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An amygdalo-parabrachial pathway regulates pain perception and chronic pain

Charles Raver, Olivia Uddin, Yadong Ji, Ying Li, Nathan Cramer, Carleigh Jenne, Marisela Morales, Radi Masri, View ORCID ProfileAsaf Keller
doi: https://doi.org/10.1101/2020.01.10.902205
Charles Raver
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201
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Olivia Uddin
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201
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Yadong Ji
Department of Advanced Oral Sciences and Therapeutics, University of Maryland School of Dentistry, Baltimore, Maryland 21201
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Ying Li
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201
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Nathan Cramer
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201
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Carleigh Jenne
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201
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Marisela Morales
Neuronal Networks Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224
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Radi Masri
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201Department of Advanced Oral Sciences and Therapeutics, University of Maryland School of Dentistry, Baltimore, Maryland 21201
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Asaf Keller
Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201
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  • ORCID record for Asaf Keller
  • For correspondence: akeller@som.umaryland.edu
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Abstract

The parabrachial (PB) complex mediates both ascending nociceptive signaling and descending pain modulatory information in the affective/emotional pain pathway. We have recently reported that chronic pain is associated with amplified activity of PB neurons in a rat model of neuropathic pain. Here we demonstrate that similar activity amplification occurs in mice, and that this is related to suppressed inhibition to PB neurons from the central nucleus of the amygdala (CeA). Animals with pain after chronic constriction injury of the infraorbital nerve (CCI-Pain) displayed higher spontaneous and evoked activity in PB neurons, and a dramatic increase in after-discharges—responses that far outlast the stimulus—compared to controls. PB neurons in CCI-Pain animals showed a reduction in inhibitory, GABAergic inputs. We show that—in both rats and mice—PB contains few GABAergic neurons, and that most of its GABAergic inputs arise from CeA. These CeA GABA neurons express dynorphin, somatostatin and/or corticotropin releasing hormone. We find that the efficacy of this CeA-LPB pathway is suppressed in chronic pain. Further, optogenetically stimulating this pathway suppresses acute pain, and inhibiting it, in naïve animals, evokes pain behaviors. These findings demonstrate that the CeA-LPB pathway is critically involved in pain regulation, and in the pathogenesis of chronic pain.

Significance Statement We describe a novel pathway, consisting of inhibition by dynorphin, somatostatin and corticotropin-releasing hormone expressing neurons in the central nucleus of the amygdala that project to the parabrachial nucleus (PB). We show that this pathway regulates the activity of pain-related neurons in PB, and that, in chronic pain, this inhibitory pathway is suppressed, and that this suppression is causally related to pain perception. We propose that this amygdalo-parabrachial pathway is a key regulator of both chronic and acute pain, and a novel target for pain relief.

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    Posted January 11, 2020.
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    An amygdalo-parabrachial pathway regulates pain perception and chronic pain
    Charles Raver, Olivia Uddin, Yadong Ji, Ying Li, Nathan Cramer, Carleigh Jenne, Marisela Morales, Radi Masri, Asaf Keller
    bioRxiv 2020.01.10.902205; doi: https://doi.org/10.1101/2020.01.10.902205
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    An amygdalo-parabrachial pathway regulates pain perception and chronic pain
    Charles Raver, Olivia Uddin, Yadong Ji, Ying Li, Nathan Cramer, Carleigh Jenne, Marisela Morales, Radi Masri, Asaf Keller
    bioRxiv 2020.01.10.902205; doi: https://doi.org/10.1101/2020.01.10.902205

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