamp
Journal
Neuropharmacology
ISSN: 1873-7064
Titre abrégé: Neuropharmacology
Pays: England
ID NLM: 0236217
Informations de publication
Date de publication:
01 03 2021
01 03 2021
Historique:
received:
23
10
2020
revised:
01
01
2021
accepted:
05
01
2021
pubmed:
15
1
2021
medline:
3
3
2022
entrez:
14
1
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33444637
pii: S0028-3908(21)00010-1
doi: 10.1016/j.neuropharm.2021.108456
pmc: PMC7887082
mid: NIHMS1663481
pii:
doi:
Substances chimiques
Benzeneacetamides
0
Pyrrolidines
0
Receptors, Opioid, kappa
0
Corticotropin-Releasing Hormone
9015-71-8
U 69593
J5S4K6TKTG
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
108456Subventions
Organisme : NIDA NIH HHS
ID : R01 DA041809
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS038261
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS106902
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS109255
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.
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