Pathophysiology of Pruritus Flashcards
What nerve fibers in the skin respond to light touch and moving stimuli?
A-beta (Abeta)
What are the two myelinated types of nerves in the skin?
A-beta and A-delta
What size are the A-beta and A-delta nerves relatively?
A-beta are large diameter fibers A-delta are small diameter fibers
Which nerve fibers are unmyelinated?
C fibers
What are the relative conduction velocities of the A-beta, A-delta, and c fibers?
A-beta are the fastest (large/myelinated), A-delta are the middle (slow but myelinated) and then C fibers are the slowest
What is the key difference in sensation between the A-delta and C fibers?
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.
What are 3 peripheral mediators of itch?
Histamine, proteases, and interleukin-31
What are 3 types of central itch mediators?
Opioids, gastrin-releasing peptide, and B-type natriuretic peptide
What is the difference between the histamine-sensitive C-fibers and the other C fibers?
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.
What is the signifcance of cowhage on C fibers?
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
How do Cowhage spicules induce itch?
Release of protease mucanain, which activates proteinase-activated receptor (PAR)-2 and PAR-413.
What sensations are transmitted with the cowhage-sensitive fibers?
burning sensation and the itch.
Can you still feel itch if you remove the epidermis?
No, removal of the epidermis abolishes itch.
What neural mediators and receptors do keratinocytes express?
Opioids, proteases, substance P, Nerve growth factor, Neurotrophin 4
What are the 4 primary mediators of itch?
Histamine, tryptase (protease), Cathepsin S (protease), Interleukin 31
What are the 5 secondary mediators of itch?
Prostaglandin E1,2; Substance P; u-Opioid receptor agonists; Nerve growth factor; Interleukin-2
Where is histamine found primarily in the skin?
Granules of dermal mast cells
What things cause the mast cells to release histamine?
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
Is histamine involved in the majority of cutaneous disease?
No, only a few have histamine as a primary driver (chronic urticaria and mastocytosis)
How does tryptase trigger itch?
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
What effects does PAR-2 activation have on the local cutaneous environment
Transmission of itch, it also causes the release of neuropeptides including substance P and calcitonin gene-related peptide, which induce neurogenic inflammation
What is the defect in Netherton syndrome and why does it cause pruritus and atopic manifestations?
Serine protease inhibitor deficiency is the defect and this leads to excess epidermal protease activity.
What is the relative role of u and k opioid receptors in itch transmission?
These can act peripherally or centrally and the u-opioid receptors can activate itch and the k-opioid receptors reduce itch
What are the two possible mechanisms of morphine as an inducer of itch?
- Degranulation of cutaneous mast cells (pre-treatment with doxepin reduces itch
- Activation of u-opioid receptors with direct central and peripheral purritogenic effects (naloxone reduces itch too).
What role does substance P play in itch?
Thought to intensify itch perception. Interacts with mast cells, neurokinin 1 –> increased TNF-alpha.
What roles do neurotrophins play in itch?
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.
What role do prostanoids play in itch?
Prostaglandins enhance histamine-induced itch.
What is the treatment for polycythemia vera and why?
Oral aspirin only, works through prostanoid blocking
How does itch sensitization occur in the peripheral nervous system?
Increased skin innervation, NGF and neurotrophin
How does central sensitization to itch occur?
- Allokenisis: stimuli that normally do not cause itch now do
- Punctate: prick induced itch sensation
Which histamine receptors are involved in pruritus?
H1
As compared to A-beta fibers do C-fibers innervate a larger or smaller area?
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.
How does cowhage generate pruritus?
It is histamine independent. -the spicules release protease mucunain, which activates PAR-2 and PAR-4.
What is the difference between alloknesis and hyperknesis?
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.
What enzyme is involved in cholestatic pruritus?
Autotaxin
Levels of what enzyme correlate with itch intensity in cholestatic pruritus?
Autotaxin levels
Pathogenesis of cholestatic pruritus?
Autotaxin and its product lysophosphatidic acid, a neuronal activator have a pathogenic role.
