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Neuron. 2018 Apr 4;98(1):90-108.e5. doi: 10.1016/j.neuron.2018.03.002. Epub 2018 Mar 22.

Functional Divergence of Delta and Mu Opioid Receptor Organization in CNS Pain Circuits.

Author information

1
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, CA 94304, USA; Department of Molecular and Cellular Physiology, Stanford University, Palo Alto, CA 94304, USA; Department of Neurosurgery, Stanford University, Palo Alto, CA 94304, USA; Stanford Neurosciences Institute, Stanford University, Palo Alto, CA 94304, USA.
2
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, CA 94304, USA; Department of Molecular and Cellular Physiology, Stanford University, Palo Alto, CA 94304, USA; Department of Neurosurgery, Stanford University, Palo Alto, CA 94304, USA; Stanford Neurosciences Institute, Stanford University, Palo Alto, CA 94304, USA; New York Stem Cell Foundation - Robertson Investigator, Stanford University, Palo Alto, CA 94304, USA. Electronic address: gs25@stanford.edu.

Abstract

Cellular interactions between delta and mu opioid receptors (DORs and MORs), including heteromerization, are thought to regulate opioid analgesia. However, the identity of the nociceptive neurons in which such interactions could occur in vivo remains elusive. Here we show that DOR-MOR co-expression is limited to small populations of excitatory interneurons and projection neurons in the spinal cord dorsal horn and unexpectedly predominates in ventral horn motor circuits. Similarly, DOR-MOR co-expression is rare in parabrachial, amygdalar, and cortical brain regions processing nociceptive information. We further demonstrate that in the discrete DOR-MOR co-expressing nociceptive neurons, the two receptors internalize and function independently. Finally, conditional knockout experiments revealed that DORs selectively regulate mechanical pain by controlling the excitability of somatostatin-positive dorsal horn interneurons. Collectively, our results illuminate the functional organization of DORs and MORs in CNS pain circuits and reappraise the importance of DOR-MOR cellular interactions for developing novel opioid analgesics.

KEYWORDS:

G protein-coupled inwardly rectifying potassium channels; analgesia; brain; co-expression; distribution; internalization; mu and delta opioid receptors; neurons; pain neural circuits; spinal cord

PMID:
29576387
PMCID:
PMC5896237
DOI:
10.1016/j.neuron.2018.03.002
[Indexed for MEDLINE]
Free PMC Article

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