PathophysioIogy of pruritus

Greg Burton
Animal Skin Ear and Allergy Clinic
Melbourne Veterinary Referral Centre
70 Blackburn Rd, Glen Waverley VC 3150


Pruritus, what is it?

Pruritus is deIined as a sensation that elicits the desire to scratch or induces scratching. It is commonly reIerred
to as 'itch. The most objective measure oI pruritus is observed scratching however pruritic behaviour may also
involve pinching, slapping, rubbing, licking, biting, rolling, barbering and Ieather plucking depending on the
species involved.

Types of pruritus. (Yosipovitch et al 2003)

1. Pruritoceptive itch is an itch originating Irom the skin eg atopic dermatitis
2. Neuropathic itch is an itch arising Irom neuroanatomic dysIunction eg nerve entrapment injuries.
3. Neurogenic itch is an itch arising Irom neurochemical action eg opioids in liver disease.
4. Psychogenic itch is a delusional state.

Neuroanatomy of itch.


From Paus et al 2006
Peripheral processing

The primary aIIerent neurones (sensory neurones) are located in the dorsal root ganglia oI spinal nerves or the
sensory ganglia oI cranial nerves. Axons oI neurones that conduct itch are unmyelinated C Iibres that terminate
at the dermoepidermal junction (DEJ) or penetrate into the epidermis as Iree nerve endings. Substance P (SP),
neurokinin A and calcitonin gene related peptide (CGRP) are the main transmitters (Wallengren et al 1987). C
Iibres associated with conduction oI histaminergic itch (pruriceptors) are slow velocity Iibres that have large
innervation territories compared to polymodal C Iibres. They comprise about 5 oI aIIerent C Iibres in the skin.
They are responsive to pruritogenic stimuli and thermal stimuli but not mechanical (Schmelz M et al 1997).
Other classes oI primary aIIerents exist that are involved with histamine independent generation oI pruritus
(Ikoma, et al. 2005). Diversity oI aIIerent Iibres probably explains some the variations in perceived itch quality
(Darsow et al. 2000).

Once C Iibres are activated there is release oI transmitters into the tissue (neurogenic inIlammation) and
orthodromic transmission is processed along the peripheral nerves to the spinal ganglia. Nocioceptor aIIerents
terminate in the superIicial area oI the dorsal horn and 'itch speciIic neurones have been identiIied in the cat in
the dorsal horn lamina 1 spinothalamic tract (Andrew and Craig 2001).

Heat activated and cold activated vanilloid and cold-menthol sensitive receptors TRPs (transient receptor
potential) can modulate peripheral itch processing. They are inducible receptors belonging to a Iamily oI
excitatory ion channels. They can be activated by heat and cold and may explain why peripheral application oI
heat and cold can modulate itch (Stander et al 2004, McKemy eta al 2002). The vanilloid receptors TRPV2,
TRPV3 and TRPV4 are activated by diIIering temperatures (Caterina et al. 1999, Peier, et al. 2002 , Smith et al.
2002). TRPV3 has a very similar neuronal expression pattern to that oI TRPV1 (see later Ior discussion on
TRPV1) and TRPV3 subunits may Iorm heteromultimeric structures by interacting with TRPV1 monomers
(Smith et al. 2002). TRPV3 may act as signal cotransducer and/or regulator oI TRPV1-mediated pain and itch.
Functional TRPV2, TRPV3 and TRPV4 channels are also highly expressed by epidermal keratinocytes and mast
cells (Peier, et al. 2002, Chung et al 2004, Moqrich, et al. 2005). Physical and thermal activation oI TRPV2
causes mast cells to degranulate (Stokes et al 2004). TRPM8 (menthol) receptors are expressed by C-type
sensory neurones, they serve as thermosensors Ior coolness and cold (i.e., 8C to 28C). TRPM8 is also
activated by chemicals like menthol that produce sensations oI cold (McKemy et al 2002).

Itch may be under tonic inhibitory control oI pain-related signals (Greaves et al 2004).

Spinal processing

'Itch-speciIic neurones oI the cat cross over to the contralateral side oI the spinal cord with speciIic projections
terminating in the lateral thalamus. They have slow central conduction. Lamina 1 spinothalamic tract neurones in
primates have a direct path to the ventral medial nucleus and the medial dorsal nucleus oI the thalamus. The
thalamus plays a role in the emotional processing oI pain but it is unsure as to whether it has a modulating role
with itch. These 'itch dedicated projections do not show spontaneous activity as in pain Iibres and may also be
under tonic negative control (Schmelz, 2001). Suppression oI this negative tone may induce itching Irom a
purely spinal origin. Conduction oI pruritus is associated with increased opioidergic tone at the spinal level
(Summey and Yosipovitch 2005). Spinal transmission oI itch signals results in release oI CGRP and SP with
activation oI CGRP receptor (CGRPR) and neurokinin 1 receptor (NK1R) to transit itch signals centrally (Paus
et al 2006). Endovanilloids and endocannabinoids are Iound in the dorsal root ganglia. The latter can be
produced on demand similar to eicosanoids and provides another potential avenue Ior spinal regulation oI itch
(van der Stelt and Di Marzo 2004).

Central processing

Several pathways Irom the thalamus to the cortex have been distinguished. Neurones Irom the ventral medial
nucleus terminate in the 3a region oI the sensorimotor cortex whereas neurones Irom the medial dorsal nucleus
terminate in the anterior cingulate cortex (Jinks and Carstens 2000). Involvement oI the motor cortex explains
the urge to scratch. Involvement oI the anterior cingulate cortex may explain the emotional inIluences on 'itch
(Rees and Laidlaw 1999, Bartels and Zeki 2000). Direct excitatory connections Irom the thalamus to the insular
cortex have also been identiIied. Central imaging studies in histamine induced scratching also suggest
involvement oI the supplemental motor area, premotor area, preIrontal cortex, orbioIrontal cortex, cerebellum
and periaqueductal gray (Paus et al 2006). These centres are also activated in pain. Involvement oI the Irontal
lobe cortices may explain the compulsive nature oI itching in some patients (Kringelbach 2005). Endovanilloids
and endocannabinoids are Iound and various central locations including the thalamus and may potentially
regulate TPRV1 centrally (van der Stelt and Di Marzo 2004).

What makes us scratch?

Pruritus originating Irom skin disease is what we are most Iamiliar with. Ultimately the severity oI pruritogenic
itch is dependent on mast cell density, innervation territories, the concentration oI liberated mediators, the rate oI
degradation versus liberation and the interaction between mediators, transmitters and neurones together with
spinal and central processing oI those signals. Liberation and degradation oI mediators as well as tachyphylaxis
to mediators and up-regulation and inhibition oI spinal and central pathways is a dynamic event. Put simply it is
a complex immuno-neurological event.

Mediators of pruritoceptive itch

1. Acetylcholine (ACh)

Acteylcholine causes itch in atopics and burning sensation in non-atopics. Reaction to acetylcholine may explain
itching with sweating in atopics. Itching induced by ACh is thought to be mediated by muscarinic AChR. It is
released by keratinocytes during cutaneous inIlammation and T-lymphocytes (Schmelz 2000).

2. Amines

a. Histamine
Released Irom degranulating mast cells and basophils. Histamine can also be released Irom macrophages and
lymphocytes (Zwadlo-Klarwasser et al 1994).
Histamine acts as a neurotransmitter in neurones via H1 receptor interaction. H3 receptors have been identiIied
on peripheral endings oI SP positive Iibres and may play a role in modulating itch. There is an inverse
relationship between H1 and H3 receptor activation and itch. H3 agonists may reduce H1 mediated itching
(Sugimoto et al 2004). H4 receptor activation also increases itch (Paus et al 2006).

b. Serotonin
Released Irom mast cells. Serotonin acts as a neurotransmitter and both peripheral and central receptors may be
involved. Itch is less potent than histamine but is enhanced by prostaglandins. Cutaneous itching associated with
serotonin may be mediated by 5HT2 receptors (Yamaguchi et al 1999). Serotonin also has a central role in itch
perception and may play a role in neurogenic itching oI uremic patients in people.

3. Cytokines

Interleukin 2 (T-cells) is a potent inducer oI itch (Wahlgren et al 1990).
IL 31 (T-cells) has been shown to induce pruritus in mice and is over-represented in lesional skin oI
atopic people. IL 31 is a T cell cytokine with mRNA being over-expressed in CLA memory T-cells
(Bilsborough et al 2006). Both keratinocytes and monocytes express IL 31 R (Pause et al 2006).

4. Eicosanoids

Eicosanoids are liberated Irom inIiltrating leucocytes and mast cells. They activate both TRPV1 and TRPV4
receptors (have endovanilloid Iunctions) (Watanabe, H., et al. 2003). Prostaglandins reduce the threshold Ior
pruritus induced by other mediators (Greaves and McDonald-Gibson 1973). The mechanism oI this may involve
their endovanilloid action. Leukotriene B4 is pruritogenic in the mouse (Andoh and Kuraishi 1998). PAF
stimulates itch that is histamine mediated. Eicosanoids also stimulate production oI Th-2 attracting chemokines
and promote Th-2 T-cell recruitment during inIlammation.

a. Endovanilloids and Endocannabinoids

Endovanilloids such as unsaturated

N-acyldopamines, lipoxygenase products oI arachidonic acid and

the
endocannabinoid anandamide activate and/or sensitize TRPV1 (transient receptor potential vanilloid type I).
These molecules act as nonselective calcium permeable sensory transduction channels expressed on sensory
neurons and non-neuronal cell types (Langerhan cells, mast cells, keratinocytes, sebocytes, Iollicular
keratinocytes). They augment the bi-directional intercellular network to initiate itch. Activation oI TRPV1 on
keratinocytes results in pruritogenic mediator release as well as proliIeration, diIIerentiation and apoptosis.
TPRV1 activation on neurones may lower the threshold oI stimulation Ior other mediators and play a role in
reduced pruritic threshold and allokinesis in chronic inIlammation (Southall et al. 2003, Bodo et al. 2005.)

Cannabinoid receptor CB1 shows close co-localisation with TRPV1 in sensory neurones. CB1 agonists suppress
itch. In inIlamed skin cannabinoids can activate TPRV1. CB1 agonists used in conjunction with TPRV1 agonists
will suppress itch without the burning sensation oI TPRV1 agonists.

Repeatedly applied topical vanilloids (such as capsaicin) may desensitize neuronal and non-neuronal TRPV1
mediated signaling so as to counteract the pruritogenic intercellular network and hence terminate itch.



Neuropeptides

a. Substance P
SP reactive nerve Iibres are Iound in the skin and are particularly numerous around blood vessels and sweat
glands. C Iibre activation results in SP release and neurogenic Ilare. This requires intact axons (is an axon reIlex)
and includes release oI eicosanoid mediators oI inIlammation AND histamine release Ior dermal mast cells AND
has direct pruritogenic eIIects. In people the severity oI the reaction in decreased by stress and increasing age
and increased at night (Paus et al 2006).

b. Calcitonin gene related peptide
Tends to co-localise with SP in the skin. It causes vascular changes (erythema) but is NOT mediated via
histamine or abolished by blocking axonal transmission. It is a major neurotransmitter along with SP in
peripheral and central neurones.

c. Vasoactive intestinal peptide (VIP)
VIP and acetylcholine co-localise in autonomic nerve Iibres. VIP is increased in atopic skin.

d. Endothelin
Endothelin acts as a neurotransmitter on C Iibres within the skin. Mast cell degranulation up-regulates
endothelial endothelin release and modulates degradation oI endothelin via neutral proteases (Metsarinne et al
2002).

e. Neurotensin
Neurotransmitter that may interact with dopamine and opioid receptors centrally.

I. Neurotrophins
Nerve growth Iactor is involved in control oI skin sensation and may play role in pruritus in atopic dermatitis. It
is pruritogenic when injected into the skin (Tanaka and Matsuda 2005). Increased neutrophin production in AD
reduces itch threshold, up-regulates vanilloid receptors and up-regulates SP production (Groneberg et al. 2005,
Botchkarev et al 2006).

Opioids

agonists induce pruritus. It is likely that tonic inhibition oI itch involves pain pathways. Analgesia via
agonists may abolish this tonic inhibition and lead to central perception oI pruritus. Central opioid receptors
are up-regulated in AD. agonists (spinal level) inhibit pruritus (Stander et al 2003).

endorphins Irom keratinocytes and enkephalins increase histamine responses in the skin without increasing
histamine levels or inducing eicosanoid release. They can also aIIect central perception oI itch via interaction
with opioid receptors and possibly serotonin (Fjellner and Hagermark 1982).

Proteases and kinins

a. Chymase
Skin mast cells release the neutral protease chymase along with histamine during degranulation. Chymase
greatly augments histamine-induced wheal Iormation in Ragweed sensitized dogs and this is abolished by
blocking H-1 receptors (Rubinstein et al 1990). Chymase augments histamine mediated itching presumable by
increasing histamines aIIinity with H1 receptors.

b. Tryptase
Tryptase induces itch via activation oI proteinase-activated receptor 2 (PAR2) on sensory neurones and induces
neuropeptide release. Both chymase and tryptase are released together with histamine when mast cells
degranulate (SteinhoII et al 2000). PARs play a key role in pruritus during neurogenic inIlammation. Tryptase
released Irom degranulated mast cells activates PAR at the plasma membrane oI sensory nerve endings.
Activation oI PAR by tryptase, trypsins, kallikreins,) stimulates the release oI calcitonin generelated peptide
(CGRP) and tachykinins, e.g., SP, Irom sensory nerve endings. CGRP interacts with the CGRP1 receptor to
induce arteriolar dilation and hyperaemia. SP may stimulate degranulation oI mast cells, providing a positive-
Ieedback mechanism. Tryptase degrades CGRP and terminates its eIIects. CGRP inhibits SP degradation by
neutral endopeptidase and also enhances SP release, thereby ampliIying its eIIects. At the spinal cord level,
PAR-induced intracellular Ca2 mobilization leads to release oI CGRP (and SP) Irom central nerve endings,
thereby activating CGRP receptor (CGRPR) and NK1R to transmit itch responses to the central nervous system
(Pause et al 2006). PAR 2 activation (similar to TRPV1) may be involved with the lowering oI the pruritic
threshold in chronic skin inIlammation (Amadesi., et al. 2004, Vergnolle, et al. 2001). PAR2 expression in the
spinal and central neurons implies PARs may play a role in spinal and central mediation oI itch as well.

c. Other proteases
From keratinocytes and protease IV Irom endothelial cells and/or probably exogenous proteinases (bacteria,
house dust mite, pollens) also activate PARs.

d. Kallikrein
PAR2 activation.

e. Bradykinin
Endovanilloid activity

Neuropathic itching

Itch sensation induced by spontaneous Iiring along axons OR dorsal horn neurones in the spinal cord as seen in
nerve entrapment injuries and post herpetic pruritus. Central neuropathic itching has been described due to
cerebral, parietal, thalamic and internal capsular lesions.

Neurogenic itching

Neuromediator induced and oIten poorly understood. Itch associated with cholestasis appears to be due to
increased opioid peptides produced by the liver. The presence oI and opioid receptors centrally can modulate
the central perception oI itch. agonists and antagonists INDUCE itch while antagonists and agonists
INHIBIT itch. Allokinesis associated with atopic eczema is believed to be due to altered central processing oI
itch such that atopic pruritus may have both pruritoceptive and neurogenic components. Opioid actions may be
augmented by IL6.

Induction oI dry skin results in itching that can be modulated by opioid antagonists but not histamine or
serotonin inhibitors, suggesting neurogenic or neuropathic origin (Fujii et al 2005).

Why does scratching modulate itch?

When a large area oI skin is scratched or rubbed there is activation oI touch and pressure conducting myelinated
A Iibres resulting in down regulation oI itch processing at the level oI the substantia gelatinosa. The dorsal horn
also receives inhibitory signals Irom the mid-brain periaqueductal region. (Greaves and Wall 1996). Rubbing
thereIore can modulate itch (and pain). The scratch reIlex is a more common response to itch to counteract the
itch by slightly painIul stimuli. This itch reduction is based on a spinal antagonism between pain- and itch-
processing neurons (Schmelz 2001).

Understanding pruritus creates new potential therapies

Peripheral acting
HI antagonist (pyrilamine)
H3 agonists
SP antagonists (spantide I and II)
Vanilloid receptor agonists (dronabinol, resiniIeratoxin. Topical capsaicin)
TRPV1 antagonists
CB1 Agonists
PAR- 2 antagonists
Electrical stimulation

Central acting
Opioid antagonist (naloxone) or kappa agonists
Serotonin uptake inhibitors (paroxetine)
Mirtazapine (psycotropic drug) central adrenergic receptor antagonist
Gabapentin Ior neuropathic itch
Thalidomide (nerve suppression)
Conclusion

Pruritus is multiIactorial in origin and a complex interaction between mediators, and neurotransmitters with
peripheral, spinal and central processing. Not surprisingly the best treatment Ior pruritus is diagnosis and
removal oI the trigger. In cases where this is not possible, a better understanding oI the pathophysiology oI
pruritus may allow Ior more eIIective and saIer treatments in the Iuture.


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