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 lesional 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 recent findings, which pro- duced7,8 when tested in nonlesional skin. vided evidence for a neuronal 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

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©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 nonlesional 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 ratings, and diameters of flare and wheal were compared between 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 nonlesional 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

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©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 compared with skin from healthy volunteers (control) and AD 20 nonlesional skin (2544±381 vs 850±123 and 719±254, respectively [PϽ.001 for both]). Maximum itch rating (mean±SEM) was significantly higher in AD lesion com- 10 pared with control and AD nonlesion groups (4.4±0.3 vs mm Area Diameter, 3.1±0.2 [PϽ.01] and 1.5±0.3 [PϽ.001]). Additionally, 0 maximum itch (mean±SEM) was significantly lower in AD Control AD Nonlesion AD Lesion nonlesional skin compared with skin from the control group (n = 15) (n = 18) (Flare: n = 8, (1.5±0.3 vs 3.1±0.2 [PϽ.05]) (Figure 1). In patients with Wheal: n = 18) PSO, maximum itch perception did not differ signifi- Figure 2. Axon reflex flare induced was significantly smaller in nonlesional cantly between their lesional and nonlesional skin sites skin of patients with atopic dermatitis (AD) and also reduced in their (1.3±0.6 and 1.0±0.4, respectively). Ratings were lower corresponding lesional skin site compared with healthy controls. Wheal size than those in lesional and nonlesional skin of AD as well was not significantly different among the 3 groups. Data are mean±SEM. as in controls. In contrast, no significant differences were found between nonlesional skin of patients with AD or healthy controls. a conditioning peripheral histamine stimulus changed the spinal processing such that mechanical stimuli (eg, touch FLARE AND WHEAL and pinprick) applied adjacent to the prestimulated site were felt as itch. Yet only mechanical stimuli were found to pro- As might be expected from the lower itch ratings, the di- voke increased itch sensation, whereas in our study, chemi- ameter of the axon reflex erythema (neurogenic flare) was cally induced itch was enhanced. Facilitated spinal pro- also significantly smaller in nonlesional skin of patients cessing (“lower-itch threshold”), which even overrides a with AD than in the control group (mean±SEM diam- reduced peripheral pruriceptive input, could offer an ex- eter, 12.3±2.0 vs 25.3±2.5 mm [PϽ.01]). In contrast, planation for the enhanced perception of itch. the neurogenic flare in lesional skin did not differ sig- There are already hypotheses of lowered itch thresh- nificantly from nonlesional AD skin and was smaller com- olds based on human psychophysics: LaMotte et al11 re- pared with healthy controls, albeit this difference did not port of delayed but increased and long-lasting histamine- reach statistical significance. The wheal reaction did not induced itch when the injection site had been transiently differ significantly between lesional and nonlesional AD anesthetized. The authors suggest that the injection pain skin and controls (Figure 2). would normally increase the central itch threshold. As the local anesthetic abolishes the injection pain, this COMMENT threshold increase does not occur, and thereby the itch processing is facilitated. In this respect, it is interesting In this study, we have confirmed previous reports that dem- to note that histamine induces ongoing activity in pru- onstrated nonlesional skin of patients with AD is less sen- riceptors, which by far outlasts the perception of itch.1 sitive to histamine stimulation compared with skin of Thus, there is ongoing activity in pruriceptors after his- healthy volunteers.6,14-19 The reduced histamine sensitiv- tamine application for about 1 hour,1 albeit at a low fre- ity equally affects the maximum itch ratings and the ex- quency. This low level of ongoing activity following his- tent of the neurogenic flare reaction. This flare reaction is tamine application is not felt as long because the spinal based on an axon reflex20-23 and increases with the num- threshold is high enough to “ignore” this peripheral sig- ber of action potentials generated by the peripheral neu- nal. It would therefore be conceivable that our patients ron.24 The area of the neurogenic flare is therefore an in- with AD felt more intense itch because of a lower cen- direct measure of activity in primary afferent neurons excited tral itch threshold for input from their lesional skin by the administered histamine. Thus, in nonlesional skin, (Figure 3). lower itch ratings and smaller flare reactions indicate a Although a lower central itch threshold is a good weaker response of the primary afferent neurons that un- explanation for the present observations, our results do derlies the alleviated itch sensation in these patients. not prove its existence. Only electrophysiological re- The most intriguing result of this study is the mas- cordings of the neuronal activity of pruriceptors could sively enhanced itch following histamine prick tests in- provide direct evidence. However, this information is very side the eczema, which was not accompanied by an in- difficult to obtain, since pruriceptors only constitute a creased neurogenic flare reaction. Obviously, there is a minor percentage of afferent fibers and, even worse, the mismatch of a reduced activation of peripheral hista- predominant location of the AD lesions is technically not mine sensitive “itch fibers” (pruriceptors), as indicated suitable for recording the supplying skin nerves. by the smaller flare reaction, and the augmented percep- Another approach to prove the induction of cen- tion of itch. tral sensitization for itch is the exploitation of ongoing An increased sensitivity of the spinal itch processing activity of pruriceptors, which is apparently required12 might explain this phenomenon. Central sensitization for to sensitize spinal pruriceptors. It is remarkable that on- itch has been described previously.12,25,26 In these studies, going activity in peripheral pruriceptors has already been

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Mannheim, Germany (e-mail: martin.schmelz@anaes Itch Threshold of .ma.uni-heidelberg.de). Central Neurons

Itch REFERENCES Control

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