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This functional magnetic resonance imaging (fMRI) study explored the central nervous processing of itch induced by histamine and capsaicin, delivered via inactivated cowhage spicules, and the influence of low-dose naltrexone. Scratch bouts were delivered at regular intervals after spicule insertion in order temporarily to suppress the itch. At the end of each trial the subjects rated their itch and scratch-related sensations. Stepwise multiple regression analyses were employed for identifying cerebral networks contributing to the intensities of "itching", "burning", "stinging", "pricking" and "itch relief by scratching". In the capsaicin experiments a network for "burning" was identified, which included the posterior insula, caudate and putamen. In the histamine experiments networks for "itching" and "itch relief" were found, which included operculum, hippocampus and amygdala. Naltrexone generally reduced fMRI activation and the correlations between fMRI signal and ratings. Furthermore, scratching was significantly less pleasant under naltrexone.

Cowhage, capsaicin and histamine, all applied via spicules, were used to induce itch and pain-related sensations in 15 male and 15 female subjects. Sensory qualities were assessed by questionnaire; intensities and time courses of the "itching" and "burning" sensation were measured alternately, but continuously on a VAS. In addition, axon reflexes were assessed. Only histamine and capsaicin produced a clear axon reflex flare (histamine > capsaicin, male = female). The 3 types of spicules caused mixed burning and itching sensations with different time courses. In the beginning burning prevailed, in the following minutes histamine induced mostly itching, capsaicin predominantly burning, cowhage both sensory components equally. Female subjects experienced more pain-related sensations (questionnaire), and their ratings leaned more toward burning than those of males. These findings indicate that the mixed itching and burning sensations are differentially processed by both genders. No indications were found for gender specific differential processing in the primary afferents as reflected by nearly identical flare responses.

Having observed altered itch and flare reactions after histamine application in patients with atopic eczema, we tried to determine these reactions in patients with urticaria and psoriasis. We investigated 16 healthy non-atopic subjects, 16 atopics in an eczema-free interval, 16 with acute atopic eczema, 16 with urticaria and 16 with psoriasis. Histamine was iontophoretically applied. The resulting sensations were rated on a visual analogue scale. Flare areas were measured 6 min after stimulation. Itch ratings of urticaria and psoriasis patients did not differ significantly from controls, whereas both atopic groups, regardless of acute or symptom-free state, reported significantly reduced intensity of itching. Flares were significantly diminished in all subjects with acute skin disease (psoriasis, urticaria and atopic eczema), regardless of diagnosis. However, flares were "normal" in symptom-free atopics and were not significantly different from controls. In conclusion, all "acute" patients showed a diminished axon-reflex function, possibly due to a downregulation of C-fiber responsiveness to histamine or an increased turnover rate of inflammatory mediators. Both atopic groups reported weaker itching, suggesting altered central nervous processing of itch.

Alloknesis ("itchy skin") after histamine iontophoresis was studied together with itch sensations and skin reactions in 19 atopic eczema patients and 20 controls at the forearm and at the scapular area. Compared to controls, atopic eczema patients showed significantly reduced alloknesis or total lack of it in the area around a skin site to which histamine had been iontophoretically applied, although histamine elicited itching in most patients. As previously demonstrated, patients with atopic eczema also developed significantly smaller flares. However, covariance analysis revealed that the smaller alloknesis areas in atopic patients were not statistically related to the smaller flares. Our results suggest that in atopic eczema a diminished responsiveness of primary afferent nerves to histamine is not compensated by a higher central nervous sensitivity reflected in more vivid alloknesis responses to histamine. Therefore, we conclude that histamine is probably not the key factor of the spontaneous itch experienced by patients with atopic eczema.

Skin reactions and itch or burning pain sensations following intradermal injection of the neuropeptide substance P and topical application of the substance P releasing agent mustard oil were studied in 20 atopic dermatitis patients and 20 healthy controls. Changes in skin blood flow were measured with a Laser Doppler flowmeter. Areas of wheal and flare reactions were evaluated planimetrically. Simultaneous with Laser Doppler flowmeter measurements, subjective itch and burning pain ratings were verbally reported on a category partitioning scale at 10-second intervals. Substance P evoked dose-dependent wheal, flare, and itch reactions in both patients and controls. However, substance P doses of 10(-9) -10(-11) mol elicited smaller flares in patients than in the controls whereas the wheal sizes were similar in both groups. Substance P-induced itch ratings were lower in patients at a dose of 10(-10) mol, and the onset of itching was delayed at all substance P levels applied. Mustard oil elicited similar neurogenic inflammatory reactions in both groups, although pain sensations were significantly delayed in atopic dermatitis patients at two mustard oil concentrations, which is further indication of a desensitization of afferent nerve endings contributing to the neurogenic inflammatory reactions in the skin of these patients.