title: Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord.
abstract: Menthol and other counterstimuli relieve itch, resulting in an antipruritic state that persists for minutes to hours. However, the neural basis for this effect is unclear, and the underlying neuromodulatory mechanisms are unknown. Previous studies revealed that Bhlhb5(-/-) mice, which lack a specific population of spinal inhibitory interneurons (B5-I neurons), develop pathological itch. Here we characterize B5-I neurons and show that they belong to a neurochemically distinct subset. We provide cause-and-effect evidence that B5-I neurons inhibit itch and show that dynorphin, which is released from B5-I neurons, is a key neuromodulator of pruritus. Finally, we show that B5-I neurons are innervated by menthol-, capsaicin-, and mustard oil-responsive sensory neurons and are required for the inhibition of itch by menthol. These findings provide a cellular basis for the inhibition of itch by chemical counterstimuli and suggest that kappa opioids may be a broadly effective therapy for pathological itch.
authors.affiliation: Department of Neurobiology, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA; University of Pittsburgh Pain Center, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Kardon
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Erika
authors.initials: E
authors.lastname: Polgár
authors.affiliation: Department of Neurobiology, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA; University of Pittsburgh Pain Center, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA.
authors.forename: Junichi
authors.initials: J
authors.lastname: Hachisuka
authors.affiliation: Department of Neurobiology, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA; University of Pittsburgh Pain Center, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA.
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Snyder
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Cameron
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Sinead
authors.initials: S
authors.lastname: Savage
authors.affiliation: Department of Neurobiology, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA; University of Pittsburgh Pain Center, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Neurobiology, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA; University of Pittsburgh Pain Center, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Karnup
authors.affiliation: Department of Neurobiology, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Fan
authors.affiliation: Department of Neurobiology, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Hemenway
authors.affiliation: Department of Neurobiology, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA.
authors.forename: Carcha S
authors.initials: CS
authors.lastname: Bernard
authors.affiliation: University of Pittsburgh Pain Center, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA; Department of Anesthesiology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
authors.forename: Erica S
authors.initials: ES
authors.lastname: Schwartz
authors.affiliation: International Institute for Integrative Sleep Medicine, University of Tsukuba, Life Science Center of Tsukuba Advanced Research Alliance C-1F, 1-1-1 Tenoudai Tsukuba Ibaraki, Tsukuba 305-8577, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.affiliation: Department of Pharmacology, Innsbruck Medical University, A-6020 Innsbruck, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schwarzer
authors.affiliation: Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Morphological Brain Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Furuta
authors.affiliation: Department of Morphological Brain Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kaneko
authors.affiliation: Department of Neurobiology, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA; University of Pittsburgh Pain Center, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA.
authors.forename: H Richard
authors.initials: HR
authors.lastname: Koerber
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. Electronic address: andrew.todd@glasgow.ac.uk.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Todd
authors.affiliation: Department of Neurobiology, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA; University of Pittsburgh Pain Center, University of Pittsburgh, 200 Lothrop St. Pittsburgh, PA 15213, USA; Department of Anesthesiology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA. Electronic address: saross@pitt.edu.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Ross
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004399:Dynorphins / Q000378:metabolism* / Q000502:physiology; D007395:Interneurons / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology*; D015282:Octreotide / Q000494:pharmacology; D009924:Organ Culture Techniques; D020671:Posterior Horn Cells / Q000378:metabolism*; D011537:Pruritus / Q000378:metabolism* / Q000517:prevention & control*; D017473:Receptors, Opioid, kappa / Q000819:agonists; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D017473:Receptors, Opioid, kappa; D004399:Dynorphins; D015282:Octreotide; D002211:Capsaicin
references.citation: Science. 2013 May 24;340(6135):968-71
references.pmid: 23704570
references.citation: Nat Neurosci. 2013 Jul;16(7):910-8
references.pmid: 23685721
references.citation: Brain. 2007 Apr;130(Pt 4):1017-28
references.pmid: 17347252
references.citation: Pain. 1997 May;71(1):49-55
references.pmid: 9200173
references.citation: Eur J Pharmacol. 2004 Oct 19;502(3):233-7
references.pmid: 15476749
references.citation: Nat Rev Neurosci. 2010 Dec;11(12):823-36
references.pmid: 21068766
references.citation: Anesth Analg. 1990 Oct;71(4):367-70
references.pmid: 2205128
references.citation: Science. 1986 Aug 15;233(4765):774-6
references.pmid: 3016896
references.citation: J Pain. 2002 Apr;3(2):115-25
references.pmid: 14622798
references.citation: Psychopharmacology (Berl). 2010 Jun;210(2):109-19
references.pmid: 20372880
references.citation: Physiol Rev. 2009 Apr;89(2):707-58
references.pmid: 19342617
references.citation: J Neurophysiol. 2007 Sep;98(3):1057-63
references.pmid: 17567772
references.citation: Mol Pain. 2011 Sep 29;7:76
references.pmid: 21958458
references.citation: J Physiol. 2007 Jun 1;581(Pt 2):603-18
references.pmid: 17347278
references.citation: J Clin Invest. 2010 Nov;120(11):3773-8
references.pmid: 21041959
references.citation: Br J Dermatol. 2007 Apr;156(4):629-34
references.pmid: 17263822
references.citation: Science. 2009 Sep 18;325(5947):1531-4
references.pmid: 19661382
references.citation: Mol Pain. 2013 Oct 31;9:56
references.pmid: 24176114
references.citation: J Physiol. 2002 May 15;541(Pt 1):231-44
references.pmid: 12015432
references.citation: Clin J Pain. 2010 Jan;26 Suppl 10:S10-5
references.pmid: 20026960
references.citation: J Comp Neurol. 1993 Sep 15;335(3):320-33
references.pmid: 8227522
references.citation: Jpn J Pharmacol. 2002 Mar;88(3):285-92
references.pmid: 11949883
references.citation: Neurosci Lett. 2010 Oct 22;484(1):62-5
references.pmid: 20709155
references.citation: Eur J Anaesthesiol. 2001 Jun;18(6):346-57
references.pmid: 11412287
references.citation: Pharmacol Rev. 2013 Jan 15;65(1):223-54
references.pmid: 23321159
references.citation: J Neurosci. 2010 Jun 16;30(24):8251-62
references.pmid: 20554877
references.citation: J Physiol. 2007 Oct 15;584(Pt 2):521-33
references.pmid: 17717012
references.citation: J Physiol. 2010 Jun 15;588(Pt 12):2065-75
references.pmid: 20403977
references.citation: Mol Pain. 2011 May 15;7:36
references.pmid: 21569622
references.citation: Pain. 2010 Nov;151(2):475-488
references.pmid: 20817353
references.citation: Neuron. 2012 Jan 26;73(2):292-303
references.pmid: 22284184
references.citation: Am J Nephrol. 2012;36(2):175-83
references.pmid: 22868684
references.citation: Nat Neurosci. 2014 Feb;17(2):183-91
references.pmid: 24473266
references.citation: PLoS One. 2011;6(7):e22665
references.pmid: 21818363
references.citation: Chang Gung Med J. 2011 Mar-Apr;34(2):172-8
references.pmid: 21539759
references.citation: Pain. 1996 Jan;64(1):129-138
references.pmid: 8867255
references.citation: Neuron. 2010 Nov 4;68(3):543-56
references.pmid: 21040853
references.citation: Anesthesiology. 2000 Mar;92(3):795-805
references.pmid: 10719958
references.citation: Neuroscience. 1998 Jul;85(2):459-73
references.pmid: 9622244
references.citation: Nat Neurosci. 2013 Feb;16(2):174-82
references.pmid: 23263443
references.citation: Curr Opin Neurobiol. 2011 Dec;21(6):880-7
references.pmid: 22054924
references.citation: J Physiol. 2012 Aug 15;590(16):3927-51
references.pmid: 22674718
references.citation: Eur J Pharmacol. 2002 Jan 25;435(2-3):259-64
references.pmid: 11821035
references.citation: Neuron. 2010 Nov 4;68(3):529-42
references.pmid: 21040852
references.citation: J Physiol. 2002 Apr 1;540(Pt 1):189-207
references.pmid: 11927679
references.citation: Nature. 1997 Sep 25;389(6649):382-5
references.pmid: 9311779
references.citation: Peptides. 1982 Jan-Feb;3(1):49-54
references.pmid: 6176976
references.citation: Acta Derm Venereol. 2009;89(4):339-50
references.pmid: 19688144
references.citation: Nat Neurosci. 2014 Feb;17(2):175-82
references.pmid: 24473265
references.citation: J Physiol. 2004 Oct 1;560(Pt 1):249-66
references.pmid: 15284347
references.citation: Pain. 2004 Sep;111(1-2):144-50
references.pmid: 15327818
references.citation: Br J Pharmacol. 1988 Mar;93(3):553-60
references.pmid: 2836010
references.citation: Am J Psychiatry. 1998 Apr;155(4):470-3
references.pmid: 9545990
references.citation: Br J Pharmacol. 2011 Oct;164(4):1322-34
references.pmid: 21434879
references.citation: Neurosci Lett. 1995 Mar 3;187(2):119-22
references.pmid: 7540270
references.citation: J Clin Anesth. 2003 May;15(3):234-9
references.pmid: 12770663
references.citation: Neuron. 2010 Mar 25;65(6):886-98
references.pmid: 20346763
references.citation: Exp Dermatol. 2011 Oct;20(10):778-82
references.pmid: 21929688
references.citation: Pain. 2008 Oct 31;139(3):681-687
references.pmid: 18789837
references.citation: Nature. 1996 Oct 31;383(6603):819-23
references.pmid: 8893006
references.citation: Dev Biol. 2008 Oct 15;322(2):381-93
references.pmid: 18721803
references.citation: J Pharmacol Exp Ther. 1997 Apr;281(1):499-507
references.pmid: 9103537
references.citation: J Am Soc Nephrol. 2005 Dec;16(12):3742-7
references.pmid: 16251241
references.citation: Neurosci Lett. 1995 Mar 10;187(3):157-60
references.pmid: 7624016
references.citation: J Pharmacol Exp Ther. 2003 Apr;305(1):173-9
references.pmid: 12649366
references.citation: J Pharmacol Exp Ther. 1986 Sep;238(3):833-8
references.pmid: 2875172
references.citation: Pain. 2013 Dec;154(12):2606-2615
references.pmid: 23707280
references.citation: Nature. 1996 Oct 10;383(6600):535-8
references.pmid: 8849726
references.citation: Acta Derm Venereol. 2010 Nov;90(6):575-81
references.pmid: 21057739
references.citation: PLoS One. 2013 Oct 25;8(10):e78309
references.pmid: 24205193
references.citation: Proc Natl Acad Sci U S A. 1995 May 23;92(11):5062-6
references.pmid: 7539141
references.citation: Pain. 2003 Jul;104(1-2):229-39
references.pmid: 12855333
references.citation: Neuron. 2010 Nov 4;68(3):334-9
references.pmid: 21040839
references.citation: Neuroscience. 1999;88(4):1093-135
references.pmid: 10336124