Definition of pruritus pathophysiology of pruritus mechanism of pruritus mediators of prutitus histamine opioids serotonin neurokinins itch scratch cycle sensitization alloknesis

1. Dr. Azmiree Binte Aslam

2. Pruritus
• Pruritus (itching) is the predominant symptom of skin diseases
and can best be defined as An unpleasant sensation that leads
to a desire to scratch.

3. • Acute itch is experienced for a limited period of time,
ranging from seconds to weeks.
Such as – insect bite reaction.
• Chronic itch, which is a multidimensional phenomenon
consisting of sensory, emotional and cognitive
components, lasts for months and results from brain –
skin axis most cases.
Such as- prurigo nodularis

4. Pathophysiology of Pruritus

5. Pathophysiology of Itch
• Pruritus may originate in the skin or in the CNS.
• The only peripheral tissue from which itch can be evoked are
– Skin
– Mucous membrane: tracheal mucous membrane.
– Several mucocutenous junction. (eg. Conjuctivae).

6. •Itch transmission in the skin:
• Epidermis acts as a receptor for itch, but a specific receptor
has not yet been identified.
• Intraepidermal nerve fibers with free nonspecialized nerve
ending extending to stratum granulosum and many
epidermal nerve fibers that stains positively for
neuropeptides implicated in itch transmission.
• MRGPRS, MAS –related G protein-coupled receptors
expressed exclusively in peripheral sensory neurons,
function as itch receptors.

7. •Keratinocytes express a variety of neural mediators and
receptors, all of which are involved in the itch sensation.
Mediators Receptors
1) Opioids 1) μ and κ opiod receptor
2) Proteases 2) Proteinase activated receptor -2
3) Substance P (SP) 3) Vanilloid receptors
4) Nerve Growth factor (NGF) 4) Tropomysin- related kinase A (TRKA)
5) Neurotrophin 5) Transient receptor potential vanilloid (TRPV)
6) Gastrin releasing peptide recptor
7) Cannabinoid receptor 1& 2

8. Itch transmitting nerve fibers
Histamine sensitive C nerve fibers:
–Sensitive to
Pruritogenic stimuli
Thermal stimuli
Capsaicin
–Not sensitive to
Mechanical stimuli

9. Non- histaminergic C nerve fibers:
–Activated by cowhage (mucuna pruriens) that act
through PAR 2 & PAR 4
–Found in –
• peripheral nerve fibers
• spinothalamic tract.
–They are not itch specific, they also transmit
burning sensation and respond to allogen and
capsaicin.

10. Gastrin releasing peptide (GRP) receptor
positive neurons.
Thinly myelinated Aδ fibers may transmit fast
pricking component of itch

11. Central processing of itch
• Histamine induced itch activates various brain areas
implicated in sensory and motor function as well as
emotion.
• Central processing of itch in Atopic Dermatitis is
different from that healthy subjects.

12. Areas of brain involved-
– Somastosensory area I & II:
a) Detection of itch
b) Localization of itch
c) Discrimination of itch
– Precuneus
– Anterior & posterior cingulate cortex:
 Anterior cingulate cortex: intregate the sensory
and emotional experience of pruritus

13.  Posterior cingulate cortex: posterior cortex
and precuneous are involved in-
 visuospatial imagery,
 episodic memory retrival,
 self awareness
 thus controlling emotional and affective
processing of itch
 Activated in atopic eczema
– Supramagrinal gyrus

14. – Inferior parietal lobe
– Insula claustrum complex
– Cerebellum:
• Has role in co-ordination of the itch scratch cycle.
• Atopic Dermatitis- more activation in posterior singulate cortex
and precuneus.
• Scratching found to inhibit the perfrontal cortex and
cerebellum.
• Scratching also inhibits the histamine evoked activity of
spinothalamic neurons.

16. Pruritogen
Free nerve endings
Unmyelinated C fibers(1st order Neuron)
Dorsal horn of gray matter of spinal cord(2nd order neuron)
Cross over and join contralateral spinothalamic tract
Posterolateral and ventral Thalamus
Different areas of brain

17. Mediators of pruritus
1. Histamine
2. Opioids
3. Proteases
4. Substance P (SP)
5. Nerve Growth factor (NGF)
6. Neurotrophin
7. Prostanoids
8. Gastrin related peptide
9. Neurotransmitters

18. Histamine
• Receptor:
Histamine Receptors are-
a) H1R
b)H2R
c) H3R
d)H4R
• Receptors expressed by:
a) Sensory fibers

19. • Comment:
a)Induce itch by stimulating specific sensory fibers
b)H4 Receptors expressed by Neurons and bone
marrow derived cells
c)H4 mediate chemotaxis & have role in pruritus in
AD

21. • Associated with pruritus of:
a)Acute and chronic urticaria
b)Insect bite reaction

22. Protease
• Protase are-
a) Tryptase
b) Trypsin
c) Cathepsins
d) Chymase
e) Serin protease
• Receptor:
Proteinase activated
receptors
(PARs- PAR1, PAR2, PAR3, PAR4)

23. • Source:
a) Keratinocyte
b)Skin Mast cells (Tryptase, Chymase)
c) Endothelial cells
d)Platelets
• Comment:
Tryptase, Trypsin & Cathepsins, induces inflammation
& itch via neurogenic mechanism via PAR 2

24. They binds to the proteinase activated
receptor (PAR2) and stimulate cutaneous C
fibers.
Receptors for tryptase signifiacantly elevated
in epidermis and at nerve fibres of eczematuos
skin of AD.
Microbial protease may induced itch and
inflammation via PAR 1 & PAR 4

25. • Associated with pruritus of:
a)Mastocytosis
b)Atopic dermatitis

26. Opioids
• Receptors:
a)µ receptor
b)κ receptors
• Source:
a)Nerve
b)Keratinocyte

27. • Comment:
µ receptor:
a) Activation of µ receptors stimulates itch perception
b) In AD, it is upregulated.
κ receptors:
a) Stimulation of this receptor inhibits µ effect both
centrally and peripherally
Opioids induce itch via 2 possible mechanism .
1. Degranulation of cutaneous mast cells
2. Activation of µ receptors with a direct central and
peripheral pruritogenic stimuli.

28. Substance P
• Receptors: Neurokinin receptor
• Source:
a) Sensory nerve fiber (CNS and PNS)
b)Keratinocyte
• Comments:
– Mediated skin edema and pruritus and intensifies itch
perception
– Induce release of interleukin 8, TNF α, histamine, tryptase,
LB4, prostaglandin D

29. –Level of substance P is elevated in atopic
dermatitis and correlates with disease activity
–High concentration of substance P can cause mast
cell degranulation
–Low concentration activates neurokinin receptor
on mast cell, leading to sensitization and increased
production of TNF α. This TNF α sensitizes
nociceptive nerve ending, produces self amplifying
loop between neuron and mast cell.

31. • Associated with pruritus of:
1. Atopic dermatitis
2. Prurigo
3. psoriasis

32. Neurotrophins
Neurotrophins are-
1. Nerve growth factor
2. Brain derived neurotrophic factors (BDNF)
3. Neurotrophin 3
4. Neurotrophin 4
Receptors: Specific receptor
Receptors expressed by:
– Keratinocytes
– Mast cell

33. • Nerve growth factor causes
1. Sprouting nerve fiber
2. Sensitization of nerve ending
3. Axonal transport in dorsal root ganglia cells.
4. increased expression of Substance P

35. • AD Patients have increased expression of NGF in
cutaneous mast cells, keratinocytes and fibroblast.
• Upregulation of NT4 is also seen in patient with
Atopic Dermatitis
• Associated with pruritus of:
1. Atopic dermatitis
2. psoriasis

36. Prostanoids
Prostanoids are:
– PGE2
– PGE1
• Receptors: Prostanoid receptors (P receptor)
• Comment:
Prostaglandins enhances Histamine induced itch.

37. Gastrin Releasing Peptide
Receptor: GRPR
Comment:
a)Itch specific GRPR positive neurons found in dorsal
horn of spinal cord.
b)Mediates itch but not pain (both histamine
depended and independed)

38. Neurotransmitter:
Ach Acetylcholine
• Receptors: Nicotinergic and mascarinergic Ach recptor
• Receptors expressed by:
– Autonomic cholinergic nerve
– Keratinocytes
– Lymphocytes
– Dermal Fibroblast
– Endothelial Cell
• Associated with pruritus of:
1. Atopic Eczema

39. Peptides: Acei
• Can induce itch.

40. Immune cells as
itch mediators and modulators
• Neuropeptides released by sensory nerve (substance P,
Calcitonin gene related peptide, VIP) influence-
– Activation of transcription factor and
– Regulation of expression of adhesion molecule and
proinflammatory cytokines
– Modulation immune and inflammatory response
– Cellular proliferation and differentiation

41. –Antigen presentation
–Tissue repair
By working with keratinocyte, mast cells, dermal microvascular
endothelial cells and langerhans cells.
• This interaction is bidirectional as cytokines and chemokines
are also able to regulate primary nerve afferents via receptor
activation.

42. • IL 2
–Source: T Lymphocyte
–Cause intanse generalized pruritus
–Direct-receptor mediated effect and indirect-via mast
cells effect
–Application:
• Topical calcineurin inhibitor block IL 2, thus reduces pruritus.

43. • IL 31
– Source: th2 cells
– Induce pruritus by modutating function of sensory neuron
– Acts by IL31R
– Found in pruritus of:
• Atopic dermatitis
• Prurigo nodularis
• Amyloidosis

44. • TNF α
– Sensitize nociceptive nerve ending
• IL6
–Increased level found in Prurigo Nodularis

45. Intrinsic antipruritic system:
• Ascending singnals from the periaquedactal gray (PAG) to
thalamus
• Descending signal from the PAG to Dorsal horn.
• K Receptor-
– This opioid receptor located in both PNS and CNS, inhibit itch .

46. Scratching
• Scratching is the reflex functioning at spinal level, although
modified greatly by higher center.
• It inhibits histamine evoked activity of spinothalamic tract.
• It also inhibit the activation of cingulate cortex and activate
the prefrontal cortex and cerebellum

47. • Scratching relieves itch for several minutes after
scratching has ceased.
• 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.

48. • Alternatively, scratching could simply damage sensory nerve
endings, repair needs several minutes.

49. Itch scratch cycle
• Repetitive scratching activates the pre frontal cortex that is
implicated in goal directed and habit learning system.
• This may serve to drive compulsion to continue scratching
and could also account for the highly rewarded aspect of
scratching.

50. • These may cause endogenous
opioid release.
• This further damage skin and
cause release of neuropeptides
and opiates.
• This further augment scratch –
resulting in itch scratch cycle.

51. Sensitization
• Sensitization defined as increased response to primary
sensory neurons to itch or pain.
• Type:
a) Peripheral sensitization: occurs via
• increased density of cutaneous nerves
• Increased neurotrophin level – NGF, NT4
b) Central sensitization: sensitization of 2nd order neuron,
there by increased sensitivity to itch.

52. Alloknesis:
–Stimuli that normally do not produce itch do so in the
skin
• Touch
• Gentle warming
–Ex:
• Sweating induced itch in Atopic dermatitis
• temperature change induced itch
• dressing-undressing induced itch.

53. Punctate hyperknesis
– More intense prick Induces itch sensation in the zone
surrounding an area of inflammation.
– In patient with chronic itch, painful stimulus may be
perceived as itch

54. Thank you