The Neurokinin-1 Receptor is Expressed with Gastrin-Releasing Peptide Receptor in Spinal Interneurons and Modulates Itch

• Published in: The Journal of neuroscience Vol. 40; no. 46; pp. 8816 - 8830
• Main Authors: Sheahan, Tayler D, Warwick, Charles A, Fanien, Louis G, Ross, Sarah E
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 11.11.2020
• Subjects: Ablation; Adult; Animals; Behavior, Animal; Brachial Plexus - physiopathology; Calcium imaging; Calcium ions; Circuits; Dorsal horn; Female; Fluorescence; Fluorescence in situ hybridization; Gastrin; Gastrin-releasing peptide; Gene expression; Humans; Interneurons; Male; Mice, Inbred C57BL; Middle Aged; Nerve Net - physiopathology; Neurokinin; Neurokinin NK1 receptors; Neurons; Neurotoxicity; Pain - psychology; Parabrachial nucleus; Peptides; Pharmacology; Posterior Horn Cells - metabolism; Pruritus - genetics; Pruritus - physiopathology; Pruritus - psychology; Receptors; Receptors, Bombesin - biosynthesis; Receptors, Bombesin - genetics; Receptors, Neurokinin-1 - biosynthesis; Receptors, Neurokinin-1 - genetics; Releasing; Rodents; Signal processing; Spinal cord; Spinal Cord - metabolism; Spinal Cord - physiopathology; spinal circuitry; NK1R; spinal cord; projection neurons; GRPR; dorsal horn
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1832-20.2020

The neurokinin-1 receptor (NK1R; encoded by ) is expressed in spinal dorsal horn neurons and has been suggested to mediate itch in rodents. However, previous studies relied heavily on neurotoxic ablation of NK1R spinal neurons, which limited further dissection of their function in spinal itch circuitry. To address this limitation, we leveraged a newly developed mouse line to characterize the role of NK1R spinal neurons in itch. We show that pharmacological activation of spinal NK1R and chemogenetic activation of spinal neurons increases itch behavior in male and female mice, whereas pharmacological inhibition of spinal NK1R suppresses itch behavior. We use fluorescence hybridization (FISH) to characterize the endogenous expression of throughout the superficial and deeper dorsal horn (DDH), as well as the lateral spinal nucleus (LSN), of mouse and human spinal cord. Retrograde labeling studies in mice from the parabrachial nucleus (PBN) show that less than 20% of superficial dorsal horn neurons are spinal projection neurons, and thus the majority of are local interneurons. We then use a combination of hybridization and two-photon Ca imaging of the mouse spinal cord to establish that NK1R and the gastrin-releasing peptide receptor (GRPR) are coexpressed within a subpopulation of excitatory superficial dorsal horn (SDH) neurons. These findings are the first to suggest a role for NK1R interneurons in itch and extend our understanding of the complexities of spinal itch circuitry. The spinal cord is a critical hub for processing somatosensory input, yet which spinal neurons process itch input and how itch signals are encoded within the spinal cord is not fully understood. We demonstrate neurokinin-1 receptor (NK1R) spinal neurons mediate itch behavior in mice and that the majority of NK1R spinal neurons are local interneurons. These NK1R neurons comprise a subset of gastrin-releasing peptide receptor (GRPR) interneurons and are thus positioned at the center of spinal itch transmission. We show NK1R mRNA expression in human spinal cord, underscoring the translational relevance of our findings in mice. This work is the first to suggest a role for NK1R interneurons in itch and extends our understanding of the complexities of spinal itch circuitry.