Basic Science: Physiology

Neural Circuits for Pain Modulation in the CeA

It is well known that expectations, experiences, and context can amplify or suppress pain perception. However, the neural mechanisms underlying bidirectional modulation of pain remain largely unknown. I will discuss the evidence from my laboratory that the central nucleus of the amygdala (CeA) functions as a pain rheostat, decreasing or increasing pain-related behaviors in mice in a cell-type-specific manner. In particular, I will show evidence that cells expressing protein kinase C-delta (CeA-PKCδ) are sensitized by nerve injury and increase pain-related responses, and those expressing somatostatin (CeA-Som) are inhibited by nerve injury, and their activity drives antinociception. In this Refresher Course, I will discuss this previously unknown mechanism with which the CeA can bidirectionally modulate pain.

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Amygdala Neuroplasticity and Pain Behaviors with a Focus on CRF Neurons

Neuroplasticity in the central amygdala is causally linked to pain behaviors in different models. Electrophysiological approaches for the analysis of neural activity changes in pain conditions will be discussed. Pharmacological, optogenetic and chemogenetic techniques will be presented to link neural activity and neuroplastic changes to pain behaviors. A focus will be on CRF neurons.

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What has Made the Central Amygdala so Central in Understanding Non-Thalamic Pain System? – History, Circuits, Translation, and Prospective

The amygdala has been well known as a site for emotional behaviors and learning since 90 years ago. Jean-Francois Bernard and his group were the first to show the direct projections from the spinal cord to the parabrachial nucleus and then to the capsular part of the central amygdala (CeA) in 1988. They dubbed it spino-(trigemino-)parabrachio-amygdaloid pathway. They also provided the first electrophysiological evidence for noxious stimulation-induced excitation in a majority of the neurons in this CeA region, calling it “the nociceptive amygdala”. Later, Neugebauer’s group pioneered in demonstrating increased nociceptive responses, widened receptive fields, and augmented emotional behaviors in persistent pain models. These seminal studies opened the door to the neuroscience of the central amygdala in pain, followed by demonstrations of synaptic potentiation in neuropathic pain models by Kato’s group and tactile sensitization by MAP kinase activation in the CeA in the intact animals by Carrasquillo and Gereau, and many other studies supporting the concept that the CeA plays kernel roles not only in the nociception-emotion link but also in the central regulation of nociceptive function. The attendees will obtain fundamental and up-to-date knowledge about what the central amygdala does in pain.

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The Central Amygdala in Chronic Pain – Circuit, Neuropeptides, and Nociplasticity

Recently accumulated lines of evidence in these years indicate that a small limbic structure called the central amygdala (CeA) plays an essential role in establishing chronic pain and related symptoms such as negative emotion, autonomic maladaptation, and widespread sensitization. The CeA has also been known as a site for fear/threat learning, taste aversion, responses to predator odor, and stress responses, thus making it a kernel structure for survival and defense. In this sense, it is reasonable that it plays a central role in the “pain,” an unpleasant sensory and emotional experience, of various forms. It is also well described as the site of adaptive neuroplasticity involving diverse neuropeptides and receptors, including CRF, oxytocin, CGRP, and opioids. In addition, the CeA is strategically well located to receive and send nociception-associated information through rich mutual connections. Evidence in human studies also suggests the involvement of the CeA in patients with chronic pain, suggesting understanding its function would have translational value to tackle the unexplored mechanisms underlying chronic nociplastic pain. This refresher course will provide you with the most updated information to understand the CeA and what makes the CeA the primary player in various forms of pain.

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