The neurokinin-1 receptor is expressed with gastrin-releasing peptide receptor in spinal interneurons and modulates itch

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      The neurokinin-1 receptor (NK1R, encoded by Tacr1) is expressed in spinal dorsal horn neurons and has been suggested to mediate itch. However, previous studies relied heavily on neurotoxic ablation of NK1R spinal neurons, which limited further dissection of their function in spinal itch circuitry. Thus, we leveraged a newly developed Tacr1-CreER mouse line to characterize the role of NK1R spinal neurons in itch. We show that pharmacological activation of spinal NK1R and chemogenetic activation of Tacr1-CreER spinal neurons increases itch behavior, whereas pharmacological inhibition of spinal NK1R suppresses itch behavior. We use fluorescence in situ hybridization to characterize the endogenous expression of Tacr1 throughout the superficial and deeper mouse dorsal horn, as well as the lateral spinal nucleus of mouse. Notably, TACR1 expression was evolutionarily conserved in the human spinal cord dorsal. Retrograde labeling studies from the parabrachial nucleus show that less than 20% of superficial Tacr1-CreER dorsal horn neurons are spinal projection neurons, and thus the majority of Tacr1-CreER are local interneurons. We then use a combination of in situ hybridization and ex vivo two-photon Ca2+ imaging of the spinal cord to establish that NK1R and the gastrin-releasing peptide receptor (GRPR) are coexpressed within a subpopulation of excitatory superficial dorsal horn neurons. These findings are the first to describe a role for NK1R interneurons in itch and extend our understanding of the complexities of spinal itch circuitry. NINDS T32NS086749 (TDS), NINDS F32NS110155 (TDS), NINDS T32 NS073548 (CAW), and NIH NINDS R01NS096705 (SER).
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