Effects of Short-term Temperature Change in the Innocuous Range on Histaminergic and Non-histaminergic Acute Itch.

While temperatures in the noxious range are well-known to inhibit acute itch, the impact of temperature in the innocuous temperature range is less well understood. We investigated the effect of alternating short-term temperature changes in the innocuous range on histamine and cowhage-induced acute itch, taking into account individual differences in baseline skin temperature and sensory thresholds. Results indicate that cooling the skin to the cold threshold causes a temporary increase in the intensity of histamine-induced itch, in line with previous findings. Skin warming increased cowhage-induced itch intensity. Potential mecha-nisms of this interaction between thermosensation and pruritoception could involve cold-sensitive channels such as TRPM8, TREK-1 or TRPC5 in the case of histamine. The rapid modulation of cowhage induced itch - but not histamine-induced itch - by transient skin warming could be related to the lower temperature threshold of pruriceptive polymodal C-fibres (cowhage) as compared to the higher temperature threshold of the mechanoinsensitive C-fibres conveying histaminergic itch.

Comparison of pruritus and sensory qualities induced by capsaicin, histamine and cowhage.

BACKGROUND: In skin diseases and experimental models of pruritus, pure itch is accompanied by additional sensations that are poorly characterized. OBJECTIVES: This study compared the sensory qualities evoked by different models of experimentally induced pruritus including skin prick testing (SPT) with histamine or capsaicin and application of cowhage spicules. SPT as a method of capsaicin application was validated for this purpose. METHODS: Two pilot experiments were performed in eight healthy volunteers. First, a concentration of 8% capsaicin was identified as evoking a reproducible itch using SPT. Further, a list of the seven most frequently reported sensations was chosen after SPT with 10 mg/mL histamine, 8% capsaicin and application of 40-45 cowhage spicules. Finally, 31 subjects were challenged with the same itch-inducers. Wheal and flare were measured at 10, 20, 40, 60 and 90 min, itch intensity every minute for 30 min, and the overall evaluation of sensory descriptors were recorded on a 100-mm visual analogue scale once itching had subsided. RESULTS: Skin prick testing with histamine and capsaicin resulted in flare reactions, which were 23% smaller for capsaicin (P < 0.001). Histamine, capsaicin and cowhage-induced pruritus, the duration of which was shorter for cowhage than for histamine (13.5 ± 1.4 vs. 8.8 ± 1.2 min, P = 0.005). Different mediators induced sensations of different intensities. Capsaicin produced less itch and physical urge to scratch than histamine (P = 0.001) and cowhage (P < 0.001). However, both capsaicin and cowhage induced more burning than histamine (P = 0.002 and P = 0.04, respectively). Provocation with cowhage caused more intense sensations of pricking than histamine (P = 0.033). CONCLUSION: This study shows that provocation with histamine, capsaicin and cowhage results in itch responses that are different in their duration, the profile of accompanying sensations, and the flare that comes with the itch.

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

Exaggerated itch responses to pruritic chemical provocations and mechanical stimuli are evident in patients with chronic itch, for example, in atopic dermatitis. Currently used human models of itch do not account for such itch sensitization features, and the mechanisms underlying clinical itch sensitization are unknown. This study utilized two established human models of cutaneous nociceptive sensitization to explore how pre-established inflammatory hyperalgesia (ultraviolet-B-irradiation; "UVB") and non-inflammatory neurotrophic pain sensitization (nerve growth factor; "NGF") alter sensitivity to chemical and mechanically evoked itch. Twenty healthy volunteers participated in the UVB experiment. Six volar forearm areas (2 cm diameter) were UVB irradiated with ≤2 × minimal erythemal dose, and two non-irradiated areas were used as controls. Sixteen healthy volunteers participated in the NGF experiment and had 2 µg intradermally injected (4 × 50 µL in 2 cm diameter areas) into both volar forearms. Isotonic saline was applied as control. Pain sensitivity measurements (mechanical and heat pain thresholds) were conducted to validate the models. Subsequently, itch was evoked using histamine and cowhage spicules in the sensitized skin areas, and itch/pain was rated using visual analogue scales. Mechanical hyperknesis (increased itch to punctuate stimuli) was probed with von Frey filaments before/after each itch provocation. Both UVB- and NGF models induced robust primary mechanical hyperalgesia (P < .01) and hyperknesis (P < .05). Neither of the models augmented itch in response to chemical itch provocations but significant increases specifically for pain ratings were observed for both histamine and cowhage (P < .05). This suggests that these models are of limited value as proxies for itch sensitization to pruritogens observed, e.g., in inflammatory dermatoses.

Antipruritic effect of pretreatment with topical capsaicin 8% on histamine- and cowhage-evoked itch in healthy volunteers: a randomized, vehicle-controlled, proof-of-concept trial.

BACKGROUND: Chronic itch is difficult to treat. Low-concentration topical capsaicin (0·006-0·05%) has previously been applied in itch therapy but evidence on its efficacy is contradictory. OBJECTIVES: This vehicle-controlled, double-blinded study investigated the effect of topical capsaicin 8% after 1- and 24-h application on evoked itch, neurogenic inflammation and itch-associated dysaesthesia. METHODS: Sixteen healthy volunteers (aged 22 ± 0·5 years, nine female) were treated with capsaicin for 1 h and 24 h, and vehicle for 24 h on each volar forearm. Subsequently, histamine (1%, administered prick test lancets) and cowhage (40-45 spicules) were applied to the pretreated areas. Evoked itch and pain intensities were recorded for 10 min using a visual analogue scale (0-10 cm), while sensitivity to touch-evoked itch was evaluated using von Frey filaments before and after itch provocations. Neurogenic inflammation was assessed using perfusion imaging. RESULTS: In the vehicle areas peak itch responses to histamine and cowhage were 4·67 ± 0·58 and 5·15 ± 0·71, respectively. Capsaicin pretreatment reduced peak itch responses to histamine and cowhage after 24-h pretreatment to 1·41 ± 0·58 (P = 0·003) and 0·81 ± 0·18, (P < 0·001), respectively. Capsaicin pretreatment for 1 h reduced only cowhage-induced itch (P = 0·023). Furthermore, 24-h capsaicin pretreatment abolished punctuate hyperknesis and lowered histamine-induced neurogenic inflammation but did not affect weal reactions. CONCLUSIONS: Topical capsaicin 8% pretreatment for 24 h reduced histaminergic and nonhistaminergic itch by about 75%, while a significant reduction (≈60%) was achieved for only nonhistaminergic itch in a standard 1-h treatment. Further investigations are needed to elucidate the clinical potential of high-concentration capsaicin as an antipruritic.

A novel topical formulation containing strontium chloride significantly reduces the intensity and duration of cowhage-induced itch.

The aim of this double-blinded, vehicle-controlled study was to test the antipruritic efficacy of topical strontium to relieve a nonhistaminergic form of itch that would be clinically relevant for chronic pruritic diseases. Itch induced with cowhage is mediated by PAR2 receptors which are considered to play a major role in itch of atopic dermatitis and possibly other acute and chronic pruritic conditions. The topical strontium hydrogel formulation (TriCalm®) was tested in a head-to-head comparison with 2 common topical formulations marketed as antipruritics: hydrocortisone and diphenhydramine, for their ability to relieve cowhage-induced itch. Topically-applied strontium salts were previously found to be effective for reducing histamine-induced and IgE-mediated itch in humans. However, histamine is not considered the critical mediator in the majority of skin diseases presenting with chronic pruritus. The current study enrolled 32 healthy subjects in which itch was induced with cowhage before and after skin treatment with a gel containing 4% SrCl2, control vehicle, topical 1% hydrocortisone and topical 2% diphenhydramine. Strontium significantly reduced the peak intensity and duration of cowhage-induced itch when compared to the control itch curve, and was significantly superior to the other two over-the-counter antipruritic agents and its own vehicle in antipruritic effect. We hereby show that a 4% topical strontium formulation has a robust antipruritic effect, not only against histamine-mediated itch, but also for non-histaminergic pruritus induced via the PAR2 pathway, using cowhage.

Daily intake of Mucuna pruriens in advanced Parkinson's disease: A 16-week, noninferiority, randomized, crossover, pilot study.

BACKGROUND: Thousands of individuals with Parkinson's disease (PD) in low-income countries have limited access to marketed levodopa preparations. Mucuna pruriens (MP), a levodopa-containing leguminous plant growing in tropical areas, may be a sustainable alternative therapy for indigent patients. Single-dose intake of MP proved noninferior to marketed levodopa preparations. METHODS: Fourteen PD patients with motor fluctuations and dyskinesias received MP powder (obtained from roasted seeds) and marketed levodopa/carbidopa (LD/CD) in a randomized order and crossover design over a 16-week period. Efficacy measures were changes in quality of life, motor and non-motor symptoms, and time with good mobility without troublesome dyskinesias. Safety measures included tolerability, frequency of adverse events, changes in laboratory indices and electrocardiogram. RESULTS: Daily intake of MP was associated with a variable clinical response, especially in terms of tolerability. Seven patients (50%) discontinued MP prematurely due to either gastrointestinal side-effects (n = 4) or progressive worsening of motor performance (n = 3), while nobody discontinued during the LD/CD phase. In those who tolerated MP, clinical response to MP was similar to LD/CD on all efficacy outcome measures. Patients who dropped out entered a study extension using MP supernatant water (median[IQR], 16 [7-20] weeks), which was well tolerated. CONCLUSIONS: The overall benefit provided by MP on the clinical outcome was limited by tolerability issues, as one could expect by the relatively rapid switch from LD/CD to levodopa alone in advanced PD. Larger parallel-group studies are needed to identify appropriate MP formulation (e.g. supernatant water), titration scheme and maintenance dose to minimize side-effects in the long-term. CLINICAL TRIALS. GOV IDENTIFIER: NCT02680977.

Nonhistaminergic and mechanical itch sensitization in atopic dermatitis.

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.

Cowhage-induced itch as an experimental model for pruritus. A comparative study with histamine-induced itch.

BACKGROUND: Histamine is the prototypical pruritogen used in experimental itch induction. However, in most chronic pruritic diseases, itch is not predominantly mediated by histamine. Cowhage-induced itch, on the other hand, seems more characteristic of itch occurring in chronic pruritic diseases. OBJECTIVES: We tested the validity of cowhage as an itch-inducing agent by contrasting it with the classical itch inducer, histamine, in healthy subjects and atopic dermatitis (AD) patients. We also investigated whether there was a cumulative effect when both agents were combined. METHODS: Fifteen healthy individuals and fifteen AD patients were recruited. Experimental itch induction was performed in eczema-free areas on the volar aspects of the forearm, using different itch inducers: histamine, cowhage and their combination thereof. Itch intensity was assessed continuously for 5.5 minutes after stimulus application using a computer-assisted visual analogue scale (COVAS). RESULTS: In both healthy and AD subjects, the mean and peak intensity of itch were higher after the application of cowhage compared to histamine, and were higher after the combined application of cowhage and histamine, compared to histamine alone (p<0.0001 in all cases). Itch intensity ratings were not significantly different between healthy and AD subjects for the same itch inducer used; however AD subjects exhibited a prolonged itch response in comparison to healthy subjects (p<0.001). CONCLUSIONS: Cowhage induced a more intense itch sensation compared to histamine. Cowhage was the dominant factor in itch perception when both pathways were stimulated in the same time. Cowhage-induced itch is a suitable model for the study of itch in AD and other chronic pruritic diseases, and it can serve as a new model for testing antipruritic drugs in humans.

Similar itch and nociceptive sensations evoked by punctate cutaneous application of capsaicin, histamine and cowhage.

Itch evoked by cowhage or histamine is reduced or blocked by capsaicin desensitization, suggesting that pruriceptive neurons are capsaicin-sensitive. Topical capsaicin can evoke both nociceptive sensations and itch, whereas intradermal injection of capsaicin evokes only burning pain. To dissociate the pruritic and nociceptive sensory effects caused by the chemical activation of sensory neurons, chemicals were applied in a punctiform manner to the skin of the forearm using individual, heat-inactivated cowhage spicules treated with various concentrations of capsaicin (1-200 mg/ml) or histamine (0.01-100 mg/ml). Perceived intensities of itch, pricking/stinging and burning were obtained every 30 s using the general version of the Labeled Magnitude Scale and compared with ratings evoked by individual native cowhage spicules. Similar to cowhage, capsaicin and histamine spicules reliably evoked sensations of itch in a dose-dependent manner which were most often accompanied by pricking/stinging and to a lesser extent burning. Spicules containing 200 mg/ml capsaicin or 10 mg/ml histamine yielded peak magnitudes and durations of sensations comparable to those elicited by cowhage. Each type of spicule also produced comparable areas of dysesthesias (enhanced mechanically evoked itch or pain) and/or skin reactions (wheal and/or flare) in surrounding skin, though inconsistently. The incidence of flare was greater in response to histamine than to capsaicin or cowhage. These results suggest the possibility that capsaicin, histamine and cowhage activate common peripheral or central neural mechanisms that mediate pruritic sensations and associated dysesthesias.