Kappa opioid receptor activation in the amygdala disinhibits CRF neurons to generate pain-like behaviors

• Published in: Neuropharmacology Vol. 185; p. 108456
• Main Authors: Hein, Matthew, Ji, Guangchen, Tidwell, Dalton, D'Souza, Preston, Kiritoshi, Takaki, Yakhnitsa, Vadim, Navratilova, Edita, Porreca, Frank, Neugebauer, Volker
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-03-2021
• Subjects: Amygdala; Amygdala - drug effects; Amygdala - metabolism; Animals; Behavior; Benzeneacetamides - administration & dosage; Corticotropin-releasing factor; Corticotropin-Releasing Hormone - antagonists & inhibitors; Corticotropin-Releasing Hormone - metabolism; Kappa opioid receptor; Male; Pain; Pain - metabolism; Pain Measurement - drug effects; Pain Measurement - methods; Patch clamp; Pyrrolidines - administration & dosage; Rats; Rats, Transgenic; Rats, Wistar; Receptors, Opioid, kappa - metabolism; Stereotaxic Techniques; Vocalization, Animal - drug effects; Vocalization, Animal - physiology; Patch clamp; Corticotropin-releasing factor; Pain; Behavior; Amygdala; Kappa opioid receptor
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2021.108456

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.
•Kappa opioid receptors in the amygdala facilitate averse-affective pain behaviors.•Optogenetic silencing of CRF neurons in the amygdala blocks behavioral effects.•Kappa opioid receptors attenuate feedforward inhibition of CRF amygdala neurons.•Kappa opioid receptors act presynaptically to disinhibit CRF neurons.•Blockade of KOR signaling in the amygdala may have therapeutic implications.