Yin-and-yang bifurcation of opioidergic circuits for descending analgesia at the midbrain of the mouse

Jong Hyun Kim, Gireesh Gangadharan, Junweon Byun, Eui Ju Choi, C. Justin Lee, Hee Sup Shin

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


In the descending analgesia pathway, opioids are known to disinhibit the projections from the periaqueductal gray (PAG) to the rostral ventromedial medulla (RVM), leading to suppression of pain signals at the spinal cord level. The locus coeruleus (LC) has been proposed to engage in the descending pathway through noradrenergic inputs to the spinal cord. Nevertheless, how the LC is integrated in the descending analgesia circuit has remained unknown. Here, we show that the opioidergic analgesia pathway is bifurcated in structure and function at the PAG. A knockout as well as a PAG-specific knockdown of phospholipase C ß4 (PLCß4), a signaling molecule for G protein-coupled receptors, enhanced swim stress-induced and morphine-induced analgesia in mice. Immunostaining after simultaneous retrograde labeling from the RVM and the LC revealed two mutually exclusive neuronal populations at the PAG, each projecting either to the LC or the RVM, with PLCß4 expression only in the PAG-LC projecting cells that provide a direct synaptic input to LC-spinal cord (SC) projection neurons. The PAG-LC projection neurons in wild-type mice turned quiescent in response to opiates, but remained active in the PLCß4 mutant, suggesting a possibility that an increased adrenergic function induced by the persistent PAG-LC activity underlies the enhanced opioid analgesia in the mutant. Indeed, the enhanced analgesia in the mutant was reversed by blocking a2-noradrenergic receptors. These findings indicate that opioids suppress descending analgesia through the PAG-LC pathway, while enhancing it through the PAG-RVM pathway, i.e., two distinct pathways with opposing effects on opioid analgesia. These results point to a therapeutic target in pain control.

Original languageEnglish
Pages (from-to)11078-11083
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number43
Publication statusPublished - 2018 Oct 23

Bibliographical note

Publisher Copyright:
© 2018 National Academy of Sciences. All rights reserved.


  • Descending analgesia pathway
  • Locus coeruleus
  • Opioid
  • Periaqueductal gray
  • Phopholipase C

ASJC Scopus subject areas

  • General


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