Itch for itch sensitisation [4]. Three main

Itch is detected by pruriceptive receptors on free nerve
endings in the epidermis through the action of pruritogens and transferred to
the dorsal root and trigeminal ganglia in the spinal cord via afferent nerve
fibres and then to the brain, where the central processing and motor output
(scratch) of the itch stimulus takes place 15. Both exogenous and
endogenous mediators interfere with sensory nerve fibres in the skin to produce
itch. The sensory itch-relaying fibres are either A-delta fibres or C fibres,
with the former being the myelinated, fast-transmission type. C fibres are
subdivided into CMH fibres, responsive to mechanical and heat stimuli, and CMi,
which are responsive to histamine 1. Both of these fibre sub-types are
implicated in itch, with the histamine-sensitive fibre releasing substance P
and calcitonin gene-related peptide, thus potentiating mast cell activation. On
the other hand, the CMH fibres have been shown to respond to cowhage, which
mimics the sensation of clinical itch, such as in atopic dermatitis 1. The
histaminergic and non-histaminergic pathways are entirely separate starting
from the periphery in the skin. Each path involves unique sets of receptors and
mediators and travel separately to the central nervous system 7. On a similar
note, it is known that itch and pain are similar modalities, however, it has
not been elucidated fully whether there exits fibres specifically responsible
for transferring itch as a separate modality to pain 1. When it comes to
chronic itch, both the peripheral and the central nervous systems can become
sensitised such that the itch persists despite lack of the stimulus. It has
been shown though histological observation that in cases of chronic itch due to
atopic dermatitis, the epidermis is hyper-innervated, thus allowing for itch
sensitisation 4.

Three main receptor sub-types are
activated by itch stimuli, such as proteases and contact allergens leading to
the release of itch mediators such as histamine. These receptors include
certain G protein coupled receptors (GPCRs), Toll-like receptors (TLRs),
cytokine families (IL 2 & IL 31) and, finally, the Transient Receptor
Protein (TRP) channel family has also been implicated in itch 13.  

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Given that anti-histamines are
not effective in most cases of itch, the previous importance attributed to
histamine as an itch mediator has subsided and current focus is placed on
GPCRs. Although the H1 receptor is a known player in itch, and is used as a
pharmacological target (H1 receptor blockers), it is no longer considered to be
the most salient 14. Histamine-dependent itch signalling works mainly
through the subsequent activation of TRPV1 channels, whilst non histamine-dependent
signalling involves GPCRs and TRPA1 channels 18. TRPA1 is a universal
chemo-irritant receptor implicated in nociceptive and inflammatory pain,
headaches and migraines, and, of course, itch. Many endogenous compounds that
have implications for itch act upon this receptor. These include, endothelin
and serotonin, which acts on this receptor indirectly via the serotonin
receptor HTR7 6. The majority of currently recognised pruritogens activate
GPCRs, of which Mas-related G-protein receptors are of importance. They are
activated by some proteases and other substances including anti-microbial
peptides. Furthermore, Substance P (implicated in atopic dermatitis) is not
only active at Mas-related G-protein receptors but also the neurokinin 1 receptor,
targets for which are currently being investigated further in clinical trials. Proteases,
such as tryptases, kallikreins and cathepsin S are mainly active at
protease-activated receptors. GPCRs, as well as being implicated in synthesis
of the itch signal are also known to potentiate the signal mainly in the spinal
cord through being activated by prostaglandins and leukotrienes. Similarly, the
role of TLRs has not yet been found to be anything more than potentiating itch
transmission, despite certain variants being present in the nerve fibres in the
skin. TLR7, expressed by C-fibres, seems to play an important part in
non-histaminergic signalling 3. Another important indirect mediator of itch
is interleukin 31 (IL 31), which has been shown to have a role in atopic
dermatitis and, moreover, the receptor is expressed on sensory neurones.
However, the indirect role is apparent given the slow onset of itch after
activation of the receptor via injection 1.