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Pathophysiology and
Clinical Aspects of
Pruritus
Gil Yosipovitch & Tejesh S. Patel
SUBSTANCE P.
SP is a neuropeptide widely distributed in the
periphery and CNS and is thought to intensify itch
perception. SP is synthesized in the cell bodies of
C neurons and causes vasodilation and increased
vascular permeability. Intradermal injection of SP
provokes itch as well as characteristics of neurogenic inflammation such as erythema, wheal, and
flare.5153 SP is elevated in atopic dermatitis patients
compared to controls and significantly correlates
with disease activity.54
SP is co-localized with other neurotransmitters, such as serotonin, dopamine, or calcitonin
gene-related peptide, and acts as a neuromodulator. Although endogenously released SP does not
degranulate mast cells in healthy human skin55 or
cause any sensation at physiological concentrations,56 direct communication between nerve fibers
and mast cells through SP has been verified.57
High concentrations of SP are required to cause
immediate mast cell degranulation; however, low
concentrations can specifically activate neurokinin
1 receptors on mast cells, leading to sensitization
of these cells and increased production of tumor
necrosis factor (TNF-).58 In turn, TNF- sensitizes
nociceptive nerve endings, which provide further
evidence of the extensive crosstalk between nerve
and mast cells.
TRANSIENT RECEPTOR POTENTIAL
CHANNELS.
Transient receptor potential (TRP) channels are thermal receptors that are expressed in sensory neurons
as well as cutaneous keratinocyte and mast cell.
They are activated by chemical and thermal stimuli
and may have a role in pain and itch. Transient
receptor potential vanilloid receptor-1 (TRPV1) is a
nonselective cation channel activated by capsaicin,
heat and acid, and has recently been found to have
a significant role in behavioral scratching responses
in mice.59 Interestingly, it was shown TRPV1 mediates histamine-induced itching via the activation of
phospholipase A2 and 12-lipoxygenase.60 Recently,
a TRPV3 mutation produced an itchy phenotype in
mice suggesting that TRPV3 may also have a role
in itch.61 Together, these results indicate that TRPV1
and TRPV3 play a key role in mediating pruritogenic
action via histaminergic and nonhistaminergic
pathways.
Chapter 103:
PROSTANOIDS.
PGs enhance histamine-induced itch in the skin.81,82
PGs are generally not themselves pruritogenic
when injected into skin; however, intradermal injection of PGE1 enhances pruritus due to histamine
subsequently injected into the same site.83 Only
pruritic neurons that display lasting activation after
histamine are excited by PGE2, and mechanosensitive fibers are unresponsive to both histamine and
PGE2.24 Evidence suggests that cyclooxygenase 2 is
induced in the spinal cord in response to cutaneous
inflammation, and that spinal cord tissue levels of
PGE1 and PGE2 correlate with central pruritus. PGE2
has a direct, low-level pruritogenic effect without
inducing protein extravasation in healthy and atopic dermatitis patients, suggesting that prostanoids
peripheral action is not solely via histamine and
that they may potentiate pruritus via a nonspecific
effect on nerve fibers. Oral administration of aspirin,
a cyclooxygenase inhibitor, does not ameliorate