Highlights
- •Delta- Opioid Receptor(DOR) in the spinal dorsal horn bidirectionally modulates itch
- •The endogenous ligand for DOR, enkephalin, is expressed on spinal neurons that co-express neuropeptide Y (NPY)
- •Spinal neurons that express DOR co-express NPY1R and Kappa-opioid Receptor(KOR).
- •Neurons that co-express the DOR and KOR are activated following peripheral chloroquine injection
Abstract
Opioid signaling has been shown to be critically important in the neuromodulation
of sensory circuits in the superficial spinal cord. Agonists of the mu-opioid receptor
(MOR) elicit itch, whereas agonists of the kappa-opioid receptor (KOR) have been shown
to inhibit itch. Despite the clear roles of MOR and KOR for the modulation itch, whether
the delta-opioid receptor (DOR) is involved in the regulation of itch remained unknown.
Here, we show that intrathecal administration of DOR agonists suppresses chemical
itch and that intrathecal application of DOR antagonists is sufficient to evoke itch.
We identify that spinal enkephalin neurons co-express neuropeptide Y (NPY), a peptide
previously implicated in the inhibition of itch. In the spinal cord, DOR overlapped
with both the NPY receptor (NPY1R) and KOR, suggesting that DOR neurons represent
a site for convergent itch information in the dorsal horn. Lastly, we found that neurons
co-expressing DOR and KOR showed significant Fos induction following pruritogen-evoked
itch. These results uncover a role for DOR in the modulation of itch in the superficial
dorsal horn.
Perspective: This article reveals the role of the delta-opioid receptor in itch. Intrathecal administration
of delta agonists suppresses itch whereas the administration of delta antagonists
is sufficient to induce itch. These studies highlight the importance of delta-opioid
signaling for the modulation of itch behaviors, which may represent new targets for
the management of itch disorders.
Keywords
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Article info
Publication history
Published online: November 30, 2022
Accepted:
September 6,
2022
Received in revised form:
September 5,
2022
Received:
August 10,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Research in the publication was supported by grants NIH/NINDS F31NS113371 and NIH/NIGM T32GM008208 (E.N) and grants NIH/NIAMS R01AR063772, NIH/NINDS R01NS119410 and NIH/NINDS R01NS096705 (S.E.R).
Identification
Copyright
© 2022 by United States Association for the Study of Pain, Inc.
