Kappa opioid receptors in the central amygdala modulate spinal nociceptive processing through an action on amygdala CRF
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Kappa opioid receptors in the central amygdala modulate spinal nociceptive processing through an action on amygdala CRF neurons Guangchen Ji1,2 and Volker Neugebauer1,2,3*
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. Keywords: Amygdala, Kappa opioid receptor, Spinal dorsal horn, Nociception, Optogenetics
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 * Correspondence: [email protected] 1 Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, School of Medicine, 3601 4th St, Lubbock, TX 79430-6592, USA 2 Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, USA Full list of author information is available at the end of the article
as from thalamic and cortical regions through the basolateral amygdala network [2]. Importantly, synaptic plasticity in the CeA in different pain models has been linked to emotional responses such as vocalizations, aversive behaviors in conditioned place preference/aversion assays, and anxio-depressive behaviors [7–16]. The contribution of the amygdala to sensory aspects of pain such as hypersensitivity in pain models is less clear. Manipulations of amygdala activity provided evidence for dual pro- and an
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