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

Highlights

• DOR and MOR segregate in dorsal horn interneurons, and amygdalar and cortical neurons

• DOR and MOR are co-expressed in dorsal horn projection neurons and in ventral horn

• MOR is not co-degraded with DOR in neurons that co-express both receptors in vivo

• DOR in SOM+ dorsal horn interneurons controls mechanical pain and but not heat pain

Summary

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.