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

Guangchen Ji,Volker Neugebauer

doi:10.1186/s13041-020-00669-3

Abstract

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.

Highlights

The amygdala has emerged as an important node of the emotional-affective aspects of pain and pain modulation [1–6]
Experiments were designed to test the hypothesis that kappa opioid receptors (KOR) activation in the amygdala under normal conditions increases activity of spinal dorsal horn neurons through the activation of corticotropin releasing factor (CRF) neurons in the amygdala (CeA)
Facilitatory effects of KOR activation on central nucleus (CeA) neurons Extracellular single-unit recordings of 19 CeA neurons were made in 9 animals (1–2 neurons were studied in each animal)

Summary

Introduction

The amygdala has emerged as an important node of the emotional-affective aspects of pain and pain modulation [1–6]. The central nucleus (CeA) serves major amygdala output functions and receives pain-related information through the spino-parabrachio-amygdala pathway as well. Ji and Neugebauer Molecular Brain (2020) 13:128 circuits and cell types serve different functions related to different aspects of pain. There is little information about the modulation of dorsal horn activity by the amygdala, amygdala neurons project to and can modulate descending pain control centers such as periaqueductal gray PAG [2, 35, 36]. A recent study showed that morphine injection into the CeA, but not anterior cingulate cortex (ACC), reduced the responses to spinal dorsal horn neurons to noxious mechanical stimulation in a neuropathic pain model [37]. Block of kappa opioid receptors (KOR) in the CeA restored the loss of diffuse noxious inhibitory control (DNIC) in a neuropathic pain model, implicating amygdala KOR in descending pain modulation

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Discussion

Conclusion