Non-histaminergic and mechanical itch sensitization in atopic dermatitis

Chronic or episodic severe itch is recurrent in atopic dermatitis (AD). Non-histaminergic neuronal 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 non-histaminergic neuronal sensitization contributes to itch in AD. Hence, we compared sensitivity to thermal, mechanical, and chemical pruritic stimuli in AD patients and controls. The study comprised 25 AD patients with chronic itch and 25 healthy controls. Questionnaires on itch characteristics were administered, and sensory tests were conducted intra-lesionally, extra-lesionally, 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 AD patients were 60.7±4.3 and 39.7±5.2 (VAS0-100), respectively. Patients experienced significantly higher itch from cowhage both intra- and extra-lesionally compared to controls, whereas histamine-evoked itch intensity was not significantly different between groups. No group differences were found for thermal QSTs or pain evoked by itch provocations. Patients had decreased mechanical detection thresholds intra-lesionally and increased mechanical pain sensitivity intra- and extra-lesionally. Lastly, patients exhibited intra- and extra-lesional hyperknesis prior to chemical itch provocations and augmented hyperknesis following itch provocations. Increased itch to a non-histaminergic pruritogen (but not histamine) suggests pathway-specific itch sensitization in AD while increased susceptibility to mechanically-evoked itch and pain, particularly intra-lesionally, suggests sensitization of normally non-pruritic mechano-sensitive circuitry. Drugs targeting the non-histaminergic (PAR2/TRPA1) itch-pathway and itch sensitization are promising for treating AD itch.