Itch: Anatomy & Physiology
- Definitions
- Itch: Sensation resulting in an urge to scratch
- Hyperknesis: Excessive itch induced by stimuli that normally cause mild itch or pain
- Punctate Hyperknesis: Touch evoked itch
- Alloknesis: Considerable itch evoked by light tactile stimuli
- Itch: 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: Categories
- Endogenous/exogeneous pruritogens
- Proteases
- Cytokines/Chemokines
- Amines
- Spicules from Mucuna pruriens (Cowhage)
- Mediated by mucunain cysteine protease: Activates PAR2
- Location related: More on ankle & back than forearm
- Basophils
- Stimuli: Molecules
- Epithelial cytokines
- Molecules blocked by Dupilumab (IL-4Rα blockade)
- IL-4 & IL-13 cytokine-induced responses
- Release of proinflammatory cytokines, chemokines & IgE
- Activates
- Channels: VR1/TRPV1; TRPA1;
Nav1.7
- IL-4Rα
- Polymodal C-fibers (Mechano/heat sensitive)
- Second messengers: JAK; STAT
- Insular cortex
- Features
- 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
6
- C-fibers
- Chronic itch: Associated with reduced numbers of intraepidermal axons
- 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
- Prostaglandins
- Oxidants
- Capsaicin
- Heat [>42°C)
- TRPV4 channels
- TRPA1
- Stimuli: Allyl isothiocyanate (Wasabi), Cold (<17°C)
- 1°: Sensory neurons: Events
- Response to pruritic stimuli
- 1°: sensory neurons: Release glutamate & natriuretic polypeptide B
- Molecules activate 2°: natriuretic peptide receptor A–positive neurons
- 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
- Reduced itch mechanism: 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
|
| Cations |
|
TRP channels |
| Other |
Bile acids |
TGR5 (GPBAR1)
|
|
