Pathophysiology of Pruritus

Question 1

What nerve fibers in the skin respond to light touch and moving stimuli?

Answer 1

A-beta (Abeta)

Question 2

What are the two myelinated types of nerves in the skin?

Answer 2

A-beta and A-delta

Question 3

What size are the A-beta and A-delta nerves relatively?

Answer 3

A-beta are large diameter fibers A-delta are small diameter fibers

Question 4

Which nerve fibers are unmyelinated?

Answer 4

C fibers

Question 5

What are the relative conduction velocities of the A-beta, A-delta, and c fibers?

Answer 5

A-beta are the fastest (large/myelinated), A-delta are the middle (slow but myelinated) and then C fibers are the slowest

Question 6

What is the key difference in sensation between the A-delta and C fibers?

Answer 6

The A-delta senses pain, itch, cowhage-sensitive, thermal and mechanical sensation. They are split. Histamine-sensitive C fibers are sensitive to heat and pruritogenic stimuli but not mechanical. The majority of C fibers, however, are sensitive to mechanical and heat stimuli but have little or no response to histamine. The A-delta ones can transmit pruritis but also a burning sensation along with mechanical stimuli.

Question 7

What are 3 peripheral mediators of itch?

Answer 7

Histamine, proteases, and interleukin-31

Question 8

What are 3 types of central itch mediators?

Answer 8

Opioids, gastrin-releasing peptide, and B-type natriuretic peptide

Question 9

What is the difference between the histamine-sensitive C-fibers and the other C fibers?

Answer 9

The histamine C-fibers are sensitive to pruritus via histamine and temperature but they are not responsive to mechanical. The other C-fibers, however, are not sensitive to histamine.

Question 10

What is the signifcance of cowhage on C fibers?

Answer 10

For non-histaminergic c fibers they are activated by spicules of the tropical legumes cowhage (mucuna pruiens) which causes intense itch without producing a histaminergic axon reflex

Question 11

How do Cowhage spicules induce itch?

Answer 11

Release of protease mucanain, which activates proteinase-activated receptor (PAR)-2 and PAR-413.

Question 12

What sensations are transmitted with the cowhage-sensitive fibers?

Answer 12

burning sensation and the itch.

Question 13

Can you still feel itch if you remove the epidermis?

Answer 13

No, removal of the epidermis abolishes itch.

Question 14

What neural mediators and receptors do keratinocytes express?

Answer 14

Opioids, proteases, substance P, Nerve growth factor, Neurotrophin 4

Question 15

What are the 4 primary mediators of itch?

Answer 15

Histamine, tryptase (protease), Cathepsin S (protease), Interleukin 31

Question 16

What are the 5 secondary mediators of itch?

Answer 16

Prostaglandin E1,2; Substance P; u-Opioid receptor agonists; Nerve growth factor; Interleukin-2

Question 17

Where is histamine found primarily in the skin?

Answer 17

Granules of dermal mast cells

Question 18

What things cause the mast cells to release histamine?

Answer 18

High-affinity IgE receptor (FceRI), KIT receptor for stem cell factor, and receptors for neuropeptides (Substance P, NGF) and complement C5a -Can be potentiated by prostaglandin E1 and E1

Question 19

Is histamine involved in the majority of cutaneous disease?

Answer 19

No, only a few have histamine as a primary driver (chronic urticaria and mastocytosis)

Question 20

How does tryptase trigger itch?

Answer 20

Tryptase is released by activate dmast cells and cleaves PAR-2, a g-protein coupled receptor on C-fiber terminals and exposes a tethered ligand domain and thereby “self-activates” PAR-2 leading to itch transmission

Question 21

What effects does PAR-2 activation have on the local cutaneous environment

Answer 21

Transmission of itch, it also causes the release of neuropeptides including substance P and calcitonin gene-related peptide, which induce neurogenic inflammation

Question 22

What is the defect in Netherton syndrome and why does it cause pruritus and atopic manifestations?

Answer 22

Serine protease inhibitor deficiency is the defect and this leads to excess epidermal protease activity.

Question 23

What is the relative role of u and k opioid receptors in itch transmission?

Answer 23

These can act peripherally or centrally and the u-opioid receptors can activate itch and the k-opioid receptors reduce itch

Question 24

What are the two possible mechanisms of morphine as an inducer of itch?

Answer 24

1. Degranulation of cutaneous mast cells (pre-treatment with doxepin reduces itch
2. Activation of u-opioid receptors with direct central and peripheral purritogenic effects (naloxone reduces itch too).

Question 25

What role does substance P play in itch?

Answer 25

Thought to intensify itch perception. Interacts with mast cells, neurokinin 1 –> increased TNF-alpha.

Question 26

What roles do neurotrophins play in itch?

Answer 26

Nerve growth factor is the prototype. It causes the proliferation of terminal cutaneous nerves and upregulation of neuropeptides. Known to induce sprouting and sensitization of nerve.

Question 27

What role do prostanoids play in itch?

Answer 27

Prostaglandins enhance histamine-induced itch.

Question 28

What is the treatment for polycythemia vera and why?

Answer 28

Oral aspirin only, works through prostanoid blocking

Question 29

How does itch sensitization occur in the peripheral nervous system?

Answer 29

Increased skin innervation, NGF and neurotrophin

Question 30

How does central sensitization to itch occur?

Answer 30

1. Allokenisis: stimuli that normally do not cause itch now do
2. Punctate: prick induced itch sensation

Question 31

Which histamine receptors are involved in pruritus?

Answer 31

H1

Question 32

As compared to A-beta fibers do C-fibers innervate a larger or smaller area?

Answer 32

C-fibers innervate a much larger area. This is why the much faster touch receptors like a-beta are so precise, they have a lot more endings innervating smaller areas.

Question 33

How does cowhage generate pruritus?

Answer 33

It is histamine independent. -the spicules release protease mucunain, which activates PAR-2 and PAR-4.

Question 34

What is the difference between alloknesis and hyperknesis?

Answer 34

Alloknesis: stimuli that normally does not induce itch such as touch or gentle warming do so in the skin that surrounds a pruritic area. Hyperknesis: More intense itch induced by a stimulus that usually produces sight itch and occurs with in the skn surrounding an area of inflammation.

Question 35

What enzyme is involved in cholestatic pruritus?

Answer 35

Autotaxin

Question 36

Levels of what enzyme correlate with itch intensity in cholestatic pruritus?

Answer 36

Autotaxin levels

Question 37

Pathogenesis of cholestatic pruritus?

Answer 37

Autotaxin and its product lysophosphatidic acid, a neuronal activator have a pathogenic role.