Dataset Information

Dual and Opposing Functions of the Central Amygdala in the Modulation of Pain.

ABSTRACT: Pain perception is essential for survival and can be amplified or suppressed by expectations, experiences, and context. The neural mechanisms underlying bidirectional modulation of pain remain largely unknown. Here, we demonstrate that the central nucleus of the amygdala (CeA) functions as a pain rheostat, decreasing or increasing pain-related behaviors in mice. This dual and opposing function of the CeA is encoded by opposing changes in the excitability of two distinct subpopulations of GABAergic neurons that receive excitatory inputs from the parabrachial nucleus (PB). Thus, cells expressing protein kinase C-delta (CeA-PKC?) are sensitized by nerve injury and increase pain-related responses. In contrast, cells expressing somatostatin (CeA-Som) are inhibited by nerve injury and their activity drives antinociception. Together, these results demonstrate that the CeA can amplify or suppress pain in a cell-type-specific manner, uncovering a previously unknown mechanism underlying bidirectional control of pain in the brain.

SUBMITTER: Wilson TD

PROVIDER: S-EPMC6816228 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Dual and Opposing Functions of the Central Amygdala in the Modulation of Pain.

Wilson Torri D TD Valdivia Spring S Khan Aleisha A Ahn Hye-Sook HS Adke Anisha P AP Martinez Gonzalez Santiago S Sugimura Yae K YK Carrasquillo Yarimar Y

Cell reports 20191001 2

Pain perception is essential for survival and can be amplified or suppressed by expectations, experiences, and context. The neural mechanisms underlying bidirectional modulation of pain remain largely unknown. Here, we demonstrate that the central nucleus of the amygdala (CeA) functions as a pain rheostat, decreasing or increasing pain-related behaviors in mice. This dual and opposing function of the CeA is encoded by opposing changes in the excitability of two distinct subpopulations of GABAerg ...[more]

PMID: 31597095

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Project description:The amygdala is a brain area involved in emotional regulation and pain. Over the course of the last 20 years, multiple researchers have studied sensory and motor connections within the amygdala in trying to understand the ultimate role of this structure in pain perception and descending control of pain. A number of investigators have been using cell-type specific manipulations to probe the underlying circuitry of the amygdala. As data have accumulated in this research space, we recognized a critical need for a single framework to integrate these data and evaluate emergent system-level responses. In this manuscript, we present an agent-based computational model of two distinct inhibitory neuron populations in the amygdala, those that express protein kinase C delta (PKCδ) and those that express somatostatin (SOM). We utilized a network of neural links to simulate connectivity and the transmission of inhibitory signals between neurons. Type-specific parameters describing the response of these neurons to noxious stimuli were estimated from published physiological and immunological data as well as our own wet-lab experiments. The model outputs an abstract measure of pain, which is calculated in terms of the cumulative pro-nociceptive and anti-nociceptive activity across neurons in both hemispheres of the amygdala. Results demonstrate the ability of the model to produce changes in pain that are consistent with published studies and highlight the importance of several model parameters. In particular, we found that the relative proportion of PKCδ and SOM neurons within each hemisphere is a key parameter in predicting pain and we explored model predictions for three possible values of this parameter. We compared model predictions of pain to data from our earlier behavioral studies and found areas of similarity as well as distinctions between the data sets. These differences, in particular, suggest a number of wet-lab experiments that could be done in the future.

Project description:BackgroundChronic neck pain is a leading cause of disability worldwide, affecting the lives of millions of people. Research investigating functional brain alterations in relation to somatosensory function is necessary to better understand mechanisms underlying pain development and maintenance in individuals with chronic neck pain, yet remains scarce. This case-control study aimed to examine resting-state functional connectivity alterations and associations with pain outcomes, self-reported central sensitization-related symptoms and quantitative sensory testing (QST) measures in patients with chronic non-traumatic (idiopathic/CINP) neck pain and chronic traumatic (whiplash associated/CWAD) neck pain compared to pain-free controls.MethodsResting-state functional magnetic resonance images were acquired in 107 female participants (38 CINP, 37 CWAD, 32 healthy controls). After data pre-processing, seed-to-seed analyses were conducted focusing on resting-state functional connectivity involving pre-defined regions of interest that have previously been observed to be structurally or functionally altered and/or associated with pain-related measures in this patient population.ResultsFindings demonstrate enhanced left amygdala functional coupling during rest with the left frontal operculum in women with CINP and CWAD compared to controls. This increased resting-state functional connectivity was associated with more self-reported symptoms related to central sensitization and decreased efficacy of conditioned pain modulation. Furthermore, enhanced connectivity between the left amygdala and left frontal orbital cortex, and between the left pallidum and the left frontal operculum was observed only in patients with CWAD compared to healthy controls. In patients, additional associations between local hyperalgesia and enhanced connectivity between the left superior parietal cortex and the left and right precentral gyrus were found.ConclusionsIn line with our hypotheses, patients with CWAD showed the most pronounced alterations in resting-state functional connectivity, encompassing subcortical limbic (amygdala) and basal ganglia (pallidum), and ventral frontal regions (frontal operculum, orbitofrontal cortex) when compared to CINP and controls. Findings are generally in line with the idea of a continuum, in absence of significant group differences across CINP and CWAD. Enhanced amygdala-frontal operculum functional connectivity was the most robust and only connectivity pair in the cluster that was associated with QST (i.e., dynamic QST; endogenous pain inhibition), and that was observed in both patient groups. In addition, independent of group differences, enhanced resting-state functional connectivity between superior parietal cortex (involved in attention) and primary motor cortex was associated with static QST (i.e., greater local hyperalgesia). Taken together, our findings show a key role for enhanced amygdala-ventral frontal circuitry in chronic neck pain, and its association with diminished endogenous pain inhibition further emphasizes the link between cognitive-affective and sensory modulations of pain in women with chronic non-traumatic and traumatic neck pain.

Dataset Information

Dual and Opposing Functions of the Central Amygdala in the Modulation of Pain.

Publications

Dual and Opposing Functions of the Central Amygdala in the Modulation of Pain.

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