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Functional Divergence of Delta and Mu Opioid Receptor Organization in CNS Pain Circuits
<span title="">2018</span>
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Highlights d DOR and MOR segregate in dorsal horn interneurons, and amygdalar and cortical neurons d DOR and MOR are co-expressed in dorsal horn projection neurons and in ventral horn d MOR is not co-degraded with DOR in neurons that coexpress both receptors in vivo d 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
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<a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1016/j.neuron.2018.03.002">doi:10.1016/j.neuron.2018.03.002</a>
<a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/29576387">pmid:29576387</a>
<a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC5896237/">pmcid:PMC5896237</a>
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... lgesia. 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. 90 Neuron 98, 90-108, April 4, We thank Brigitte Kieffer for providing Oprd1 egfp/egfp , Oprd1 lox/lox , and Oprm1 mcherry/mcherry reporter mice, Tom Jessell for providing En1 Cre ; Rosa26 LSL-tdTomato mice, and David Julius for the anti-P2Y12 antibody. AUTHOR CONTRIBUTIONS D.W. performed spinal cord slice electrophysiology, retrograde tracing, and agonist-induced receptor internalization experiments. D.W.
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