Newly Published
Pain Medicine  |   January 2020
A Central Amygdala–Ventrolateral Periaqueductal Gray Matter Pathway for Pain in a Mouse Model of Depression-like Behavior
Author Notes
  • From the Hefei National Laboratory for Physical Sciences at the Microscale, Key Laboratory of Brain Function and Disease of Chinese Academy of Science, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, China (W.Y., L.M., T.S., Y.W., Jie Li, C.C., Z.F., Y.M., W.T., Juan Li, Z.Z.); the Department of Psychology, Anhui Mental Health Center, Hefei, China (W.X., Z.Z.); and the Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China (Y.M., W.T.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • W.Y. and L.M. contributed equally to this article.
    W.Y. and L.M. contributed equally to this article.×
  • Submitted for publication May 13, 2019. Accepted for publication December 17, 2019.
    Submitted for publication May 13, 2019. Accepted for publication December 17, 2019.×
  • Correspondence: Address correspondence to Dr. Zhang: Hefei National Laboratory for Physical Sciences at the Microscale, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, Anhui 230027, China. zhizhang@ustc.edu.cn. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Central and Peripheral Nervous Systems / Pain Medicine
Pain Medicine   |   January 2020
A Central Amygdala–Ventrolateral Periaqueductal Gray Matter Pathway for Pain in a Mouse Model of Depression-like Behavior
Anesthesiology Newly Published on January 27, 2020. doi:https://doi.org/10.1097/ALN.0000000000003133
Anesthesiology Newly Published on January 27, 2020. doi:https://doi.org/10.1097/ALN.0000000000003133
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Patients with depression are more likely to develop chronic pain and vice versa.

  • Neuroimaging studies reveal that many brain regions implicated in depression also contribute to central pain processing.

  • The mechanisms through which depressive states influence pain processing are poorly understood.

What This Article Tells Us That Is New:

  • Chemogenetic experiments in a mouse model of depression reveal the involvement of a neural circuitry between the central amygdala and the periaqueductal gray in nociception.

  • In this mouse model, pathologically increased activity of inhibitory γ-aminobutyric acid–mediated neurons in the central amygdala will result in the inhibition of inhibitory γ-aminobutyric acid–mediated neurons in the periaqueductal gray. This, in turn, will lead to the activation of glutamatergic cells involved in periaqueductal gray–mediated nociception.

  • These findings provide a framework for how the central amygdala–periaqueductal gray circuitry may play a role in coping with nociception in depressive states.

Background: The mechanisms underlying depression-associated pain remain poorly understood. Using a mouse model of depression, the authors hypothesized that the central amygdala–periaqueductal gray circuitry is involved in pathologic nociception associated with depressive states.

Methods: The authors used chronic restraint stress to create a mouse model of nociception with depressive-like behaviors. They then used retrograde tracing strategies to dissect the pathway from the central nucleus of the amygdala to the ventrolateral periaqueductal gray. The authors performed optogenetic and chemogenetic experiments to manipulate the activity of this pathway to explore its roles for nociception.

Results: The authors found that γ-aminobutyric acid–mediated (GABAergic) neurons from the central amygdala project onto GABAergic neurons of the ventrolateral periaqueductal gray, which, in turn, locally innervate their adjacent glutamatergic neurons. After chronic restraint stress, male mice displayed reliable nociception (control, mean ± SD: 0.34 ± 0.11 g, n = 7 mice; chronic restraint stress, 0.18 ± 0.11 g, n = 9 mice, P = 0.011). Comparable nociception phenotypes were observed in female mice. After chronic restraint stress, increased circuit activity was generated by disinhibition of glutamatergic neurons of the ventrolateral periaqueductal gray by local GABAergic interneurons via receiving enhanced central amygdala GABAergic inputs. Inhibition of this circuit increased nociception in chronic restraint stress mice (median [25th, 75th percentiles]: 0.16 [0.16, 0.16] g to 0.07 [0.04, 0.16] g, n = 7 mice per group, P < 0.001). In contrast, activation of this pathway reduced nociception (mean ± SD: 0.16 ± 0.08 g to 0.34 ± 0.13 g, n = 7 mice per group, P < 0.001).

Conclusions: These findings indicate that the central amygdala–ventrolateral periaqueductal gray pathway may mediate some aspects of pain symptoms under depression conditions.