Altered skin sensitivity in chronic itch: role of peripheral and central mechanisms

Neuroscience Letters 228 (1997) 199–202

Altered skin sensitivity in chronic itch: role of peripheral and central mechanisms Mari Gro¨nroos a , b ,*, Timo Reunala a, Matti Kartamaa a, Antti Pertovaara b , c a

Department of Dermatology, University Hospital of Helsinki, Helsinki, Finland Department of Physiology, Institute of Biomedicine, P.O.B. 9, University of Helsinki, FIN-00014 Helsinki, Finland c Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland

b

Received 24 March 1997; received in revised form 26 May 1997; accepted 29 May 1997

Abstract Nodular prurigo (NP) is a chronic skin disease causing severe itch of unknown origin in restricted skin areas surrounded by healthy skin areas. In the present investigation we studied cutaneous sensibility in five NP-patients and in five control subjects. Pain thresholds were determined with short argon laser pulses using two different sizes of stimulus surface (diameters 2 and 4 mm), tactile threshold with calibrated monofilaments and skin blood flow with a laser Doppler flowmeter. We also studied the effect of prolonged capsaicin treatment which should predominantly impair the function of nociceptive C-fibers. In both the itching and healthy skin areas the pain thresholds were lower in NP-patients than in healthy control subjects. Before capsaicin, an increase in stimulus area produced an equal decrease in pain threshold in all subjects. Following prolonged capsaicin treatment the pain threshold obtained with a large but not a small stimulus surface was elevated to control levels in NP-patients. Tactile thresholds in NP-patients were lower than in control subjects, and this abnormality was reversed by capsaicin. The basal skin blood flow level was more labile (fluctuating) in itching skin areas than in healthy skin areas of NP-patients. Capsaicin reduced blood flow fluctuation in the itching area. A lowered pain threshold not only in the itching area but also in the healthy skin area of NP-patients suggests that central convergence of itch and pain may contribute to increased pain sensitivity in chronic itch. Capsaicin-reversible abnormal fluctuation of the blood flow in the itching skin area might be explained by abnormal spontaneous activity of nociceptive peripheral nerve fibers and a consequent release of vasoactive agents from their terminals (axon reflex). The decreased tactile threshold and the elevation of it by capsaicin indicates that also the mechanisms underlying tactile sensibility are changed in chronic itch patients.  1997 Elsevier Science Ireland Ltd. Keywords: Heat pain threshold; Chronic itch; Capsaicin; Tactile threshold; Laser Doppler flow

Nodular prurigo (NP) is a chronic nodular skin disease causing severe itch of unknown origin in restricted skin areas [2,16]. There are itching nodules (diameter about 5– 10 mm), over various body areas, surrounded by healthy skin. Since it has been proposed that the sensations of itch and pain may share some common mechanisms [7,12,13], we attempted to study whether there are signs of abnormality in pain or tactile sensitivity in NP-patients. We determined pain threshold to argon laser stimuli in the itchy skin area with pathologically verified changes. To obtain information about a possible central converge of itch and pain, we also determined pain thresholds in the healthy skin area of NP-patients. Moreover, the difference in pain thresholds * Corresponding author. Fax: +358 9 1918681.

obtained with a large and a small stimulus surface was determined since this difference was considered to represent an index of central spatial summation of heat pain [7]. To find out a possible abnormal activation of peripheral nociceptive fibers, we determined the skin blood flow; activity in nociceptive cutaneous nerve fibers should produce skin blood flow changes due to an axon reflex and a consequent release of vasoactive agents [11]. For comparison, we determined tactile thresholds. A prolonged capsaicin-treatment was used to determine the role of capsaicin-sensitive nociceptive fibers [18] in cutaneous sensibility and blood flow changes observed in itch patients. Five patients with NP (prurigo nodularis, lichen corneus obtusus, 40–70 years; four females and one male) volunteered for this study. The patients were clinically typical

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NP-patients with the nodules and severe itch, but the disease was confirmed by skin biopsy, too. The duration of NP in the sample was 2–30 years. No antihistamines or steroid creams were used for 1 week nor phototherapy for 2 months before the measurements. Patients were not allowed to scratch the skin for 1–2 h before the measurements. Moreover, there was a bandage in the forearm for 1 week to prevent scratching. Five healthy humans (29–54 years; four females and one male) volunteered as controls for this study. The healthy controls were staff scientists and graduate students. An informed consent was obtained from the subjects before the experiments according to the ethical principles of the Helsinki convention. Also, the experiment was approved by the Ethics Committee of the Helsinki University Hospital for Skin and Allergic Diseases, Finland. The experiments were carried out between 1200 and 1700 h. The subjects and the experimenters used protective goggles during laser stimulation. Capsaicin (GenDerm; Zostrix HP 0.075% and Zostrix 0.025% in one subject) was applied four times daily to a 9 cm2 area of the dorsal forearm for 1 week [7,17]. Acute treatment with capsaicin selectively activates nociceptive fibers and a prolonged treatment with it produces a reversible block of nerve fiber conduction predominantly in nociceptive C-fibers [9,10,18–20]. The control areas (nodules and healthy skin) were treated with emollient cream (Aqualan; Orion Ltd., Espoo, Finland). Pain thresholds were measured using an argon laser stimulator (Lasertek Model 40A; Lasermatic Inc., Finland). Laser pulses activate both thin myelinated and unmyelinated nerve fibers mediating pain and warm sensations [1,3,7,15]. Laser beam diameters of 2 and 4 mm were used. With the beam diameter of 2 and 4 mm the stimulus surface was 3.1 and 12.6 mm2, respectively. The duration of the stimulus pulse was 350 ms. The wave lengths of the laser pulse were 488 (blue) and 515 nm (green). A continuous, low power beam (50 mW) from the argon laser was used to visualise the stimulation site. The single stimuli were applied at 20 s intervals to the hairy skin of the dorsal forearm. The stimuli were consecutively applied to 4–6 different adjacent locations to avoid skin damage. When the stimulus intensities were near the pain threshold the laser stimuli were delivered at 3–5 different amplitudes in a random order. Each amplitude was presented about 3–4 times. The amplitude at which there was a painful (e.g. pricking or burning) sensation to 50% of the stimuli was defined as a pain threshold. The tactile threshold was determined with a series of calibrated monofilaments (von Frey hairs; Stoelting, Wood Dale, IL, USA). A laser Doppler flowmeter (Periflux PF3 Perimed; Stockholm, Sweden) was used to provide continuous records of blood flow changes in the skin. The analogue output of this device gives no absolute values but relative changes of cutaneous blood flow. In addition to the basal blood flow (skin blood flow level) the fluctuation of skin blood flow

(peak-to-peak values in the basal blood flow) was also measured. The maximum output of the gain level used was taken as 100%. A detailed discussion of the method is presented elsewhere [14]. The blood flow changes in the skin were recorded from the dorsal skin of the forearm in the areas of capsaicin-treated NP-nodules, non-treated NP-nodules and healthy skin. All parameters were recorded before and after 1 week of capsaicin-treatment in NP-patients. Parametric statistics (paired or non-paired t-test, depending on the condition) was used to evaluate changes in pain thresholds and blood flow, whereas non-parametric statistics (Mann–Whitney U-test) was used to evaluate changes in tactile thresholds. A P , 0.05 was considered to represent a significant difference. Capsaicin produced a slightly burning pain sensation which declined with successive capsaicin administrations and disappeared within 1–3 days. The effect of capsaicin on spontaneous itch was not evaluated, because the treated area was only 9 cm2 and the patients had NP-nodules over large skin areas. Pain thresholds to laser stimuli were significantly lower in all skin areas of the NP-patients (in the itching skin area P = 0.038 and in the healthy skin area P = 0.020) than in healthy control subjects (Fig. 1A). However, the difference between the pain thresholds obtained with a large and small stimulus surface (an index of spatial summation) was of equal magnitude in itch patients and control subjects. After the prolonged topical application of capsaicin the pain threshold obtained with the larger stimulus surface was significantly elevated in the treated nodules (P = 0.007) but not in the control areas (non-treated nodules and healthy skin surrounding the capsaicin-treated area of NP-patients). With the smaller stimulus surface the pain threshold was not changed by capsaicin. Tactile threshold in the NP-nodules was significantly lower than in healthy controls (P = 0.032) (Fig. 1B). Following capsaicin treatment tactile threshold of NP-patients was elevated to control levels. The skin blood flow of NP-patients was more labile in the NP-nodules than in the healthy skin surrounding them (Fig. 2). Capsaicin significantly attenuated the fluctuation of blood flow in the itching area. There was no difference in the skin temperature of the itchy versus the healthy area in NP-patients (mean temperature (±SEM) in nodules was 31.4°C ± 0.6°C and in healthy skin 32.3°C ± 0.4°C). Mean skin temperature in NP-patients was not significantly different from that in control subjects (32.7°C ± 0.4°C). One of the main findings of this study was that the pain threshold to laser stimuli was significantly lower in all skin areas (both in the itching skin area and in a healthy skin area) of NP-patients than in healthy control subjects. The lowered pain threshold in NP can be explained by a central facilitation of pain-mediating neurons, since pain thresholds were lower also outside of the itching region. The identical decrease of pain threshold with an increase in the stimulus area in NP patients and in control subjects indicates that

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Fig. 1. (A) Pain thresholds to argon laser pulses in healthy control subjects (n = 5) and in NP-patients (n = 5). Contr subj, healthy control subjects; pre caps, itching area of NP-patients before capsaicin treatment; prol caps, itching skin area of NP-patients following prolonged capsaicin treatment; healthy skin, healthy skin area of NP-patients following prolonged capsaicin treatment. The diameter of the stimulation surface (2 or 4 mm) is indicated in the abscissa. The vertical error bars represent ± SEM. Note that in some cases the error bar is not larger than the symbol. (B) Tactile threshold of healthy control subjects (contr subj) and NP-patients before (pre caps) and following (prol caps) prolonged capsaicin treatment. The vertical error bars represent ± SEM (n = 5). *P , 0.05 (Mann–Whitney U-test).

the spatial summation mechanisms were, however, not saturated in NP patients. After a prolonged topical application of capsaicin the pain threshold obtained with the larger stimulus surface was significantly elevated in the treated nodules but in the control nodules and healthy skin it did not change. These results indicate a centrally mediated facilitation of pain in NP, depending, at least partly, on activation of capsaicin-sensitive peripheral nerve fibers. The difference in pain thresholds obtained with the larger versus smaller stimulus surface was significantly decreased by capsaicin (P , 0.001) in NP-patients. In contrast, in healthy subjects a prolonged capsaicin produced an opposite effect on the laser-evoked pain: thresholds obtained with a smaller stimulus were more elevated and the index of spatial summation was increased [7]. Thus, there may be fundamental differences in central summation mechanisms between healthy subjects and chronic itch patients. The finding that the skin blood flow was more labile (fluctuating) in the NP-nodules than in the healthy skin surrounding them might be explained by increased activity in peripheral nociceptors (axon reflex-induced blood flow increase [11]). A changed function in the efferent side of autonomic nervous system does not seem a likely explanation for the blood flow changes, because the blood flow changes were local and seen only in the nodules. The frequency of fluctuation was about 3–5/min, so it does not seem to be a reflection of heart rate or breathing. The patients were not allowed to scratch the skin for 1–2 h before the measurements. Moreover, there was a bandage in the forearm for 1 week to prevent scratching. For these reasons, it does not seem likely that the blood flow changes were due to a scratching-induced artifact. Prolonged application of capsaicin changed the increased fluctuation of skin

blood flow towards normal. This finding gives further support to the proposal that the enhanced skin blood flow depends, at least partly, on nociceptive C-fibers, which

Fig. 2. (A) Fluctuation in basal blood flow of the skin in NP-patients. In both graphs: healthy skin, healthy skin area of NP-patients before capsaicin treatment; pre caps, itching skin area before capsaicin treatment; prol caps, itching skin area following prolonged capsaicin treatment. The vertical error bars represent SEM (n = 5). ***P , 0.001 (paired t-test). (B) A representative original recording of cutaneous blood flow in one NPpatient. NP-nodulus pre capsaicin, itching skin area before capsaicin treatment; healthy skin, healthy skin area before capsaicin treatment; NP-nodulus prol capsaicin, itching skin area following capsaicin treatment. Notice the marked fluctuation of basal blood flow and its attenuation by capsaicin treatment in itching skin area.

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unlike sympathetic efferent fibers, are known to be sensitive to capsaicin [18]. Interestingly, the qualitative change in blood flow in the itchy area (abnormal fluctuation) was not accompanied by a corresponding increase in skin temperature. Identical skin temperature in healthy controls and NP-patients also excludes the possibility that the decreased pain threshold in NP-patients was due to a skin temperature-related artifact; i.e. with increased skin temperature less heat energy is needed to reach the critical threshold temperature [15]. Tactile threshold was significantly elevated by a prolonged capsaicin-treatment in the itching NP-nodules. In healthy humans prolonged application of capsaicin to the skin has not elevated tactile thresholds [4,7,17]. These results indicate that capsaicin-sensitive nerve fibers may also contribute to mechanoreception in chronic itch patients. Whether this interaction between mechanoreception and itch is due to central or peripheral mechanisms, or both, remains to be studied. It is still not well established whether itch is caused by activation of a specific class of peripheral itch-sensitive fibers, a population code in various types of primary afferent fibers, or a combination of these [6,12,13]. However, there is evidence that pruritic chemicals may activate some of the nociceptive primary afferent fibers [8]. This finding is in line with the present conclusion that cutaneous blood flow changes in NP-patients might be explained by spontaneous activity in nociceptive primary afferent fibers. Also, a convergence of signals evoked by pruritic and algesic chemicals has been demonstrated in the presumed pain-relay neurons of the spinal dorsal horn [5]. This type of convergence of itch and pain may underlie the enhancement of pain sensitivity in chronic itch patients observed in the present study. Since chronic itch-associated cutaneous sensory and circulatory changes were attenuated by topical capsaicin, it seems that nociceptive primary afferent fibers have an important role in sensory and circulatory pathophysiology observed in chronic itch patients. This study was supported by the Finnish Medical Society Duodecim, Helsinki, Finland, and the Medical Research Council, Academy of Finland. [1] Bromm, B., Jahnke, M.T. and Treede, R.-D., Responses of human

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