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

Dong Wang; Vivianne L Tawfik; Gregory Corder; Sarah A Low; Amaury François; Allan I Basbaum; Grégory Scherrer

doi:10.1016/j.neuron.2018.03.002

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

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

Authors

Dong Wang¹, Vivianne L Tawfik¹, Gregory Corder¹, Sarah A Low¹, Amaury François¹, Allan I Basbaum², Grégory Scherrer³

Affiliations

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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anterior Horn Cells / chemistry
Anterior Horn Cells / metabolism*
Anterior Horn Cells / pathology
Central Nervous System / chemistry
Central Nervous System / metabolism
Central Nervous System / pathology
Male
Mice, Inbred C57BL
Mice, Knockout
Nerve Net / chemistry
Nerve Net / metabolism*
Nerve Net / pathology
Pain / metabolism*
Pain / pathology
Pain Measurement / methods
Posterior Horn Cells / chemistry
Posterior Horn Cells / metabolism*
Posterior Horn Cells / pathology
Receptors, Opioid, delta / biosynthesis*
Receptors, Opioid, delta / genetics
Receptors, Opioid, mu / biosynthesis*
Receptors, Opioid, mu / genetics

Substances

Receptors, Opioid, delta
Receptors, Opioid, mu

Abstract

Publication types

MeSH terms

Substances

Grants and funding