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ITCH (Pruritis) 1

Itch: Anatomy & Physiology

  • Definition: Sensation resulting in an urge to scratch
  • Peripheral Stimuli
    • General
      • Itch axons may be mechanically insensitive or sensitive
      • Mustard oil: Stimulates axons conveying dysesthesias associated with itch
    • Histamine pathway: Acute itch
      • Histamine
        • Mostly released by: Mast cells
        • Other: Basophils; Keratinocytes
      • Course
        • Onset: Delay of 30 to 60 seconds
        • Maximum: 2 to 3 minutes
        • Duration: 10 minutes
      • Afferents: Mechanoinsensitive C-fibers
        • Extensive branching in skin
        • Endings probably located in deeper skin layers
        • Histamine stimulates: H1 & H4 receptors
        • Histamine stimulation: Activates TRPV1 via phospholipase system
        • Excited histaminergic neurons: Release CGRP & Substance P
      • Only small inhibition by capsaicin
      • Itch associated with Flare response
        • Correlation between itch intensity & flare area
    • Non-histamine pathway: Chronic itch 3
      • Stimuli: Endogenous/exogeneous pruritogens; Proteases, Cytokines/Chemokines, Amines
      • May be stimulated by spicules from the plant Mucuna pruriens (Cowhage)
        • Mediated by mucunain cysteine protease: Activates PAR2
      • Activates
      • Time course: Decline over 10 minutes
      • Inhibition: Desensitization with capsaicin; No effect of anti-histamine
      • No associated flare response: Vasodilation only in specific area of stimulus
      • No correlation in magnitude of itch stimulated by histamine & cowhage
  • Primary itch afferents
    • C-fibers
    • Physiology
      • Transcutaneous electrical threshhold: High
      • Conduction velocity: Low
      • Mechanical stimuli: Unresponsive
      • Histamine sensitive
    • May be associated with
      • VR1/TRPV1 channels (Capsaicin/Heat receptor)
        • Stimuli: Extracellular pH, ATP, Rrostaglandins, Oxidants, Capsaicin, Heat [>42°C)
      • TRPV4 channels
      • TRPA1
        • Stimuli: Allyl isothiocyanate (Wasabi), Cold (<17°C)
    • 1°: Sensory neurons: Events
      • 1°: sensory neurons respond to pruritic stimuli by releasing glutamate & natriuretic polypeptide B
      • Molecules then activate 2°: natriuretic peptide receptor A–positive neurons to release GRP
    • Itch: Gastrin-releasing peptide (GRP; Bombesin)4
      • Expressed in subset of small and medium-sized dorsal root ganglion neurons
      • Colocalized with: Peripherin, CGRP, Substance P, TRPV1
      • Spinal cord fibers: Lamina I & II outer layer
      • GRP receptor mutant (reduced function) mice
        • Reduced response to pruritogenic agents: 48/80; PAR2 agonist (SLIGRL-NH2); Chloroquine
        • No change in pain responses
        • Mechanism: Reduced itch probably related to histamine-independent itch pathway
  • Secondary itch afferents
    • Location of cell bodies: Lamina I of spinal dorsal grey
    • Projection pathway
      • Spinothalamic tract
        • Conduction velocity of axons: Slow
      • Termination: Thalamic nuclei
        • Ventral posterior inferior (VPI)
        • Periphery of Ventral posterior lateral (vVPL)
      • Inhibited by painful stimuli
    • Other itch-related spinal circuit
      • Mechanical itch, Alloknesis, Hyperknesis
      • Neuropeptide Y–positive neurons
Pruritogens & Receptors
Type Pruritogens Receptors
Amines Histamine
Serotonin
H1 /H4 receptors
5-HT2 receptor
Proteases Kallikreins
Tryptase
Trypsin
Cathepsin S
Exogenous
  proteases
PAR-2
(PAR-4)
Neuropeptides Substance P
Endothelin-1
NGF
Opioids
NK1R (TACR1)
ETA receptor
TrkA (NTRRK1)
MORs (OPRM1) /KORs
Lipid
  mediators
PAF
LPA
PAF receptor (PTAFR)
LPA5 receptor (LPAR5)
Cytokines IL-4 /13
IL-31

TSLP
IL-17
IL-4Rα
IL-31RA /Oncostatin,
  M receptor β
TSLP receptor (CRLF2)
IL-17RA-C
Mrgpr agonists Chloroquine MrgprX1
Other Bile acids TGR5 (GPBAR1)

Itch: Clinical Syndromes


Familial Neuropathic Chronic Itch 5

  Collagen, type VI, Alpha-5 (COL6A5; COL29A1) ; Chromosome 3q22.1; Dominant

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References
1. Nature Neuroscience 2001;4:9-10,72-77; J Allergy Clin Immunol 2018;142:1375-1390
2. Gut 2003;52:1233–1235
3. J Neurosci 2007;27:7490-7497
4. Nature 2007; Online 25 July 2007
5. Brain 2017; Online January

11/18/2018