Nonhistaminergic and mechanical itch sensitization in atopic dermatitis

Abstract

Chronic or episodic severe itch is recurrent in atopic dermatitis (AD). Nonhistaminergic itch pathways are suggested to dominate in AD itch, contributing to an "itch-scratch-itch cycle" that prolongs and worsens itch, pain, and skin lesions. We hypothesized that nonhistaminergic neuronal sensitization contributes to itch in AD. Hence, we compared sensitivity with thermal, mechanical, and chemical pruritic stimuli in patients with AD and controls. The study comprised 25 patients with AD with chronic itch and 25 healthy controls. Questionnaires on itch characteristics were administered, and sensory tests were conducted intralesionally, extralesionally, and in homologous areas of controls. Thermal and mechanical quantitative sensory testing (QST) as well as histamine and cowhage provocations were performed. Subsequently, hyperknesis and vasomotor reactivity were assessed. Average itch and associated pain among patients with AD were 60.7 ± 4.3 and 39.7 ± 5.2 (VAS0-100), respectively. Patients experienced significantly higher itch from cowhage both intralesionally and extralesionally compared with controls, whereas histamine-evoked itch intensity was not significantly different between groups. No group differences were found for thermal quantitative sensory testings or pain evoked by itch provocations. Patients had decreased mechanical detection thresholds intralesionally and increased mechanical pain sensitivity intralesionally and extralesionally. Lastly, patients exhibited intralesional and extralesional hyperknesis before chemical itch provocations and augmented hyperknesis after itch provocations. Increased itch in response to cowhage (but not histamine) suggests nonhistaminergic pathway-specific itch sensitization in AD, whereas increased susceptibility to mechanically evoked itch and pain, particularly intralesionally suggests sensitization of mechanosensitive circuitry not normally associated with itch. Drugs targeting the nonhistaminergic (PAR2/TRPA1) itch pathway and itch sensitization are promising for treating AD itch.

Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch

“…Therefore, our findings demonstrate that although type 2 cytokines are not potent acute pruritogens themselves, they act to sensitize sensory neurons to many different pruritogens. These observations mirror prior human studies that have shown that challenge with pruritogens in lesional skin of AD patients results in amplified itch responses compared to control subjects (Andersen et al, 2017; Ikoma et al, 2003). Thus, we hypothesized that, rather than acute itch, neuronal type 2 cytokine signaling promotes pathologic chronic itch and that interrupting these signals may represent an effective strategy to target chronic itch.…”

Neuroimmune interactions in chronic itch of atopic dermatitis

“…57,58 In the skin of patients with AD, the threshold for electrically evoked itch is lower than in healthy controls, 18,59,60 and the sensitivity to pruritogens is increased. 61 NK-1R-and GRPR-expressing dorsal spinal neurons were shown to play a key role in central sensitization, with involvement of NK-1R in both alloknesis and hyperknesis, and GRPR in hyperknesis alone. 61 NK-1R-and GRPR-expressing dorsal spinal neurons were shown to play a key role in central sensitization, with involvement of NK-1R in both alloknesis and hyperknesis, and GRPR in hyperknesis alone.…”

UVB‐ and NGF‐induced cutaneous sensitization in humans selectively augments cowhage‐ and histamine‐induced pain and evokes mechanical hyperknesis

“…In inflammatory dermatoses, such as atopic dermatitis (AD), the lesional skin may not only be spontaneously itching, but it also displays altered sensitivity to various cutaneous stimulation modalities. This includes increased itch in response to pruritic chemical provocations, for example with histamine or cowhage, as well as increased itch in response to mechanical stimuli (punctuate hyperknesis) . Occasionally such sensory aberrations have also been detected perifocally to the lesions or even in entirely non‐lesional skin and are expected to be caused by neuronal sensitization of peripheral and/or central afferents .…”

“…This includes increased itch in response to pruritic chemical provocations, for example with histamine or cowhage, as well as increased itch in response to mechanical stimuli (punctuate hyperknesis) . Occasionally such sensory aberrations have also been detected perifocally to the lesions or even in entirely non‐lesional skin and are expected to be caused by neuronal sensitization of peripheral and/or central afferents . These processes lead to exacerbated itch in affected patients, for example as itch become evocable by environmental stimuli such as wool fabric or warmth and the sensitization probably counteracts normal itch‐fibre tachyphylaxis .…”