Faculty Collaboration Database

The Neurokinin-1 Receptor is Expressed with Gastrin-Releasing Peptide Receptor in Spinal Interneurons and Modulates Itch. J Neurosci 2020 Nov 11;40(46):8816-8830

Date

10/15/2020

Pubmed ID

33051347

Pubmed Central ID

PMC7659450

DOI

10.1523/JNEUROSCI.1832-20.2020

Scopus ID

2-s2.0-85096062416 (requires institutional sign-in at Scopus site)   23 Citations

Abstract

The neurokinin-1 receptor (NK1R; encoded by Tacr1) 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 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 in male and female mice, whereas pharmacological inhibition of spinal NK1R suppresses itch behavior. We use fluorescence in situ hybridization (FISH) to characterize the endogenous expression of Tacr1 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 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 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.SIGNIFICANCE STATEMENT 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.

Author List

Sheahan TD, Warwick CA, Fanien LG, Ross SE

Author

Tayler D. Sheahan PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Animals
Behavior, Animal
Brachial Plexus
Female
Humans
Interneurons
Male
Mice, Inbred C57BL
Middle Aged
Nerve Net
Pain
Posterior Horn Cells
Pruritus
Receptors, Bombesin
Receptors, Neurokinin-1
Spinal Cord