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Chapter 103

Pathophysiology and
Clinical Aspects of
Pruritus
Gil Yosipovitch & Tejesh S. Patel

ETIOLOGY AND PATHOGENESIS


Mediators of Pruritus
Both central and peripheral mediators are important in pruritus. Proinflammatory pharmacologic
mediators cause pruritus in inflammatory skin diseases, such as urticaria. Most such mediators also
cause other signs of inflammation (pain, erythema
due to vasodilation, increased vascular permeability). Several mediators cause pruritus indirectly
by evoking release of histamine and other mediators from mast cells (e.g., SP and several opioid
peptides) or by potentiating the actions of other
mediators [e.g., prostaglandin E1 (PGE1)]. Potentially
important peripheral and central mediators of
pruritus include histamine, proteases, cathepsins,
gastrin-releasing peptide (GRP), opioids, substance
P, nerve growth factor (NGF), interleukins (IL), PGs,
and noradrenaline.38
HISTAMINE.
Histamine is the archetypal mediator of signs and
symptoms of inflammation including pruritus.
Histamine is synthesized in the mast cells of the
skin and stored in mast cell granules. It is released
by these cells in response to a variety of injurious
stimuli. Histologically, dermal mast cells and unmyelinated neurons are closely juxtaposed, raising the
possibility of a pseudosynaptic relationship and implying a close functional relationship between the
immune and nervous systems. Histamine acts to
produce itch by way of the H1 receptor and not via
H2 receptors.39 Histamine also rapidly causes tachyphylaxis in human skin40; therefore, it is unlikely to
be responsible for sustained pruritus. Nevertheless,
it is an important mediator in short-lived urticarial
wheal-and-flare reactions and causes pruritus after
a single intradermal injection. Histamines pruritic
action can be potentiated by PGE1. Firm evidence
for histamine as the main mediator of pruritus is
limited to skin diseases such as acute and chronic
urticaria, mastocytosis, insect bite reactions, and al-

lergic drug reactions. H1 antihistamines are usually


effective in these disorders. The role of histamine in
most types of chronic itch is minimal, and antihistamines do not alleviate itch. In atopic dermatitis,
histamine has no significant role, and low-sedation
H1 antihistamines are ineffective. Other histamine
receptors such as H3- and H4-receptors may also
play a role in itch, as demonstrated through mouse
models.41 In particular, H4-receptor antagonists
have been shown to inhibit experimentally induced
itch.42,43
PROTEINASES.
Proteinases and their respective receptors (PARs)
appear to play an important role in chronic pruritus
and in the regulation of cutaneous inflammatory
and immune responses. Human dermal mast cells
produce two proteases: tryptase and chymase. The
proximity of dermal mast cells to afferent C neuron
terminals in skin allows a functional relationship by
which tryptase induces itch.44 The activated mast
cell releases tryptase (along with other mediators,
including histamine), which in turn activates the
PAR-2 receptor, a G protein-coupled receptor subfamily localized on C fiber terminals. 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 SP. This forms an additional pathway for
itch, and represents another example of interaction
between the immune and nervous systems.
PARs may play a significant role in regulation of
cutaneous neurogenic inflammation. In the skin,
PAR-2 expressed on sensory neurons is self-activated by peptide ligands exposed after extracellular
cleavage by trypsin or mast cell tryptase. PAR-2
agonists have been demonstrated to induce release
of calcitonin gene-related peptide and SP, which
induce neurogenic inflammation.45 In addition,
PAR-2 agonists elicit dose-related scratching in
mice supporting a role for PAR-2 in peripheral itch
transduction.46,47 Furthermore, studies using dermal
microdialysis have shown that levels of tryptase
and its receptor (PAR-2) are elevated fourfold in
atopic dermatitis.48 PAR-2 is also highly expressed
in the epidermis of atopic dermatitis patients. In
addition, recent studies have demonstrated the
cysteine proteases, cathepsin S and mucunain, to
have roles in itch transmitted through nonhistaminergic pathways.31,49 It is noteworthy that proteinase
activity can also be found in common allergens50
and staphylococcal skin infections, both of which
are known to aggravate atopic dermatitis and itch.

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142 Chapter 103: Pathophysiology and Clinical Aspects of Pruritus

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.

GASTRIN RELEASING PEPTIDE RECEPTOR.


GRP receptor positive neurons have recently been
found to constitute a dedicated neuronal pathway
for itch in the spinal cord of mice.32,62 GRP is one of
the mammalian bombesin-related peptides. The
role of GRPR in the pathogenesis of chronic itch in
humans remains to be determined.
OPIOIDS.
Opioid peptides are potent neurotransmitters and
have both a central and a peripheral itch-producing
action. Opioids appear to induce itch via two possible mechanisms. First, by degranulation of cutaneous mast cells63 and second, via a direct central
and peripheral pruritogenic effect by activating
-opioid receptors.6366 Morphine and other endogenous and exogenous -opioid receptor agonists
are known to cause generalized pruritus.6770 The
concept of central sensitization in chronic pruritus
and possible involvement of pruritic mediators
located in the CNS is becoming increasingly recognized as important in both cutaneous and systemic
diseases. The perception of pruritus is modified by
endogenous opiates via central opioid receptors.
Generalized pruritus may result from an imbalance
between the - and -opioid systems68,69,71 Activation of -opioid receptors stimulates itch perception, whereas -opioid-receptor stimulation inhibits
-receptor effects both centrally and peripherally.68,69,71,72
NEUROTROPHINS.
NGF is the prototypical neurotrophina factor
that regulates the growth and function of nerve
cells. Other members of this family include neurotrophins 3, 4, and 5 and brain-derived neurotrophic
factor.73 Increased levels of epidermal NGF correlate
with the proliferation of terminal cutaneous nerves
and upregulation of neuropeptides. NGF is known
to induce sprouting of nerve fibers, sensitization of
nerve endings, axonal transport in spinal ganglia
(dorsal root ganglion cells), and increased expression of neuropeptides. NGF is required not only for
survival and regeneration of sensory neurons but
also controls the responsiveness of such neurons
to external stimuli.74,75 Increased cutaneous gene
expression of NGF in mast cells, keratinocytes, and
fibroblasts of atopic dermatitis patients was highly
associated with plasma levels of NGF, thus providing data that NGF may contribute significantly to

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Chapter 103:

Pathophysiology and Clinical Aspects of Pruritus 143

itch in atopic dermatitis.76 Other neurotrophins,


such as neurotrophin 4, are upregulated in keratinocytes of atopic dermatitis patients.77
INTERLEUKINS.
There is increasing evidence that IL-31, a Th-2
cytokine, has a role in pruritus. It has been shown
that IL-31 and its oncostatin M receptor (OSMR) act
as inducers of itch and dermatitis in mice, and that
IL-31 is overexpressed in keratinocytes in atopic
dermatitis.78 In addition, a missense mutation in the
OSMR gene, which encodes oncostatin M-specific
receptor b (OSMRb), was found in families affected
by familial primary localized cutaneous amyloidosis,
a severe localized pruritic disease.79 Furthermore,
IL-31 antibody could effectively reduce scratching
behavior in an atopic dermatitis-like murine model
during the onset of clinical skin manifestations,
suggesting the potential therapeutic role of IL-31
antibody in treatment of chronic itch 78,80 In atopic
dermatitis, several cytokines induce itch, including
IL-2 and IL-6. IL-2, the prototype pruritogenic cytokine, induces itch in atopic dermatitis as well as in
cancer patients receiving recombinant IL-2. Inhibition of IL-2 production forms the basis for treatment
of atopic dermatitis with cyclosporine and immunomodulators such as tacrolimus and pimecrolimus.
Of note, IL-2 and IL-6 have receptors in nerve cells.

pruritus except in polycythemia vera84; however,


topical salicylates and topical aspirin often significantly reduces pruritus in patients with chronic
localized itch.85 Of note, PGD2 has been shown to
play a role in inhibiting pruritus in mice models of
atopic-like dermatitis.86,87 In addition, thromboxane (TX) A2 was shown to induce itch-associated
responses through the thromboxane prostanoid
(TP) receptors located in keratinocytes and skin
nerve fibers in mice. This response was abolished
by deficiency of the TP receptor and a TP receptor
antagonist.88

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

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144 Chapter 103: Pathophysiology and Clinical Aspects of Pruritus

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