This document discusses the definition, measurement, pathophysiology, receptors, mediators, and causes of pruritus (itch). It defines pruritus as a subjective unpleasant sensation that elicits an immediate desire to scratch. Measurement methods in animals and humans are described. The pathophysiology involves polymodal nociceptors and transient receptor potential ion channels. Mediators like histamine, proteinases, substance P, opioids, neurotrophins, prostanoids, cytokines and acetylcholine are discussed. Causes include systemic disease, dermatological conditions like atopic dermatitis, infections, neoplasms, genetic disorders and others.

2. DEFINITION
Pruritus(Itch) can be defined
subjectively as a poorly localized,
non-adapting, usually unpleasant
sensation which elicits an immediate
desire to scratch
---Samuel Hafenreffer
(1660)

3. Itch has recently been classified by
Twycross et al. as
●pruritoceptive
●neuropathic
 neurogenic
 Psychogenic

4. Measurement
 Results from animal models of pruritus need to be
interpreted with caution.
 Hind limb scratching in response to intradermal
injection of a pruritogen has been widely used.
Methods used in humans :
 visual analogue scales (VAS)
 Recording of scratch movements using limb
movement meters.

5.  The ‘Symtrack’ computerized continuous itch-
rating system, which is based on the VAS, or a
variant of it, is the most widely used.
 New method for quantifying scratching
piezoelectrical device is attached to the middle
fingernail

6. Pathophysiology of Itch –
Receptors involved
 No specific receptor structure has been
identified for itch
 Itch nerve endings are unmyelinated, confined
to the skin and cornea, and are members of the
polymodal nociceptor class

8. receptors involved.....
 close association of temperature sensitive transient
receptor potential (TRP) ion channels with
afferent itch transmitting nociceptor neurone
terminals
 other members of this same class of receptors
(TRPV1; vanilloid receptors)
 co-localization of cannabinoid receptors (CB1)
with TRPV1

9. receptors involved.....
 Apart from TRPV1 ion channels,
keratinocytes also express voltage-gated
ATP channels, adenosine receptors,
cannabinoid receptors, opioid receptors
and PAR-2 (proteinase activated
receptors-2) neurotrophic tyrosine
kinase receptor type 1 (NTRK1[TRKA])

10. Neuroanatomy of itch

11. Neuroanatomy of itch

12. Central itch
 ‘Central itch’ is itching which is
perceived as occurring in the skin but
which actually originates in the
central nervous system due to
dysfunctional processing of sensory
information in the central pathways.

13. Central itch
 Melzack and Wall proposed the
involvement of large, fast-conducting,
myelinated sensory fibres in modulation of
the discharge of the unmyelinated itch- or
pain-transmitting fibres via the substantia
gelatinosa (‘gate’ control of pain).

14. Central itch
 According to this proposal, itch is due to a
combination of peripheral excitation and
central disinhibition.
 Scratching, by activating inhibitory fast-
conducting myelinated fibres, closes the ‘gate’
by activation of suppressor neurones of the
substantia gelatinosa and reduces the itch.

15. Central itch
 Alloknesis (slight mechanical stimulation
of skin causing intense itching)
characteristically occurs in some patients
with atopic eczema. It is thought to be
due to excitation of central itch-
transmission neurones due to reduced
gating

16. Central itch
 Opioid peptides have important crucial
central role.
 μ-opioid receptor ligation causes central
pruritus, κ-opioids are antipruritic so
central pruritus may result from an
imbalance of the two systems.

17. Peripheral mediators of itching in skin
diseases
• peripheral pharmacological mediators
play a key role in the production of
itching in inflammatory skin disease,
originally proposed by Lewis as his ‘H-
substances’

18. Important mediators and receptors for itch

19. Histamine and its receptors
 Histamine is released from dermal mast cells via
a range of receptors
 high affinity IgE receptor (FceR1),
 the KIT receptor for stem cell factor,
 receptors for neuropeptides (e.g. substance P, NGF)
 complement C5a.

20. Histamine and its receptors
 In acute IgE-mediated urticaria, histamine is
released when specific antigen cross-links
adjacent FceR1 via the a-chains.
 In an important subset of chronic urticaria
(autoimmune urticaria), cross-linking occurs via
functional circulating IgG autoantibodies that
react with epitopes expressed on the a-chain of
FceR1 or, less commonly, IgE.

22. Proteinases
Human dermal mast cells produce two proteases:
Tryptase
Chymase
 The activated mast cell releases tryptase
(along with other mediators, including
histamine), which in turn activates the
proteinase-activated receptor-2 (PAR-2)
present on C fiber terminals.

23. Proteinases.....
 The activated C fibers transmit this
information to the CNS, where it may
cause the sensation of itch. Additionally,
activation leads to local release of
neuropeptides, including substance P and
calcitonin gene-related peptide, which
induce neurogenic inflammation

24. Role of proteinase-activated receptor-2 (PAR-2). SP, substance P; MC, mast cell
and C neurone terminals and dermal mast cells

25. Proteinases in skin diseases
 PAR-2, the receptor for tryptase, is significantly
elevated in the epidermis and cutaneous nerve fibers
of eczematous lesions,
 proteinase (e.g. cathepsin B) activity can also be found
in common allergens (e.g. grass pollen, house dust
mites)27, and staphylococcal skin infections
 Netherton syndrome (AR) mutations in the serine
proteinase inhibitor lymphoepithelial Kazal-type
inhibitor (LEKTI), leads to increased protease activity.

26. Substance P
 Substance P is synthesized in the cell bodies of C
neurons, transported towards the peripheral nerve
terminals, and released by antidromic depolarization
to cause vasodilation and increased vascular
permeability
 Elevated in the serum of patients with atopic
dermatitis.

27. Opioid Peptides
 Activation of mu-opioid receptors stimulates
itch perception, whereas k-opioid receptor
stimulation inhibits mu-receptor effects, both
centrally and peripherally.
 Nociceptin, the endogenous peptide ligand for
the opioid receptorlike 1 (ORL1) receptor, has
also been implicated in itch.

28. Neurotrophins
 Neurotrophins are factors that regulate the
growth and function of nerve cells.
 prototypic neurotrophic factor is nerve growth
factor (NGF). Other members of this family
include neurotrophins 3, 4 and 5 and brain-
derived neurotrophic factor (BDNF)

29. Neurotrophins in skin diseases
 Increased expression of NGF was noted in
cutaneous mast cells, keratinocytes and
fibroblasts of atopic dermatitis.

30. Prostanoids
 Prostaglandins enhance histamine-induced
itch.
 only pruritic neurons that display lasting
activation following exposure to histamine are
excited by PGE2.
 PGE2 has also been shown to have a direct,
low-level pruritogenic effect both in healthy
individuals and atopic dermatitis patients.

31. Calcitonin gene-related
peptide (CGRP)
 This 37 amino acid peptide is the most highly
expressed neuropeptide in human skin.
 Like substance P, CGRP appears to act as a
modulator of itch rather than as a pruritogen.
 Found in abundant amounts in involved skin of
prurigo nodularis.

32. Cytokines
 IL-31 is involved in the pruritus of atopic
dermatitis in man .Targeting IL-31 may be a
promising approach to improved drug treatment
of atopic eczema.
 a role for IL-2 has been proposed in atopic
dermatitis.

33. Acetyl choline
 Acetyl choline behaves as a pruritic in atopic
eczema via muscarinic receptors, although it
does not cause pruritus in healthy subjects.
 This may explain the pruritus commonly
experienced by atopic eczema patients when
they sweat.

34. Scratching
 Scratching is a reflex functioning at a spinal
level, although modified greatly by higher
centres.
 Exact mechanism of relief of itch by
scratching is unknown.

35. Scratching...probable mechanisms
 the sensation of itching is reinforced by
facilitating circuits in the relay synapses of the
spinal cord, the prolonged scratch-induced
relief could be due to temporary suppression of
these circuits. Stimulation of fast-conducting
myelinated afferents inhibits these circuits via
pre- and postsynaptic mechanisms.
 Alternatively, scratching could simply damage
sensory nerve endings, repair occupying several
minutes.

36. Causes of Pruritus(Itch)

37. A. Itch in response to systemic/internal
disease
 Uraemia
 Cholestasis and liver disease
 Haematological disease
 Iron deficiency
 Polycythaemia vera
 Malignant disease
 Solid tumours
 Lymphomas
 Endocrine disease
 Thyroid disease
 Diabetes mellitus (localized itch only)
 HIV infection
 Adverse drug reaction
 Pruritus due to morphine and related drugs

38. B. DERMATOLOGIC DISEASES WITH PRURITUS

39. Dermatologic disease Cause
Infestation • Scabies
• Pediculosis
• Arthropod bites
• Schistosomal cercarial dermatitis
Inflammation • Atopic dermatitis
• Stasis dermatitis
• Allergic or irritant contact dermatitis
• Lichen simplex chronicus
• Urticaria
• Prurigo nodularis
• Prurigo pigmentosa
• Bullous diseases, e.g. DH, BP
• PUPPP
• Eosinophilic pustular folliculitis
• Drug hypersensitivity
• Mastocytosis
• Psoriasis, parapsoriasis
• Pityriasis rubra pilaris
• Polymorphous light eruption

40. Dermatologic disease Cause
Infections • Bacterial infections, e.g. folliculitis
• Viral infections, e.g. varicella
• Fungal infections, e.g. inflammatory tinea
Neoplastic • Cutaneous T-cell lymphoma
Genetic/Nevoid • Darier disease
• Hailey–Hailey disease
• Inflammatory linear verrucous epidermal
nevus (ILVEN)
Others • Xerosis, eczema craqelé
• Senile pruritus
• Anogenital pruritus
• Notalgia paresthetica
• Primary cutaneous amyloidosis (macular,
lichenoid)
• Postburn and post-stroke pruritus
• Itching in scars
• Fiberglass dermatitis
• Aquagenic pruritus

41. Thank You