Peripheral amplification of sweating--a role for calcitonin gene-related peptide

Abstract

Neuropeptides are the mediators of neurogenic inflammation. Some pain disorders, e.g. complex regional pain syndromes, are characterized by increased neurogenic inflammation and by exaggerated sudomotor function. The aim of this study was to explore whether neuropeptides have a peripheral effect on human sweating. We investigated the effects of different concentrations of calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and substance P (SP) on acetylcholine-induced axon reflex sweating in healthy subjects (total n = 18). All substances were applied via dermal microdialysis. The experiments were done in a parallel setting: ACh alone and ACh combined with CGRP, VIP or SP in various concentrations were applied. Acetylcholine (10(-2) m) always elicited a sweating response, neuropeptides alone did not. However, CGRP significantly enhanced ACh-induced sweating (P < 0.01). Post hoc tests revealed that CGRP in physiological concentrations of 10(-7)-10(-9) m was most effective. VIP at any concentration had no significant effect on axon reflex sweating. The duration of the sweating response (P < 0.01), but not the amount of sweat, was reduced by SP. ACh-induced skin blood flow was significantly increased by CGRP (P < 0.01), but unaltered by VIP and SP. The results indicate that CGRP amplifies axon reflex sweating in human skin.

Figure 1. Measurement of sweating

A, two sweat chambers were attached to the skin. Each chamber was surrounded by two microdialysis membranes. The sweat chambers were perfused with dry nitrogen gas. Humidity was measured with hygrometers and assessed as sweat rate over time. B, example of a sweat curve of one subject. The area under the sweat curve (area hatched in grey) and the absolute humidity measured at the peak of the sweating response (marked by the grey line) were evaluated individually. C, example of sweat curves of one subject. CGRP at a concentration of 10⁻⁹m in combination with ACh induced a stronger sweating response than ACh alone.

Figure 2. Evaluation of the sweating reaction

Sweating responses of all subjects. Area under the curve (AUC) and absolute humidity at peak were evaluated. n = xx: mean of all concentrations. A, CGRP at concentrations of 10⁻⁶–10⁻¹⁰m in combination with ACh (black bars) compared with 10⁻²m ACh alone (grey bars). At concentrations of 10⁻⁶ and 10⁻¹⁰m sweating is reduced with CGRP, but at concentrations of 10⁻⁷–10⁻⁹m sweating is enhanced significantly with CGRP. Taken all concentrations together sweating is enhanced significantly with CGRP also. B, VIP at concentrations of 10⁻⁵–10⁻⁸m in combination with ACh (black bars) compared with 10⁻²m ACh alone (grey bars). No significant difference in sweat rate between VIP and ACh could be detected. C, substance P at concentrations of 10⁻⁶–10⁻⁹m in combination with ACh (black bars) compared with 10⁻²m ACh alone (grey bars). No significant difference in sweat rate between SP and ACh could be detected. Post hoc t test: ***P < 0.001, **P < 0.01, *P < 0.05, #P < 0.09.

Figure 3. Superficial skin blood flow measured with laser-Doppler imaging

Mean skin blood flow for the time of the stimulation period (40 min). Mean ± s.e.m. of all subjects. Skin blood flow was measured in perfusion units. n = xx: mean of all concentrations. A, CGRP at concentrations of 10⁻⁶–10⁻¹⁰m (black bars) was tested against 10⁻²m ACh alone (grey bars). CGRP enhanced skin blood flow at all concentrations, but this enhancement was only significant for 10⁻⁷ and 10⁻⁹m and if all concentrations were taken together. B, VIP at concentrations of 10⁻⁵–10⁻⁸m (black bars) was tested against 10⁻²m ACh alone (grey bars). No difference was significant. Only at the highest VIP concentrations (10⁻⁵ and 10⁻⁶m) could a trend for enhanced skin perfusion with VIP be found. C, substance P at concentrations of 10⁻⁶–10⁻⁹m (black bars) was tested against 10⁻²m ACh alone (grey bars). No significant differences in superficial skin blood flow could be found. Post hoc t test: **P < 0.01, ⁺P < 0.06.