PMID- 33051347
OWN - NLM
STAT- MEDLINE
DCOM- 20210216
LR  - 20240330
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 40
IP  - 46
DP  - 2020 Nov 11
TI  - The Neurokinin-1 Receptor is Expressed with Gastrin-Releasing Peptide Receptor in 
      Spinal Interneurons and Modulates Itch.
PG  - 8816-8830
LID - 10.1523/JNEUROSCI.1832-20.2020 [doi]
AB  - 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 Ca(2+) 
      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.
CI  - Copyright (c) 2020 the authors.
FAU - Sheahan, Tayler D
AU  - Sheahan TD
AUID- ORCID: 0000-0002-5015-0600
AD  - Pittsburgh Center for Pain Research and Department of Neurobiology, University of 
      Pittsburgh, Pittsburgh 15213, Pennsylvania.
FAU - Warwick, Charles A
AU  - Warwick CA
AUID- ORCID: 0000-0001-6244-9821
AD  - Pittsburgh Center for Pain Research and Department of Neurobiology, University of 
      Pittsburgh, Pittsburgh 15213, Pennsylvania.
FAU - Fanien, Louis G
AU  - Fanien LG
AD  - Pittsburgh Center for Pain Research and Department of Neurobiology, University of 
      Pittsburgh, Pittsburgh 15213, Pennsylvania.
FAU - Ross, Sarah E
AU  - Ross SE
AD  - Pittsburgh Center for Pain Research and Department of Neurobiology, University of 
      Pittsburgh, Pittsburgh 15213, Pennsylvania saross@pitt.edu.
LA  - eng
GR  - R01 NS096705/NS/NINDS NIH HHS/United States
GR  - T32 NS073548/NS/NINDS NIH HHS/United States
GR  - T32 NS086749/NS/NINDS NIH HHS/United States
GR  - F32 NS110155/NS/NINDS NIH HHS/United States
GR  - R01 AR063772/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20201013
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Receptors, Bombesin)
RN  - 0 (Receptors, Neurokinin-1)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Behavior, Animal
MH  - Brachial Plexus/physiopathology
MH  - Female
MH  - Humans
MH  - *Interneurons
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Middle Aged
MH  - Nerve Net/*physiopathology
MH  - Pain/psychology
MH  - Posterior Horn Cells/metabolism
MH  - Pruritus/genetics/*physiopathology/psychology
MH  - Receptors, Bombesin/*biosynthesis/*genetics
MH  - Receptors, Neurokinin-1/*biosynthesis/*genetics
MH  - Spinal Cord/*metabolism/*physiopathology
PMC - PMC7659450
OTO - NOTNLM
OT  - GRPR
OT  - NK1R
OT  - dorsal horn
OT  - projection neurons
OT  - spinal circuitry
OT  - spinal cord
EDAT- 2020/10/15 06:00
MHDA- 2021/02/17 06:00
PMCR- 2021/05/11
CRDT- 2020/10/14 09:12
PHST- 2020/07/15 00:00 [received]
PHST- 2020/08/25 00:00 [revised]
PHST- 2020/09/21 00:00 [accepted]
PHST- 2020/10/15 06:00 [pubmed]
PHST- 2021/02/17 06:00 [medline]
PHST- 2020/10/14 09:12 [entrez]
PHST- 2021/05/11 00:00 [pmc-release]
AID - JNEUROSCI.1832-20.2020 [pii]
AID - JN-RM-1832-20 [pii]
AID - 10.1523/JNEUROSCI.1832-20.2020 [doi]
PST - ppublish
SO  - J Neurosci. 2020 Nov 11;40(46):8816-8830. doi: 10.1523/JNEUROSCI.1832-20.2020. 
      Epub 2020 Oct 13.