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NEUROSCIENCE |
1 Department of Neurology, Johannes Gutenberg-University Langenbeckstr. 1, D-55101 Mainz, Germany
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Abstract |
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(Received 28 June 2006;
accepted after revision 17 August 2006;
first published online 24 August 2006)
Corresponding author T. Schlereth, Department of Neurology, Johannes Gutenberg-University, Langenbeckstr. 1, D-55101 Mainz, Germany. Email: schleret{at}uni-mainz.de
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Introduction |
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Some neuropathic pain states, in particular complex regional pain syndromes (CRPS) are clinically characterized not only by exaggerated neurogenic inflammation (Weber et al. 2001), but also by disturbances of the sympathetic nervous system, e.g. localized profuse sweating at the painful limb (Birklein et al. 1998). In these ‘inflammatory’ stages of CRPS, sweating in particular was increased if it was induced peripherally by axon reflex mechanisms (Birklein et al. 1997). Currently, there is no good functional explanation for this clinical phenomenon. Histological data using immunohistochemical staining revealed that CGRP is co-localized to acetylcholine in peripheral sudomotor axons, which innervate human sweat glands (Landis & Fredieu, 1986; Kruger et al. 1989). Furthermore, CGRP can also be found in the sweat glands themselves (Ishida-Yamamoto & Tohyama, 1990; Zancanaro et al. 1999). All these morphological findings suggest that CGRP might be involved in human sweating; however, well controlled functional data are missing.
Vasoactive intestinal peptide (VIP) is a peptide that acts predominantly as a neurotransmitter in the gastrointestinal system. VIP is also synthesized in neurons. In the central nervous system (CNS) it is important to coordinate daily rhythms in behaviour and physiology (Aton et al. 2005). In the peripheral tissue VIP acts as a vasodilator (Lundberg et al. 1981; Henning & Sawmiller, 2001). Compared with CGRP, however, VIP vasodilatation is less potent and shorter lasting (Brain et al. 1986). VIP was also found in neurons associated with human sweat glands (Hartschuh et al. 1984; Vaalasti et al. 1985). The functional role of VIP in human sweating is controversial. In rats, VIP itself induces sweating (Stevens & Landis, 1987) but in humans it does not (Yamashita et al. 1987; Berg et al. 1995).
Substance P (SP) is a tachykinin which is widely distributed in the peripheral and central nervous system (O'Connor et al. 2004). In the CNS, SP is involved in stress–anxiety responses of the amygdala (Ebner et al. 2004). In peripheral neurogenic inflammation it mainly causes the second component – plasma extravasation and oedema (Lembeck et al. 1982; Weidner et al. 2000; Sauerstein et al. 2000). Sympathetic ganglions and neurons innvervating sweat glands also contain substance P – besides CGRP and VIP (Lindh et al. 1989a,b). In contrast to CGRP, preliminary human studies suggest that SP should have an inhibitory effect on sweating (Kumazawa et al. 1994; Berg et al. 1995).
The aim of the present investigation was therefore to elucidate the functional effects of neuropeptides (CGRP, VIP, SP) on human sweating. In order to avoid simultaneous skin trauma, which might affect neuropeptide content of the skin by C-fibre activation, we used a dermal microdialysis system. Microdialysis membranes are inserted into the skin. After subsiding of insertion-related skin changes, substances then can be atraumatically applied to the tissue via these microdialysis fibres. In previous investigations it has been shown that acetylcholine (ACh) application via dermal microdialysis is suitable to induce axon reflex sweating (Shibasaki & Crandall, 2001; Bickel et al. 2004). In addition to ACh, different concentrations of CGRP, VIP or SP were added. Thus, we were able to investigate the role of these neuropetides in the modulation of human sweating.
Methods
Written informed consent was obtained from all subjects according to the Declaration of Helsinki and the study was approved by the local ethics committee. Three series of microdialysis experiments were done. In the first series (n = 39 experiments) the effect of CGRP on sweating was investigated. CGRP was applied either alone (n = 4), in combination with ACh (10–2 M), or ACh (10–2 M) alone for control (n = 34 experiments). In the second series of experiments VIP (n = 19 experiments) and in the third series substance P (SP; n = 18 experiments) were investigated in the same way. We started with using CGRP. Due to pilot dose-finding experiments (not mentioned here) eight subjects (age, 25 ± 1 years; 7 females, 6 males) repeatedly participated in order to yield n = 6–8 for paired comparisons of each CGRP concentration + ACh with ACh alone. Six subjects repeatedly participated in experiments using VIP (age, 25.3 ± 3 years; 3 female, 3 male) and four subjects repeatedly participated in experiments using SP (age, 25.8 ± 2 years; 1 female, 3 male) in order to yield n = 4 for paired comparison of each VIP and SP concentration. Paired comparisons were chosen since sweating could be markedly variable between subjects (Schlereth et al. 2005c). Since serum neuropeptide concentrations did not change significantly during menstrual cycle (Goodnough et al. 1979; Ottesen et al. 1982; van Leeuwen et al. 1992; Kerdelhue et al. 1997) we did not control women for their menstrual cycle.
All subjects were placed comfortably in a chair. The left lower leg was fixed by a vacuum cushion. After cooling the skin, four microdialysis membranes were inserted pain-free into the skin of the medial aspects of the lower leg. The membranes were arranged in two groups of two membranes, the distance between the two membranes in each group was about 2 cm, and between the two groups about 5 cm. The microdialysis membranes, 200 µm in width, had a cut-off of 3000 kDa and the membranes were placed intradermally at a length of 15 mm (Schmelz et al. 1997). With this technique all substances could be applied without time-related skin trauma. Between the two membranes of each group, sweat chambers were fixed to the skin (see Fig. 1). Sweat chambers covered 3.125 cm2 (1.25 cm x 2.5 cm) of skin. Dry nitrogen gas was passed through the chambers at a constant flow (90 ml min–1). The relative humidity was measured downstream by capacitance hygrometers (Hygroscope DV 2, Rotronic AG, Basel, Switzerland).
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All applied substances (ACh, CGRP, VIP and SP) caused vasodilatation to a variable degree. For measuring superficial skin blood flow laser Doppler imaging (LDI; Moor Instruments Limited, London, UK) was used. Perfusion pictures of both groups of membranes were taken every 5 min during the stimulation period. The scanner distance to the skin was 50 cm. Laser signals were stored in a PC for further computation using dedicated software (moorLDI 3.01; Moor Instruments). Offline, mean flux was calculated in an approximately 10 cm2 area of skin including membranes and the surrounding skin, which was not covered by the sweat chambers.
Control experiments to estimate diffusion capacity of ACh in human skin
In previous experiments we have been able to exclude that ACh, which is released from sudomotor fibres, reaches the dermal microdialysis membranes. All ACh, which occurred in the eluate, is of non-neuronal origin, e.g. from keratinocytes (Schlereth et al. 2006). In order to assess the diffusion capacity of ACh in the skin we therefore performed experiments in which we quantified ACh in the eluate from membranes 2 and 30 cm away from membranes, which were perfused with 10–2 M ACh, alone (n = 4) and in combination with the cholinesterase inhibitor neostigmine (10–5 M) (n = 3).
Statistical analysis
All values are given as mean and standard error (S.E.M.). For statistical analysis a repeated measures ANOVA was performed in order to assess the neuropeptide effects. Since sphericity could not be assumed we used Greenhouse-Geisser correction. In order to allocate significant neuropeptide concentrations, t tests for paired samples were used as post hoc tests. Statistical analysis was performed with the SPSS software package (release 12.0, SPSS Inc., Chicago, IL, USA). Significance was considered at P < 0.05.
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Results |
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These experiments were performed in eight subjects. Acetylcholine (10–2 M) alone always induced sweating. In contrast, CGRP alone at concentrations of 10–5–10–7 M did not induce sweating in our experiments (n = 4, data not shown). However, CGRP amplified ACh-induced sweating. The sweat response, measured as absolute humidity at the peak (F = 10.4, P < 0.005), the area under the sweat curve (F = 8.4, P < 0.01) and the duration of the sweat response (F = 10.4, P < 0.005) was increased when CGRP was added to ACh (see Figs 1 and 2). Post hoc analysis revealed that CGRP particularly enhanced sweating in physiologically reasonable concentrations from 10–7 to 10–9 M (for details see Fig. 2A). In order to rule out the possibility that the differences between CGRP and ACh stimulation depend on different results of ACh stimulation in our paired comparison setting rather than on a true CGRP effect, we additionally analysed sweating after ACh stimulation alone. There was no significant effect of the different sessions on ACh-induced sweating (F < 1.6 for all sweat measures, all not significant (n.s.)).
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The whole series of VIP experiments was performed in six subjects. VIP alone (10–5 and 10–6 M, n = 3) did not induce sweating (data not shown). VIP was added to ACh (10–2 M) in concentrations of 10–5, 10–6, 10–7 and 10–8 M and sweating was compared with ACh alone (n = 4 for each concentration). Not absolute humidity at the peak of the sweat curve (F = 0.5, n.s.), nor the area under the curve (F = 1.5, n.s.) nor the duration of the sweat response (F = 1.2, n.s.) were different between ACh and the combination of VIP and ACh (see Fig. 2B). There was again no significant effect of the different sessions on ACh-induced sweating (F < 0.9 for all sweat measures, all n.s).
In accordance with the sweating results, VIP in addition to ACh did not significantly change skin blood flow (F = 0.1, n.s.; see Fig. 3B). There was again no difference in ACh-induced vasodilatation between the different sessions (F = 0.9, n.s.)
SP (n = 18 experiments)
These experiments were performed in four subjects. Substance P alone (10–5 and 10–6 M, n = 2) did not induce sweating (data not shown). SP was added to ACh (10–2 M) in concentrations of 10–6, 10–7, 10–8 and 10–9 M and sweating was compared with ACh alone (n = 4 for each concentration). Neither absolute humidity at the peak of the sweat curve (F = 0.07, n.s.) nor the area under the curve (F = 1.8, n.s.) were different between ACh and the combination of SP and ACh (see Fig. 2C), but the duration of the sweat response was significantly shorter when SP and ACh were given in combination (F = 9.5, P < 0.01). The differences were small that post hoc tests were not able to detect them at single SP concentrations. Similar to the other experiments, there was again no significant effect of the different sessions on ACh-induced sweating (F < 1.9 for all sweat measures, all n.s.).
SP in addition to ACh did not significantly change skin blood flow (F = 0.6, n.s.; Fig. 3C). There was again no difference in ACh-induced vasodilatation between the different sessions (F = 0.2, n.s.).
Diffusion of ACh in human skin
At baseline, acetylcholine concentration (n = 4) was 1.7 pmol µl–1 in the microdialysis eluate of the two membranes 2 cm apart from the stimulation membrane. After perfusing the stimulation membrane with 10–2 M ACh, ACh concentration increased to a mean of 3.6 pmol µl–1. ACh in the eluates from membranes 30 cm away did not increase (0.5 pmol µl–1). When neostigmine (10–5 M) was added in order to block cholinesterases and to increase ACh recovery, results were the same: basal ACh increased from a mean of 103 pmol µl–1 to 451 pmol µl–1 in the nearby membranes.
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Discussion |
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Effects on sweating
Human skin is unique in respect to sweating. In contrast to most animals, human hairy skin is important for active heat dissipation (Ogawa & Low, 1997). Thus, any comparison of thermoregulatory sweat glands in human hairy skin to sweat glands in hairy animals, which are usually restricted to foot pads in order to maintain skin elasticity, must be performed with caution. There is immunohistochemical evidence from human skin that; (1) CGRP positive nerve endings are located in the vicinity of sweat glands (Kennedy et al. 1994; Schulze et al. 1997), (2) CGRP is co-localized to ACh in peripheral sudomotor nerve fibres (Lindh & Hokfelt, 1990) and (3) CGRP occurs in human sweat glands (Zancanaro et al. 1999). In addition, recent data suggest that CGRP receptors are located on myoepithelial cells of human sweat glands (Hagner et al. 2002). These anatomical data already suggest that CGRP might be involved in peripheral regulation of sweating in humans. The functional results presented herein, now confirm this assumption – ACh-induced axon reflex sweating was increased in the presence of CGRP. Previous studies, however, revealed conflicting results. In accordance with the present findings, the application of CGRP alone did not induce sweating, but the combination with methacholine, an agonist for post-junctional muscarinic ACh receptors, which are located on sweat glands, induced a stronger sweat response (Kumazawa et al. 1994, 1997). In these studies, methacholine was injected alone and in combination with CGRP, and sweating was measured quantitatively with hygrometry – according to our study design. Just the opposite, i.e. a reduction of the nicotine-induced axon reflex sweating by CGRP, but also by VIP, was found by another group (Tanaka et al. 1990). In this investigation, however, the number of sweat droplets marked by iodine starch staining after injection of nicotine with or without CGRP was counted while sweating was not quantitatively assessed. There might be several explanations for these diverging results. The most likely one is that CGRP indeed enhances the sweat production in single sweat glands (Sato, 1997), which could be measured by quantitative hygrometry. On the other hand, CGRP has no effect on the number of activated sudomotor fibres, the number of activated sweat glands, or the anatomical structure of peripheral sudomotor innervation (Schlereth et al. 2005b). This is not surprising since even on primary afferent neurons CGRP has no powerful exciting effect (Weidner et al. 2000). Alternatively, CGRP could differently affect axon reflex sweating (by nicotine) and the direct sweat response (by methacholine). CGRP has been shown to inhibit nicotinic ACh receptors in rat cell preparations (Giniatullin et al. 1999; Nistri & Di Angelantonio, 2002; Di Angelantonio et al. 2003). Smaller fragments of CGRP (CGRP1–6, CGRP1–5 or CGRP1–4), however, which occur after degradation of CGRP by peptidases in human tissue, enhance the activity of nicotinic ACh receptors. Thus, there might be very differential effects, depending on the predominant form of CGRP in the tissue. This could explain why high concentrations of CGRP have no hyperhidrotic effects in our study. The peptidase activity is not sufficient to degrade CGRP rapidly and inhibitory effects of the whole molecule and facilitory effects of the degredation products could neutralize themselves.
ACh also has direct muscarinergic properties on sweat glands, and in our study ACh was applied in pharmacological concentrations. Even though ACh undergoes rapid degrading by cholinesterases, we surprisingly were able to prove some diffusion of ACh over 2 cm, even if other substances like histamine do not seem to diffuse over longer distances (Petersen et al. 1997; Clough et al. 2002; Boutsiouki et al. 2004). Apart from diffusion the measured ACh could have been non-neuronal ACh released from skin cells like keratinocytes (. Schlereth et al. 2006). This means that muscarinic direct stimulation of sweat glands in the vicinity of the ACh application could at least also be possible, although previous studies have not shown functional relevance of such a diffusion in untreated skin (Low et al. 1983). CGRP receptors are expressed on myoepithelial cells of human sweat glands (Hagner et al. 2002). Therefore, an enhancement of sweat output due to increased squeeze out of sweat glands might be possible. Even if CGRP can be found in sudomotor fibres (Landis & Fredieu, 1986; Tainio et al. 1987; Dalsgaard et al. 1989), no direct evidence for functional CGRP receptors on sudomotor fibres has so far been found. We have been able to confirm this, since CGRP alone was unable to induce sweating. Therefore ACh and CGRP must act synergistically (Lindh & Hokfelt, 1990).
Another significant difference between the results of Tanaka et al. (1990) and ours might be the route of application of substances. We used dermal microdialysis, which allows the gradual application without time-related skin trauma (Sauerstein et al. 2000; Zahn et al. 2003). Tanaka et al. injected CGRP and nicotine at the same time. In particular, nicotine injection is painful, it excites C-fibres and CGRP is quickly released (Schmelz et al. 1997). Thus, skin concentration of CGRP might be higher than assumed. Besides the inhibitory effects of high concentrations of CGRP in human skin, as discussed above, high CGRP concentration further induces vasodilatation also in deeper skin layers and the injected nicotine could be cleared before it reaches sudomotor fibres. This effect could also contribute to the finding that in our study highest concentrations of CGRP were less effective. Another unavoidable problem with injection is the fluid, which causes extracellular oedema, obstructs sweat ducts and might thereby hamper sweat production. The functional relevance of such a mechanism is clinically shown by tap water iontophoreses, the standard treatment of palmoplantar hyperhidrosis (Togel et al. 2002). Extracellular oedema is completely prevented by dermal microdialyis, since application of substances solely depends on osmotic diffusion.
Similar to the findings of CGRP, histological studies revealed that VIP is co-localized with ACh in human sudomotor fibres (Lundberg et al. 1980; Vaalasti et al. 1985; Heinz-Erian et al. 1986) and sweat glands (Kummer et al. 1990). These anatomical data suggest a functional role of VIP for the control of sweating. However, no clear evidence for this assumption has been provided so far. Although the injection of VIP induced sweating in rats, which could be blocked by atropine (Stevens & Landis, 1987) and VIP enhances the ex vivo sweat rate of single sweat glands from monkeys (Sato & Sato, 1987), the results in humans were ambiguous. Increased methacholine- induced sweating was observed using quantitative sudometry (Yamashita et al. 1987), but also reduced ACh-induced sweating by counting sweat spots (Tanaka et al. 1990; Berg et al. 1995). In neither study was VIP alone sufficient to evoke a sweating response in humans. Our results suggest that VIP has no significant effect on axon reflex sweating – neither enhancing nor reducing. Since ACh iontophoresis is a very strong stimulus for sweating, our results of course could not exclude that VIP participates in the regulation of physiological sudomotor activity. However, in skin biopsies from patients with familial dysautonomia, which is clinically characterized by impaired sweating, only CGRP immunoreactivity was reduced while VIP immunoreactivity was unchanged (Hilz et al. 2004). This would confirm our results that CGRP has an influence on human sweating while VIP has not.
Substance P is a tachykinin, which mainly acts on postcapillary venules via NK1 receptors and induces plasma leakage (oedema) (Leis et al. 2003). SP can be also found in sweat glands (O'Flynn et al. 1989; Zancanaro et al. 1999) as well as in sympathetic ganglions and sympathetic neurons innervating sweat glands (Lindh et al. 1989a,b). In general, the distribution of SP immunoreactivity around sweat glands is sparser than for CGRP or VIP (Lindberger et al. 1989; Kennedy et al. 1994) and in some studies no immunoreactivity for SP was found at all (Tainio et al. 1987). In contrast to the other neuropeptides studied herein, in previous studies SP always had an inhibitory effect on methacholine-induced sweating in humans (Kumazawa et al. 1994; Berg et al. 1995). Our functional data confirm this inhibitory effect, which was very modest. We used reasonably low concentrations of SP, which were, however, probably still higher than the physiological concentration of SP in human skin (10–9 mol SP dissolved in a volume of 1 mm3 of skin (Sauerstein et al. 2000)), in particular, those doses which suppressed sweating most effectively (10–6 and 10–7 M). This fact limits our observation and it is well possible that SP has no physiological effect on sweat glands in vivo. The mechanism by which SP could suppress sweating is still unclear. The most likely explanation is the oedema, which occludes sweat ducts, in particular if higher concentrations of SP are applied (Leis et al. 2003).
Effects on vasodilatation
It has been shown previously that CGRP, VIP and SP increase skin blood flow by vasodilatation (Brain & Williams, 1988; Piedimonte et al. 1993; Weidner et al. 2000; Bennett et al. 2003). Compared with VIP and SP, CGRP is by far the strongest vasodilator among the neuropeptides in human skin (Brain et al. 1986). In our study, neuropeptides were not assessed in a way that allows us to draw final conclusions on the vasodilator effects, since we always co-applied ACh. Acetylcholine itself induces a strong vasodilatation by direct effect on endothelial cells and by axon reflex mechanisms (Rukwied & Heyer, 1998; Schlereth et al. 2005a). We therefore could only look for further enhancement of skin blood flow by the neuropeptides investigated in our study. We found no effect of VIP and SP, but CGRP further enhanced ACh-induced vasodilatation. Thus, we were able to confirm that CGRP is the strongest vasodilator. Interestingly, CGRP mainly amplifies skin blood flow in concentrations which also most effectively increase sweating. One explanation why 10–7 and 10–9 M CGRP were more effective than 10–8 M to induce vasodilatation could be that the degradation route of CGRP differs with different concentrations. As shown for axon reflex vasodilatation, different degradation products of peptidases could have very different vasodilatory potency (Kramer et al. 2006). Nevertheless, our data suggest that vasodilatation may be another factor for CGRP-induced hyperhidrosis. Vasodilatation increases skin temperature, and sweating linearly depends on skin temperature (Low & Kennedy, 2002). Furthermore, intact blood flow is the prerequisite for sustained sweating since sweat glands permanently need fluid and blood supply. Stopping the blood flow, e.g. by tourniquet, quickly stops sweating (Ogawa & Low, 1997). Our results suggest that amplification of sweating could to some extent also be secondary to the increase of skin blood flow. It will be most interesting to dissect direct CGRP fragment effects and indirect vascular effects on peripheral sweating in future studies.
Clinical implications
The major sources of CGRP in human skin are primary afferent neurons, in particular so-called silent nociceptors (Schmelz et al. 2000). If these nociceptors were sensitized and then activated, CGRP release would be facilitated, finally leading to regional vasodilatation and skin temperature increase. In complex regional pain syndromes (CRPS) such a mechanism has been postulated for generating symptoms during acute stages (Weber et al. 2001). Furthermore, hyperhidrosis regularly occurs in CRPS, and increased peripheral axon reflex sweating has been demonstrated (Birklein et al. 1997; Weber et al. 2001). Accordingly, increased CGRP concentrations in blood samples from CRPS patients have been found, in particular if hyperhidrosis was present (Birklein et al. 2001). These findings, together with the results of the present study, offer an explanation for one enigmatic symptom of acute CRPS – focal hyperhidrosis induced by local CGRP release.
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