Itch

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ITCH (Pruritis) ¹

Itch: Anatomy & Physiology

Peripheral Stimuli
- General
  - Itch axons may be mechanically insensitive or sensitive
  - Mustard oil: Stimulates distinct axons conveying dysesthesias associated with itch
- Histamine
  - 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
  - Only small inhibition by capsaicin
  - Itch associated with Flare response
    - Correlation between itch intensity & flare area
- Non-histaminergic mechanisms ³
  - May be stimulated by spicules from the plant Mucuna pruriens (Cowhage)
    - Mediated by mucunain cysteine protease: Activates PAR2
    - Activates polymodal C-fibers (mechano/heat sensitive)
  - 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)
  - TRPV4 channels
- 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

Itch: Clinical Syndromes

Dermatologic
- Dermatoses (Atopic dermatitis)
- Surface irritants (Fiberglass, wool, foreign bodies, insect bites)
- Cold urticaria
  - Distribution: Cold-exposed regions
  - Treatment: H1-selective antihistamines; Danazol
- Aquagenic pruritus
  - Associated disorder: Polycythemia vera
  - Distribution: Trunk & Proximal extremities
  - Treatment: Atenolol
- Serotonin-evoked itch: TRPV4 channels
Systemic disorders
- Endocrine: Hyperparathyroidism; Diabetes mellitus
- Renal disease: Chronic; Especially during or after dialysis
- Liver disease: Obstructive biliary disease, Cholestasis
- Infection: HIV; Trichinosis; Onchocerciasis, Echinococcosis; Hepatitis C; Chicken pox
- Malignancy: Hodgkin's disease, Polycythemia rubra vera, Leukemia, Mycosis fungoides,
  Sézary syndrome, Visceral neoplasia, Carcinoid, Multiple myeloma
- Anemia: Iron deficiency
Drugs
- Opioid administration: Systemic; Spinal
- Allergic reactions: Penicillin, Sulfa drugs
- Vasoactive drugs: Nicotinic acid, caffeine, alcohol
- CNS drugs: Morphine, cocaine, amphetamines, codeine
- Chloroquine
Neuropathic
- Small Fiber Neuropathy
- Hereditary
  - Familial Neuropathic Chronic Itch: COL6A5
  - Erythermalgia: SCN9A
  - Episodic pain syndrome, familial 2 (FEPS2): SCN10A
- Focal nerve lesions
  - Post-Herpetic neuralgia (48%): Especially on face & head
  - Trigeminal trophic syndrome: Especially after Gasserian ganglion ablation
  - Cheiralgia paresthetica
  - Brachioradial pruritis: Dorsolateral arm; C5-C8 lesions
  - Notalgia paresthetica: T2-T6 lesions
Other
- CNS: Multiple sclerosis
- Pruritis ani ²
- Pregnancy
Itch: Systemic treatment
- Treatment of underlying condition
- H1-blockers: Diphenhydramine; Hydroxyzine
- H2-blockers: Cimetidine; Ranitidine
- Tricyclic antidepressants: Doxepin; Amitriptyline
- Anticonvulsants: Gabapentin; Dilantin
- Danazole
- Prednisone

Familial Neuropathic Chronic Itch ⁵

● Collagen, type VI, Alpha-5 (COL6A5; COL29A1)

; Chromosome 3q22.1; Dominant

Epidemiology: 4 families, 9 patients
Genetics
- Mutations: c.6814G>T (p.Glu2272*); c.6486G>C (p.Arg2162Ser)
- Linked to: Atopic dermatitis (ATOD1)
COL6A5 protein
- Contains von Willebrand factor (VWF; ) type A domains
- Localization: Epithelial tissues (Lungs; GI tract; Skin, dermal–epidermal junction & reticular dermis vessels
- Mutations: ? Haploinsufficent
Clinical
- Onset age: 5 to 39 years
- Itch
  - Trunk
  - Limbs: Proximal > Distal
  - Itch may be followed by burning sensation
  - Course: Paroxysmal; May be increased with greater age
  - Treatment: Gabapentin 900 to 1200 mg per day
- Autonomic disorders: Few patients
Laboratory
- Skin biopsy: Reduced numbers of small axons common
- NCV: Normal

Return to Neuromuscular Home

References
1. Nature Neuroscience 2001;4:9-10,72-77
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

1/12/2017

ITCH (Pruritis) 1

Itch: Anatomy & Physiology

Itch: Clinical Syndromes

Itch: Systemic treatment

Familial Neuropathic Chronic Itch 5

ITCH (Pruritis) ¹

Familial Neuropathic Chronic Itch ⁵