Halophyte plants are salt-tolerant and are acclimated for growth in saline soils such as along coastal areas. Among the halophytes, the Salicornia species have been used as both folk medicine and functional food for many years due to their high levels of bioactive compounds with supposed anti-inflammatory and antioxidative effects. However, the properties of Salicornia bioactive extracts on pain and itching still remain unclear. In this study, 30 healthy volunteers were randomized to treatments with 10% Salicornia-based cream or placebo cream for 24 or 48 h. On day 0, and 24 or 48 h post cream application, cold/heat detection and pain thresholds, mechanical pain thresholds and sensitivity, trans-epidermal water loss, histamine- and cowhage-evoked itch, and micro-vascular reactivity (neurogenic inflammation) were assessed to evaluate the analgesic, anti-pruritogenic and vasomotor effects. Skin permeability was reduced in the Salicornia-treated area for 48 h compared with 24 h application (p-value < 0.05). After 48 h of application, a decrease in mechanical-evoked itching (hyperkinesis) compared with 24 h treatment (p-value < 0.05) and increased warm detection and heat pain thresholds (p-value < 0.05) was found. Histamine-induced neurogenic inflammation showed a significant reduction in the cream-treated areas after 48 h compared with 24 h (p-value < 0.05). The results of this study indicate the overall inhibitory effect of Salicornia on hyperkinesis (mechanically evoked itch), the analgesic effect on thermal sensation, and modulation of the skin barrier architecture. Further studies are needed for the assessment of the long-term effects.

Chronic itch is a socioeconomic burden with limited management options. Non‐histaminergic itch, involved in problematic pathological itch conditions, is transmitted by a subgroup of polymodal C‐fibres. Cowhage is traditionally used for studying experimentally induced non‐histaminergic itch in humans but encounters some limitations. The present study, therefore, aims to design a new human, experimental model of non‐histaminergic itch based on the application of bovine adrenal medulla (BAM)8–22, an endogenous peptide that activates the MrgprX1 receptor. Twenty‐two healthy subjects were recruited. Different concentrations (0.5, 1 and 2 mg/ml) of BAM8‐22 solution and vehicle, applied by a single skin prick test (SPT), were tested in the first session. In the second session, the BAM8‐22 solution (1 mg/ml) was applied by different number of SPTs (1, 5 and 25) and by heat‐inactivated cowhage spicules coated with BAM8‐22. Provoked itch and pain intensities were monitored for 9 min, followed by the measurement of superficial blood perfusion (SBP) and mechanical and thermal sensitivities. BAM8‐22 induced itch at the concentration of 1, 2 mg/ml (p < 0.05) and with the significantly highest intensity when applied through BAM8‐22 spicules (p < 0.001). No concomitant pain sensation or increased SBP was observed. SBP increased only in the 25 SPTs area probably due to microtrauma from the multiple skin penetrations. Mechanical and thermal sensitivities were not affected by any of the applications. BAM8‐22 applied through heat‐inactivated spicules was the most efficient method to induce itch (without pain or changes in SBP and mechanical and thermal sensitivities) suggesting BAM8‐22 as a novel non‐histaminergic, human, experimental itch model.

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Background. Itch can be transmitted by two parallel pathways, histaminergic and nonhistaminergic. Histaminergic itch is transmitted by a subgroup of mechano-insensitive C-fibers, while nonhistaminergic itch by a subgroup of polymodal C-fibers. Experimental models are used to study pruritus: histamine for the histaminergic itch by antagonizing the histamine H1-receptors, and BAM8-22 and cowhage for the nonhistaminergic by activating Mas-related G protein-coupled receptors and protease-activated receptors, respectively. This study aims to evaluate the antipruritic effects of topical doxepin (H1-receptor antagonistic effect) on histaminergic and nonhistaminergic itch induced by histamine, BAM8-22, and cowhage. Methods. This study was conducted on 22 healthy subjects. Histamine, BAM8-22, cowhage, and vehicle were applied to 4 areas on the forearms. After 7 days, the same substances were applied after 11 / 2  hour-pretreatment with doxepin. After the application of pruritogens, itch and pain intensities were assessed for 9 minutes, followed by the measurement of superficial blood perfusion (SBP), mechanical and thermal sensitivities. Results. Application of histamine, BAM8-22, and cowhage all induced itch as compared to a vehicle. The pretreatment with doxepin almost abolished the histamine-induced itch and modestly reduced BAM8-22- and cowhage-induced itch. Histamine induced a higher SBP compared to the other conditions. Doxepin reduced SBP induced by each pruritogen, even though SBP of histamine remains the highest. Conclusion. Doxepin cream abolished histaminergic itch by antagonizing the peripheral H1-histamine receptors. Moreover, doxepin reduced nonhistaminergic itch and related neurogenic inflammation. Further studies are needed to elucidate the molecular mechanisms underlying this peripheral modulation of nonhistaminergic itch by a topically applied H1-antagonist. This trial is registered with NCT04588532.