Alloknesis and hyperknesis—mechanisms, assessment methodology, and clinical implications of itch sensitization

Abstract

Itch and pain share numerous mechanistic similarities. Patients with chronic itch conditions (for instance atopic dermatitis or neuropathic itch) often experience symptoms such as mechanical alloknesis and hyperknesis. These dysesthesias are analogous to the pain-associated phenomena allodynia and hyperalgesia, which are often observed, for example, in neuropathic pain conditions. Mechanical itch dysesthesias represent abnormal sensory states (caused by neuroplastic changes), wherein considerable itch is evoked, for instance by light cutaneous stimuli such as from clothing (alloknesis), or where increased itch is perceived in response to normally itch-evoking stimuli (hyperknesis). These itch sensitization phenomena have been explored in experimental human studies, observed in chronic itch patients, and in animal models of itch. Limited attention has been paid to these sensory phenomena in clinical studies, and it is unknown how they respond to antipruritics. Psychophysical quantitative sensory testing can quantify the presence, severity, and spatial extent of itch dysesthesias in chronic itch patients, providing a proxy measurement of itch sensitization. This review outlines current assessment techniques, knowledge on the mechanisms of mechanical alloknesis and hyperknesis, and presents the diverse results derived from clinical studies exploring the presence of itch dysesthesias in chronic itch patients. A key role of quantitative sensory testing and neuronal sensitization in patients with chronic pain is accepted and used in clinical assessments. However, the precise mechanisms and potential clinical implications of itch sensitization in chronic itch patients remain to be evaluated.

Neuroimmune interactions in chronic itch of atopic dermatitis

“…15 Inflammation plays a key role in neural sensitization, as peripheral sensitization induces activation of glial cells in the spinal cord via the release of adenosine triphosphate, chemokines and proteases. 63,64 Keratinocyte-derived nerve growth factor (NGF) has been linked to peripheral sensitization through induction of hyperinnervation. 63,64 Keratinocyte-derived nerve growth factor (NGF) has been linked to peripheral sensitization through induction of hyperinnervation.…”

“…54,62 Importantly, due to sensitization, alloknesis and hyperknesis persist after dermal inflammation has subsided, as illustrated by the intense itching experienced by patients with relatively mild eczema. 63,64 Keratinocyte-derived nerve growth factor (NGF) has been linked to peripheral sensitization through induction of hyperinnervation. 65,66 It has also been associated with enhanced membrane current via upregulation of TRPV1 expression on cutaneous nerve endings.…”

Antipruritic effects of transient heat stimulation on histaminergic and nonhistaminergic itch

“…This is the first psychophysical study that has directly compared the inhibitory effect of heat on itch at homotopic, and heterotopic intrasegmental and extrasegmental sites. Endogenous antipruritic mechanisms can generally occur on three levels: (i) reduced transduction or transmission in peripheral pruriceptive fibres, (ii) in the spinal dorsal horn by segmental gating or (iii) through central modulatory mechanisms in both spinal and supraspinal compartments …”

“…Endogenous antipruritic mechanisms can generally occur on three levels: (i) reduced transduction or transmission in peripheral pruriceptive fibres, (ii) in the spinal dorsal horn by segmental gating or (iii) through central modulatory mechanisms in both spinal and supraspinal compartments. 35,47,48 Surprisingly, given that pain-evoked itch inhibition is thought to be predominantly mediated in the spinal dorsal horn, 9,47 no itch-inhibitory effects were observed when counterstimuli were delivered to a heterotopic intra-or extrasegmental site relative to the itch provocation. In terms of mechanisms, this can be interpreted in two ways.…”

How to define chronic pruritus: Symptom or disease?

“…While chronic prurigo heals, the distribution of nerve fibres normalizes . These neuroplastic changes are associated with hypersensitivity of nerves towards itch but not pain . Quantitative sensory testing, a measurement for neuropathic pain, showed no alterations in chronic prurigo .…”