Neurosensory Mechanisms

Pathogenesis of itch in atopic dermatitis

Itch begins at the skin when unmyelinated, itch-selective C fibers are activated by pruritogen(s) in the epidermis and dermal-epidermal junction. Pruritogens are substances or molecules that have the potential to cause itch ( Table 16.1 ). These nerve fibers are categorized as histaminergic or nonhistaminergic depending on the receptors they express. Activation of these receptors results in the opening of ion channels, which leads to induction of an action potential. This signal is then transmitted to the spinal cord via the spinothalamic/spinoparabrachial tract, and is ultimately processed in the cerebral cortex of brain, which interprets and signals “itch” to the patient ( ). Note that histaminergic and nonhistaminergic nerve fibers transmit itch via separate neural tracts in the peripheral and central nervous system ( ).

Neuronal sensitization of itch

The perception threshold of itch is significantly lower in AD patients as compared with healthy controls. Itch neuronal sensitization is represented by two classically known phenomena: alloknesis and hyperknesis. Alloknesis is a phenomena in which normal or nonpruritic stimuli are perceived as itchy. Hyperknesis is excessive itch perception to pruritic stimuli ( ). Neuronal sensitization can occur due to various factors acting at the peripheral level (i.e., the skin) or at the central level (i.e., the brain or spinal cord). Peripheral sensitization is characterized by hypersensitivity of sensory neurons to itch stimuli caused by inflammatory mediators. Central sensitization is promoted by upregulation of itch-related receptors and molecules, dysfunction of the inhibitor circuits in the spinal cord, attenuation of descending inhibitory pathways in the spinal cord, and functional and structural changes in the brain ( ) ( Fig. 16.1 ).

The epidermis, barrier dysfunction, and neuronal sensitization

The role of barrier dysfunction in AD-associated itch is multifactorial. Cross-talk between nerve fibers may be an explanation ( ). Impaired barrier function can promote entry of pruritogens such as allergens and proteases into the skin. In addition, damage to the stratum corneum may lead to pruritogen release by keratinocytes ( ). The acidity of the stratum corneum is important for barrier formation and defense against bacteria, and skin pH in AD patients was shown to be elevated. High skin pH enhances the activity of proteases, which can act as pruritogens, thus contributing to itch in AD.

Nerve growth factor (NGF) is a neuropeptide that is secreted mainly by epidermal keratinocytes and promotes neural survival. Expression of NGF and its high-affinity receptor TrkA (tropomyosin receptor kinase A) is increased in AD. NGF may sensitize peripheral nerve endings through promotion of nerve sprouting and elongation ( ). NGF is also capable of increasing sensory nerve sensitivity to substance P and brain-derived neurotrophic factor (BDNF), which further contributes to the lowered itch threshold seen in AD patients.

Receptors

Unmyelinated C fibers transmit itch upon activation of specific receptors. The majority of these receptors are G protein–coupled receptors (GPCRs). A notable receptor within GPCRs is protease-activated receptor-2 (PAR2), which can be activated by various proteases such as tryptase (a secretary granule primarily by mast cells) and dust mites ( ). AD patients exhibited increased levels of tryptase in lesional skin and PAR2 in both lesional and nonlesional skin ( ). Administration of a PAR2 agonist caused prolonged itching in AD patients ( ).

Ion channels

When pruritogens encounter their receptors on C nerve fibers, calcium influx through specific ion channels is required to generate action potentials and propagate the itch signal. These ion channels include the transient receptor potential (TRP) family, which is a main component of all sensory perception, including itch, and voltage-gated sodium ion channels (Na _v ).

TRP vanilloid 1 (TRPV1) exhibited increased expression in AD lesions, and its activation results in inflammation and pruritus. TRP ankyrin 1 (TRPA1) is involved in the transmission of histamine-independent itch. TRPA1 expression is enhanced in lesional skin of AD compared to healthy controls ( ). PAR2 can sensitize TRP channels, including TRPV1 and TRPA1 on peripheral nerve fibers, resulting in peripheral neuronal sensitization ( ).

TRPV1/TRPA1 activates Na _v 1.7, a subtype of the Na _v family. Na _v 1.7 controls action potentials in itch mediation. Na _v 1.7 mRNA expression is enhanced in pruritic skin lesion in AD ( ). In addition, a monoclonal antibody against Na _v 1.7 attenuates itch sensation and pain ( ). Conversely, overactivity of Na _v 1.7, which may be induced by skin inflammation, can lead to peripheral neuronal sensitization of itch.