title: A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch.
abstract: We investigated roles for spinal neurons expressing the neurokinin-1 receptor (NK1R) and/or gastrin-releasing peptide receptor (GRPR) in a mouse model of ovalbumin (OVA)-induced chronic atopic dermatitis. Mice receiving repeated topical application of OVA exhibited atopic-like skin lesions and behavioral signs of chronic itch including spontaneous scratching, touch-evoked scratching (alloknesis), and enhancement of chloroquine-evoked scratching (hyperknesis). Substance P-saporin (SP-SAP) and bombesin-saporin (BB-SAP) were intrathecally injected into OVA-sensitized mice to neurotoxically ablate NK1R- or GRPR-expressing spinal neurons, respectively. SP-SAP diminished the expression of NK1R in the superficial spinal dorsal horn and significantly attenuated all behavioral signs of chronic itch. BB-SAP reduced the spinal dorsal horn expression of GRPR and significantly attenuated hyperknesis, with no effect on spontaneous scratching or alloknesis. To investigate whether NK1R-expressing spinal neurons project in ascending somatosensory pathways, we performed a double-label study. The retrograde tracer, Fluorogold (FG), was injected into either the somatosensory thalamus or lateral parabrachial nucleus. In the upper cervical (C1-2) spinal cord, most neurons retrogradely labeled with FG were located in the dorsomedial aspect of the superficial dorsal horn. Of FG-labeled spinal neurons, 89% to 94% were double labeled for NK1R. These results indicate that NK1R-expressing spinal neurons play a major role in the expression of symptoms of chronic itch and give rise to ascending somatosensory projections. Gastrin-releasing peptide receptor-expressing spinal neurons contribute to hyperknesis but not to alloknesis or ongoing itch. NK1R-expressing spinal neurons represent a potential target to treat chronic itch.
authors.affiliation: Department of Neurobiology, Physiology and Behavior, University of California, Davis, CA, USA Department of Dermatology, Department of Anatomy and Cell Biology, and Temple Itch Center, Temple University, Philadelphia, PA, USA.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Akiyama
authors.forename: Tony
authors.initials: T
authors.lastname: Nguyen
authors.forename: Eric
authors.initials: E
authors.lastname: Curtis
authors.forename: Katsuko
authors.initials: K
authors.lastname: Nishida
authors.forename: Jahnavi
authors.initials: J
authors.lastname: Devireddy
authors.forename: Jeremy
authors.initials: J
authors.lastname: Delahanty
authors.forename: Mirela Iodi
authors.initials: MI
authors.lastname: Carstens
authors.forename: Earl
authors.initials: E
authors.lastname: Carstens
mesh_terms: D000818:Animals; D002908:Chronic Disease; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020671:Posterior Horn Cells / Q000502:physiology*; D011537:Pruritus / Q000209:etiology / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018040:Receptors, Neurokinin-1
references.citation: Neuron. 2013 Apr 24;78(2):312-24
references.pmid: 23622066
references.citation: Neuroreport. 2010 Mar 10;21(4):303-8
references.pmid: 20125052
references.citation: Clin Exp Dermatol. 2012 Apr;37(3):290-5
references.pmid: 22329438
references.citation: Nature. 2007 Aug 9;448(7154):700-3
references.pmid: 17653196
references.citation: J Comp Neurol. 2008 Nov 1;511(1):1-18
references.pmid: 18720412
references.citation: Nat Neurosci. 2014 Feb;17(2):175-82
references.pmid: 24473265
references.citation: Neuron. 2010 Mar 25;65(6):886-98
references.pmid: 20346763
references.citation: Nat Neurosci. 2011 May;14(5):595-602
references.pmid: 21460831
references.citation: J Neurophysiol. 2014 Apr;111(8):1574-89
references.pmid: 24478156
references.citation: J Neurophysiol. 2015 Jan 1;113(1):58-70
references.pmid: 25298386
references.citation: Eur J Pharmacol. 2007 Jun 22;565(1-3):225-31
references.pmid: 17459367
references.citation: J Neurosci. 2006 Feb 8;26(6):1833-43
references.pmid: 16467532
references.citation: Neuroscience. 2014 Apr 25;266:38-46
references.pmid: 24530451
references.citation: Science. 2013 May 24;340(6135):968-71
references.pmid: 23704570
references.citation: J Invest Dermatol. 2013 Jan;133(1):268-70
references.pmid: 22832487
references.citation: J Comp Neurol. 2010 Aug 15;518(16):3193-204
references.pmid: 20575056
references.citation: Science. 2009 Sep 18;325(5947):1531-4
references.pmid: 19661382
references.citation: Pain. 2010 Nov;151(2):378-383
references.pmid: 20709455
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11330-5
references.pmid: 19564617
references.citation: Eur J Neurosci. 2000 Feb;12(2):689-700
references.pmid: 10712649
references.citation: J Clin Invest. 1998 Apr 15;101(8):1614-22
references.pmid: 9541491
references.citation: Ann N Y Acad Sci. 2013 Mar;1279:90-6
references.pmid: 23531006
references.citation: J Clin Invest. 2013 Nov;123(11):4769-80
references.pmid: 24216512
references.citation: J Neurophysiol. 2013 Feb;109(3):742-8
references.pmid: 23155177
references.citation: J Neurosci. 2014 Sep 10;34(37):12402-14
references.pmid: 25209280
references.citation: J Neurophysiol. 2014 Nov 1;112(9):2283-9
references.pmid: 25122701
references.citation: Neuroscience. 2013 Oct 10;250:697-714
references.pmid: 23891755
references.citation: J Invest Dermatol. 2012 Jul;132(7):1886-91
references.pmid: 22418875
references.citation: J Comp Neurol. 2009 Aug 20;515(6):629-46
references.pmid: 19496168
references.citation: Nat Neurosci. 2013 Feb;16(2):174-82
references.pmid: 23263443
references.citation: Nat Rev Neurosci. 2014 Jan;15(1):19-31
references.pmid: 24356071
references.citation: J Clin Invest. 2014 Aug;124(8):3612-6
references.pmid: 25003193
references.citation: Nat Rev Neurosci. 2010 Dec;11(12):823-36
references.pmid: 21068766
references.citation: Neuroreport. 2013 Aug 21;24(12):652-6
references.pmid: 23778077
references.citation: Pain. 2014 Jan;155(1):80-92
references.pmid: 24041961
references.citation: Acta Derm Venereol. 2015 Feb;95(2):147-50
references.pmid: 24890341