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.

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