ArticleProceedings of the National Academy of Sciences of the United States of America2018
Yin-and-yang bifurcation of opioidergic circuits for descending analgesia at the midbrain of the mouse.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 36 citations in OpenAlex.
- Progress in pain mechanisms and management.Signal transduction and targeted therapy · 2026Review
- Neural Circuit Connections and Functions of Locus Coeruleus-Norepinephrine System.International journal of molecular sciences · 2025Review
- Pain Perception and Modulation: Fundamental Neurobiology and Recent Advances.The European journal of neuroscience · 2025Review
- Article
- The lateralized LC-NAergic system distinguishes vicarious versus direct fear in mice.Nature communications · 2025Article
- Diffuse Noxious Inhibitory Controls in Chronic Pain States: Insights from Pre-Clinical Studies.International journal of molecular sciences · 2025Review
- Expression of GAD2 in excitatory neurons projecting from the ventrolateral periaqueductal gray to the locus coeruleus.iScience · 2024Article
- The 'in's and out's' of descending pain modulation from the rostral ventromedial medulla.Trends in neurosciences · 2024Review
- Inputs to the locus coeruleus from the periaqueductal gray and rostroventral medulla shape opioid-mediated descending pain modulation.Science advances · 2024Article
- The contribution of periaqueductal gray in the regulation of physiological and pathological behaviors.Frontiers in neuroscience · 2024Review
- Cell-type specific molecular architecture for mu opioid receptor function in pain and addiction circuits.Neuropharmacology · 2023Review
- Article
- Molecular identification of bulbospinal ON neurons by GPER, which drives pain and morphine tolerance.The Journal of clinical investigation · 2023Article
- Brain circuits for pain and its treatment.Science translational medicine · 2021Review
- G-Protein-Coupled Estrogen Receptor (GPER) in the Rostral Ventromedial Medulla Is Essential for Mobilizing Descending Inhibition of Itch.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Monoaminergic and Opioidergic Modulation of Brainstem Circuits: New Insights Into the Clinical Challenges of Pain Treatment?Frontiers in pain research (Lausanne, Switzerland) · 2021Review
- Descending Modulation of Laryngeal Vagal Sensory Processing in the Brainstem Orchestrated by the Submedius Thalamic Nucleus.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Endogenous opioid peptides in the descending pain modulatory circuit.Neuropharmacology · 2020Review
- Different neuronal populations mediate inflammatory pain analgesia by exogenous and endogenous opioids.eLife · 2020Article
- μ-Opioid receptors in primary sensory neurons are involved in supraspinal opioid analgesia.Brain research · 2020Article
Corrections and comments
- Erratum issued
Authors and funding
6 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 β4 (PLCβ4), 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 PLCβ4 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 PLCβ4 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 α2-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.
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