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Neuronal Sensitization for Histamine-Induced Itch in Lesional Skin of Patients with Atopic Dermatitis

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Neuronal Sensitization for Histamine-Induced Itch in Lesional Skin of Patients with Atopic Dermatitis STUDY Neuronal Sensitization for Histamine-Induced Itch in Lesional Skin of Patients With Atopic Dermatitis Akihiko Ikoma, MD; Roman Rukwied, PhD; Sonja Sta¨nder, MD; Martin Steinhoff, MD, PhD; Yoshiki Miyachi MD, PhD; Martin Schmelz, MD, PhD Objective: Lowered threshold of neurons (ie, neuro- smaller compared with controls (mean±SEM maxi- nal sensitization) in atopic dermatitis was investigated mum itch, 1.5±0.3 vs 3.1±0.2 [PϽ.05]; mean ± SEM di- by testing sensitivity to histamine. ameter, 12.3±2.0 vs 25.3±2.5 mm [PϽ.01]). In lesional skin of patients with AD, on the contrary, massive itch Design: Comparative study. was provoked (maximum itch, 4.4±0.3), although flare was relatively small (diameter, 16.1±3.4 mm). Itch rat- Setting: A dermatological clinic and a research labora- ings in patients with psoriasis were low both in lesional tory. and nonlesional skin (maximum itch, 1.3±0.6 and 1.0±0.4, respectively). Participants: Eighteen patients with atopic dermatitis (AD) and 6 patients with chronic plaque-type psoriasis Conclusion: As the area of axon reflex flare is an indi- as well as 14 healthy control subjects. rect measure of activity in primary afferent neurons, our Interventions: Histamine prick was performed in le- results suggest a decreased activation of peripheral pru- sional and nonlesional skin of patients and in control sub- riceptors in patients with AD. The massively increased jects. itch in lesional skin of patients with AD might therefore be based on sensitization for itch in the spinal cord rather Main Outcome Measures: Axon reflex flare and wheal than in primary afferent neurons. This sensitization does were measured planimetrically, and the itch intensity was not appear to be simply based on skin inflammation be- rated on a numerical scale (0-10). cause histamine-induced itch was not augmented in le- sional skin of psoriasis. Results: In nonlesional skin of patients with AD, itch intensity and axon reflex flare were both significantly Arch Dermatol. 2003;139:1455-1458 HE NEUROPHYSIOLOGICAL ity of pruriceptors to mechanical stimu- basis for the itch sensation lation.1 Moreover, histamine sensitivity of has been clarified by re- patients with AD is equal5,6 or even re- cent findings, which pro- duced7,8 when tested in nonlesional skin. vided evidence for a neu- ronal system dedicated to itch consisting See also pages 1463, 1475, From the Departments of T 1 of specific primary afferent and spinotha- and 1479 Dermatology, Kyoto University, lamic projection neurons.2 This dedi- Kyoto, Japan (Drs Ikoma and Miyachi), and University of cated neuronal system can explain the It is well known that in inflamma- Muenster, Muenster, Germany mechanism of itch provoked by the pru- tory pain conditions, peripheral nocicep- (Drs Sta¨nder and Steinhoff); ritogen histamine. Afferent neurons acti- tors can increase their sensitivity (periph- Department of Physiology and vated by histamine (pruriceptors) are in- eral sensitization) and contribute to the Experimental Pathophysiology, sensitive to mechanical stimulation and clinical pain.9 Simultaneously, the spinal University of have very high electrical and thermal processing of the noxious signals can be Erlangen-Nuremberg, thresholds. These neurophysiologically as- facilitated (central sensitization) and Erlangen, Germany sessed characteristics are not fully consis- worsen the pain of the patient.10 Neuro- (Dr Schmelz); and Department tent with the clinical pattern observed in nal plasticity leading to sensitization is also of Anesthesiology–Mannheim, patients with chronic pruritus. For in- known to occur for the processing of itch University of Heidelberg, 11,12 Mannheim, Germany stance, in atopic dermatitis (AD), itch is following histamine stimulation. Re- (Drs Rukwied and Schmelz). also evoked by weak mechanical stimula- cently, it was even shown that histamine The authors have no relevant tion, such as in wool’s contact to the skin,3,4 can induce pain instead of itch in pa- financial interest in this article. which is at variance with the insensitiv- tients with chronic pain.13 In the present (REPRINTED) ARCH DERMATOL / VOL 139, NOV 2003 WWW.ARCHDERMATOL.COM 1455 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 HISTAMINE SKIN PRICK 4 Control (n = 15) AD Nonlesion (n = 18) Ringer’s solution (20 µL) containing 0.1% histamine was AD Lesion (n = 18) dropped onto the skin and pricked by the tip of a 27-gauge needle 3 (BD Medical Systems, Drogheda, Ireland). The prick tests were performed in lesional skin areas in the patients with AD (an- ϫ ϫ 2 tecubital fossa, 17; popliteal fossa, 1) and in visually non- lesional skin sites of the same patients in the corresponding con- Itch Rating tralateral sites. They were also performed in lesional (elbow) 1 and nonlesional (contralateral sites) skin of the patients with PSO. In all healthy control subjects, histamine prick tests were performed in the antecubital fossa. 0 0 5 10 15 20 PSYCHOPHYSICS Time, min Histamine The intensity of the evoked sensation was assessed by the par- Prick Control (n = 15) PSO Nonlesion (n = 6) ticipants on a numerical scale of 0 (no sensation) to 10 (the AD Nonlesion (n = 18) PSO Lesion (n = 6) maximum sensation imaginable). They were asked to give sepa- AD Lesion (n = 18) rate ratings for the itch and pain sensation at 10-second inter- vals following the prick test. Maximum Itch P<.01 AUC of Itch FLARE AND WHEAL P<.001 P<.001 P<.001 P<.05 P<.05 The visually estimated longest and shortest axes of the evoked 3000 5 < flare and wheal areas were measured 10 minutes after the prick 4 P .01 2000 test in patients with AD and healthy controls. The average of 3 the long and short axes was regarded as the diameter of area 2 1000 and used for statistical analysis. Histamine-induced flare de- 1 velopment in lesional skin could not be clearly identified in 8 0 0 patients with AD, since the flare reaction did not clearly sepa- rate from the eczema’s redness. Figure 1. The itch sensation was significantly intense in lesional skin of patients with atopic dermatitis (AD) compared with healthy controls, whereas it was weak in nonlesional skin of patients with AD and weak in both lesional STATISTICS and nonlesional skin of patients with psoriasis. AUC indicates area under the curve; PSO, chronic plaque-type psoriasis. Data are mean±SEM. The area under the curve of itch ratings, maximum itch rat- ings, and diameters of flare and wheal were compared be- tween normal skin of healthy volunteers and lesional as well as visually nonlesional skin of patients with AD. Maximum itch ratings were compared also with lesional and nonlesional skin study, we explored lesional skin’s sensitivity to hista- of patients with PSO. The statistical analysis was performed by mine in AD to assess a potential sensitization of periph- a Kruskal-Wallis test. Bonferroni tests (Dunnet’s type) were ap- eral pruriceptors in the inflamed skin or a putative sen- plied for multiple comparisons. P values less than .05 were re- sitization of the central processing of itch in these patients. garded as significant. To verify the results, data were compared with nonle- sional skin of patients with AD, healthy controls, and also RESULTS another inflammatory skin disease (chronic plaque- type psoriasis [PSO]). ITCH RATINGS Histamine prick tests provoked an intense itch sensa- METHODS tion in healthy subjects, which peaked at about 1 minute and then gradually declined. Fifteen minutes after his- SUBJECTS tamine administration, itch sensation had virtually sub- Study subjects comprised 18 patients with AD (11 women and sided (Figure 1). When prick tests were performed in 7 men; mean±SD age, 24.5±4.3 years), 6 patients with PSO (3 nonlesional skin of patients with AD, itch ratings in- women and 3 men; mean±SD age, 27.5±3.3 years), and 15 creased more slowly, reached their maximum between healthy volunteers (9 women and 6 men; mean±SD age, 2 and 3 minutes, and were significantly lower compared 28.7±5.1 years). The diagnoses of AD (criteria by Hanifin and with the controls. However, itch ratings also declined Rajka3) and psoriasis vulgaris were verified by a dermatolo- gradually thereafter and did not show significant differ- gist. All patients with AD had acute pruritic dermatitis with a ences to the control group. typical distribution. All the patients with PSO had typical In contrast, histamine prick tests in lesional skin of psoriasis with plaques that were diagnosed histologically as patients with AD provoked a massive itch sensation that psoriasis vulgaris. Their mean±SD Psoriasis Area and Sever- ity Index (PASI) score was 16±9.1. None of the participants peaked about 2 to 3 minutes after the application. The en- used any oral or topical medication at least 1 week prior to suing gradual decline of itch ratings was particularly slow: the experiment. This study was approved by the local ethic 10 minutes after the application, when itch ratings in the committee, and informed consent was obtained from all the control group and nonlesional AD skin already had sub- participants. sided, patients with AD still reported a moderate itch in (REPRINTED) ARCH DERMATOL / VOL 139, NOV 2003 WWW.ARCHDERMATOL.COM 1456 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 their lesional skin. Even after 20 minutes, a distinct pru- P<.01 ritus was still perceived. The area under the curve 30 Flare (mean±SEM) of itch ratings calculated for 20 minutes af- Wheal ter pricking was significantly larger in AD lesional skin com- pared with skin from healthy volunteers (control) and AD 20 nonlesional skin (2544±381 vs 850±123 and 719±254, respectively [PϽ.001 for both]).
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