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Exp Physiol 97.8 (2012) pp 930942

Research Paper

The cholinergic blockade of both thermally and

non-thermally induced human eccrine sweating
Christiano A. Machado-Moreira1 , Peter L. McLennan2 , Stephen Lillioja2,3 , Wilko van Dijk1 ,
Joanne N. Caldwell1 and Nigel A. S. Taylor1
1

Experimental Physiology

Centre for Human and Applied Physiology, School of Health Sciences,

Graduate School of Medicine and 3 Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia

Thermally induced eccrine sweating is cholinergically mediated, but other neurotransmitters

have been postulated for psychological (emotional) sweating. However, we hypothesized
that such sweating is not noradrenergically driven in passively heated, resting humans. To
test this, nine supine subjects were exposed to non-thermal stimuli (palmar pain, mental
arithmetic and static exercise) known to evoke sweating. Trials consisted of the following four
sequential phases: thermoneutral rest; passive heating to elevate (by 1.0 C) and clamp mean
body temperature and steady-state sweating (perfusion garment and footbath); an atropine
sulphate infusion (0.04 mg kg1 ) with thermal clamping sustained; and following clamp removal.
Sudomotor responses from glabrous (hairless) and non-glabrous skin surfaces were measured
simultaneously (precursor and discharged sweating). When thermoneutral, these non-thermal
stimuli elicited significant sweating only from the palm (P < 0.05). Passive heating induced
steady-state sweating ranging from 0.20 0.04 (volar hand) to 1.40 0.14 mg cm2 min1
(forehead), with each non-thermal stimulus provoking greater secretion (P < 0.05). Atropine
suppressed thermal sweating, and it also eliminated the sudomotor responses to these nonthermal stimuli when body temperatures were prevented from rising (P > 0.05). However,
when the thermal clamp was removed, core and skin temperatures became further elevated and
sweating was restored (P < 0.05), indicating that the blockade had been overcome, presumably
through elevated receptor competition. These observations establish the dependence of both
thermal and non-thermal eccrine sweating from glabrous and non-glabrous surfaces on
acetylcholine release, and challenge theories concerning the psychological modulation of
sweating. Furthermore, no evidence existed for the significant participation of non-cholinergic
neurotransmitters during any of these stimulations.
(Received 5 February 2012; accepted after revision 5 April 2012; first published online 11 April 2012)
Corresponding author N. A. S. Taylor: Centre for Human and Applied Physiology, School of Health Sciences, University
of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. Email: nigel taylor@uow.edu.au

Human eccrine sweat secretion during thermal loading is

modulated by sympathetic, cholinergic neurons (Dale &
Feldberg, 1934; Chalmers & Keele, 1952; Landis, 1990;
Kimura et al. 2007) and controlled by the preoptic
anterior hypothalamus (Hardy et al. 1964; Boulant et al.
1989). However, individual eccrine glands are innervated
by several neurons (Kennedy et al. 1994) and possess
receptors for both acetylcholine and noradrenaline (Reddy
et al. 1992; Weihe et al. 2005). Moreover, Uno (1977)
and Donadio et al. (2006) reported the existence of

noradrenergic neurons in close proximity to these glands,

albeit less dense in their distribution, while others have
shown that noradrenergic agonists can elicit sweating
(Haimovici, 1950; di SantAgnese et al. 1953; Allen &
Roddie, 1972; Wolf & Maibach, 1974; Sato & Sato, 1981).
Collectively, these observations form the background
from which some have suggested that human eccrine
sweat glands may be innervated by both cholinergic and
noradrenergic neurons that are capable of independent
glandular activation (Robertshaw, 1977; Noppen et al.

DOI: 10.1113/expphysiol.2012.065037


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Exp Physiol 97.8 (2012) pp 930942

Cholinergic modulation of non-thermal sweating

1997; Nakazato et al. 2004). The functional significance

of these interpretations was evaluated within this study.
Altered affective states can also induce eccrine sweating
(Harrison & MacKinnon, 1966; Homma et al. 2001;
Kobayashi et al. 2003), and such sweating occurs without
tissue temperatures changing. This form of non-thermal
(psychological or emotional) sweating in thermoneutral
individuals is thought by some to be induced via separate
efferent pathways (List & Peet, 1938; Chalmers & Keele,
1952), which are possibly of a noradrenergic phenotype
(Robertshaw, 1977; Noppen et al. 1997; Nakazato et al.
2004). Moreover, others have suggested that psychological
sweating is controlled by a different, possibly cortical,
centre (Darrow, 1937; Kuno, 1956; Ogawa, 1975) and that
the autonomic efferents innervate only the glabrous (nonhairy) skin of the hands and feet (Darrow, 1937; Kuno,
1956; Ogawa, 1975). Indeed, Kuno (1956) proposed that
thermal stimulation will inhibit psychological sweating,
whilst psychological provocation acts to suppress thermal
sweating. The current authors have long considered
some aspects of these hypothetical control mechanisms
to be imprecise. Indeed, recent research from our
laboratory has demonstrated psychological sweating to be
ubiquitous in its distribution, and certainly not restricted
to the glabrous skin surfaces, when evoked either in
passively heated (Machado-Moreira & Taylor, 2012a)
or in thermoneutral individuals (Machado-Moreira &
Taylor, 2012b). Therefore, the regional distribution of
psychological sweating and the inhibitory nature of
psychological stimuli upon thermal sweating were reevaluated across glabrous and non-glabrous skin surfaces,
with and without systemic cholinergic blockade. As the
cholinergic pathways dominate sudomotor control, it was
hypothesized that residual psychological sweating, in the
presence of this blockade, would reflect the participation
of a non-cholinergic mechanism.
Cholinergic sudomotor blockades have been used
for decades (Chalmers & Keele, 1951), but several
investigators have described either an incomplete or
a transient suppression of both thermal (Rodman,
1952; Cummings & Craig, 1967; Gibinski et al. 1973;
Shastry et al. 2000) and non-thermal (psychological)
sweating (Allen et al. 1972; Wolf & Maibach, 1974).
Such evidence has been used to support the premise that
neurotransmitters other than acetylcholine participate
in the control of eccrine sweating. However, as these
competitive blockades also reduce evaporative heat loss,
then, in the continued presence of a fixed external
thermal load, one may observe a further elevation
in body temperature, as reported by Clark & Lipton
(1985). In this circumstance, there will be increased
thermoreceptor feedback and an elevated acetylcholine
release from the sudomotor neurons, possibly leading
to a blockade breakthrough. This will re-establish sweat
secretion (Rodman, 1952) and it may, perhaps incorrectly,

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931

be interpreted to reflect the participation of an alternative

mode of sweat gland activation.
With this possibility in mind, the present experiment
was designed using a whole-body thermal clamp (waterperfusion suit and footbath) to stabilize core temperature
(Cotter & Taylor, 2005) after it had been passively
elevated, and to sustain that clamped state during a
systemic cholinergic blockade. This technique establishes
conditions in which both the whole-body thermal energy
content and thermoreceptor feedback are increased
and held constant, thereby ensuring that sympathetic
sudomotor drive is elevated and stable (open-loop
control). The aim was to clamp thermoafferent activity
so that the sweating responses arising from changes in
the efferent neural activity accompanying several nonthermal stimulations could be isolated. These methods
provided the experimental conditions necessary to test
the hypothesis that psychological sweating is not of a
noradrenergic origin, either at the glabrous or at the nonglabrous skin surfaces. This was achieved through the
repeated application of standardized, non-thermal stimuli
known to provoke sweat secretion in thermoneutral
individuals (Kuno, 1956; Abram et al. 1973; Amano et al.
2011; Machado-Moreira & Taylor, 2012b). Finally, to
demonstrate the importance of this clamping procedure
within the experimental design, the thermal clamp was
removed to induce a blockade breakthrough.
Methods
Ethical approval

The procedures for this research were approved by

the Human Research Ethics Committee (University of
Wollongong) in accordance with the regulations of the
National Health and Medical Research Council (Australia)
and in compliance with the Declaration of Helsinki. All
participants provided written, informed consent.
Subjects

Nine healthy males (mean SD: 29.7 9.0 years old,

179.5 9.8 cm tall and weighing 73.54 7.22 kg)
participated in a single, resting trial composed of four
sequential phases. Participants were not taking any
medication, nor did they have a history of cardiovascular
or thermal illness.
Procedures

Subjects wore a swimming costume and water-perfusion

suit (for details see Thermal stimulation and clamping)
and remained supine during both preparation and testing.
Every trial was conducted within a climate-controlled

932

C. A. Machado-Moreira and others

chamber using the same, four-phase sequence (Fig. 1), as

follows: thermoneutral rest (control); passive heating with
thermal clamping to establish a constant thermal load and
to elicit steady-state thermal sweating; atropine-induced
cholinergic blockade with the thermal clamp sustained;
and removal of the thermal clamp with a concomitant
elevation in mean body temperature.
Firstly, to establish baseline responses, sweating was
evaluated in thermoneutral conditions using three nonthermal stimuli. These included two psychological stresses
(acute pain for 15-s and cognitive challenge for 2min) and static, hand-grip exercise (for 2-min). Each
stimulus was separated by a 3-min recovery period to
restore the pretreatment sweating baseline. This was
the control phase, and a climate chamber (27.528 C)
and water-perfusion suit (33 C) were used to clamp
this thermoneutral state. Secondly, passive heating was
initiated (air temperature, 27.528 C; water temperatures,
perfusion suit 48 C and footbath 42 C), with the aim
of elevating core and mean body temperatures about 0.5
and 1 C above their respective thermoneutral baselines
for each individual. This was important, because these
temperatures are beyond the thresholds for sweating.
In combination with a skin temperature increase of
2.5 C, thermal sweating is primed, and a wholebody sweat rate of about 0.30 mg cm2 min1 could
be anticipated (Machado-Moreira & Taylor, 2012a).
Moreover, as noradrenergic sudomotor activation has
been postulated within thermoneutral individuals, it

Exp Physiol 97.8 (2012) pp 930942

was essential to minimize overall thermal strain and

ensure that systemic adrenergic influences were avoided.
Passive heating established steady-state, thermal sweating
over 2036 min, after which core temperature was
clamped (changing <0.1 C thereafter). The three nonthermal stimuli were applied for a second time,
replicating phase one. This was the passive-heating
treatment phase. Thirdly, following recovery from these
non-thermal stimulations and the return to steadystate thermal sweating, atropine sulphate (0.04 mg kg1 )
was administered intravenously to provide a systemic
cholinergic blockade. The thermal clamping of core
temperature was continued (see Pilot testing), but now by
reducing water temperatures. This prevented increments
in heat storage that would accompany sweat inhibition,
and it ensured that core temperatures matched those used
during passive heating. Following the complete blockade
of thermal sweating, the three non-thermal stimuli were
again applied, replicating all previous applications. This
was the cholinergic blockade phase. Finally, approximately
25 min (SD 7) after commencing the atropine infusion, the
thermal clamp was released, and water temperatures were
increased to levels used during passive heating (perfusion
suit 48 C and footbath 42 C). The aim of this last
experimental phase was to elicit an unchecked elevation
in heat storage whilst sweating was suppressed, inducing
a blockade breakthrough. Therefore, each trial continued
until discharged thermal sweating had been re-established
across all sites.

Figure 1. An overview of the four-phase experimental protocol

During phase one, following 10 min in the thermoneutral state (27.528 C), the following three stimuli were
applied: palmar pain (P; 15 s); mental arithmetic (M; 2-min) and hand-grip (static) exercise (H; 2-min). During phase
two, passive heating [immersion of both feet (42 C) and a water-perfusion suit (48 C)] elevated core temperature
by 0.5 C to establish steady-state thermal sweating. Core temperature was clamped, and the three stimuli
were reapplied. During phase three, a systemic blockade was used to suppress sweating and the thermal clamp
was maintained, after which these stimuli were again applied. During phase four, the clamp was removed and
core temperature elevated. The circles in the last two phases represent the unknown sudomotor responses. Times
are approximate, and varied among subjects.

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Exp Physiol 97.8 (2012) pp 930942

Cholinergic modulation of non-thermal sweating

Pilot testing. Extensive pilot research led to the use

of several strategies necessary to test the working

hypothesis. Preliminary work involved determining the
most appropriate blocking agent (intravenous atropine in
preference to oral hyoscine), the atropine dose infused
(0.04 mg kg1 ), the non-thermal treatments and their
application durations, the order of these treatments
and the interstimulus recovery period (Machado-Moreira
& Taylor, 2012a,b). These are discussed briefly in
subsequent sections. However, perhaps the most critical
pilot testing concerned the use of whole-body thermal
clamping techniques (Cotter & Taylor, 2005). When first
used, atropine sulphate fully suppressed sweat secretion.
However, body temperature soon began to rise further,
followed by a return of sweating, albeit at a lower level,
as others had noted (Rodman, 1952). When the three
non-thermal stimulations were superimposed upon this
slowly increasing secretion, clear sudomotor responses
were evident, and whilst sweating declined after each
stimulus, it did not return to a steady-state baseline, but
continued to rise. Thus, it was unclear whether or not these
responses reflected a non-cholinergic influence or merely
a breakthrough of the blockade. As core temperatures rose
soon after the blockade was administered, as previously
reported (Clark and Lipton, 1985), the latter possibility
was suspected, and it was deemed essential to prevent this
and the accompanying elevation in thermoafferent feedback. This required thermal clamping.
Thermal stimulation and clamping. The climate chamber
was regulated at 27.528 C throughout every trial.
A water-perfusion suit and footleg bath heated and
clamped skin and core temperatures. This thermal clamp
was used during the control, passive heating and blockade
phases of each trial. The perfusion suit was constructed

R
from a network of tubing (180 m Tygon tubing;
i.d. = 1.58 mm; o.d. = 3.0 mm) arranged in parallel, 1-m
lengths to form anterior and posterior jackets and trousers
(Paul Webb Associates, Yellow Springs, OH, USA), but the
head, hands and feet were not covered. Adjacent tubes
were linked to form a diamond pattern (8 cm 4 cm)
such that the temperature of approximately 90% of the
skin surface could be modified and clamped (Cotter &
Taylor, 2005). These linkages optimized skin contact and
skin temperature control, but the suit contained no other
components, nor was it covered with other garments. This
permitted precise temperature control while optimising
evaporative cooling. Two stirred water baths (38 litre;
Grant Instruments (Cambridge) Ltd, Shepreth, UK)
regulated the temperature of water delivered to this
garment. A third bath was used for immersing the feet
and lower calves. The water temperature for each bath
was independently and thermostatically regulated, with
small volumes of water at slightly different temperature
added to facilitate fine control of the clamp using core

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933

temperature feedback. As a consequence, at the onset of

passive heating, subjects were exposed to sudden heating.
However, once clamping was achieved, subtle and gradual
water temperature adjustments were used, with these
changes always being <5 C and occurring well before the
non-thermal stimuli.
Acute pain. Pain falls within the emotional or affect
domain, and elicits sweating (List & Peet, 1938; Kuno,
1956; Abram et al. 1973). It was chosen as a psychological
stimulus for which there was an extended afferent arm.
The painful stimulation (15-s) was mechanically induced
using a fine, but blunt tool attached to a dynamometer
(Nicholas MMT, model 01160; Lafayette Instrument, Co.,
Lafayette, IN, USA), through which a standardized force
was applied to the palm of the left hand. The duration of
this treatment was minimized, because the stimulus was
intense and, in these conditions, it possessed a powerful
sudorific influence (Machado-Moreira & Taylor, 2012a).
challenge. The
second
psychological
(emotional) stimulus was a cognitive challenge of
mental arithmetic (2-min). This was a central nervous
system stimulation with afferent information arising
from visual and auditory cues. Subjects solved a range of
moderately difficult addition and subtraction problems
(presented on cards) or continuously subtracted a singledigit number from either a three- or four-digit number.
These 2-min applications have been shown to induce
sweating responses from the glabrous and non-glabrous
skin surfaces of passively heated individuals (MachadoMoreira & Taylor, 2012a). The arithmetic challenge was
randomized during the first two applications to minimize
task adaptation, but the single-digit subtraction task was
always used during the blockade to avoid interference from
pupil dilatation. Subjects were constantly encouraged to
increase both speed and accuracy.

Cognitive

Static exercise. An isometric hand-grip task (2-min)

was performed using a custom-made, adjustable hand
dynamometer connected to a load cell (SBA-200L; CAS
Corporation, Seoul, South Korea). Subjects sustained
approximately 30% of their previously measured maximal
voluntary contraction (left hand), with visual feedback
provided. The duration of this stimulus matched the
cognitive challenge.
Systemic blockade. The experimental hypothesis dictated
a systemic drug delivery so that sweat production from
both the glabrous and the non-glabrous skin surfaces
of the face, and the upper and lower limbs could
be evaluated simultaneously. Furthermore, sudomotor
priming optimizes the expression of several non-thermal
sweating responses (Machado-Moreira & Taylor, 2012a).

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C. A. Machado-Moreira and others

Thus, to reveal the possibility for even a low level

of non-cholinergically driven sweating, this background
sweating first needed to be removed, and this was also
best achieved using a systemic blockade. Under dose
restrictions placed upon this investigation, hyoscine was
unable to suppress thermal sweating fully (pilot testing).
Therefore, atropine sulphate was chosen and it was
administered intravenously [dorsal hand; 0.04 mg kg1 ;
average dose, 2.94 mg (SD 0.29); AstraZeneca Pty Ltd,
North Ryde, NSW, Australia]. This dose was based on
previous research (Cummings & Craig, 1967; Gibinski
et al. 1973; Sawka et al. 1984), with its efficacy evaluated
through pilot testing. To standardize and maximize drug
delivery, a timed infusion rate was used (1-min) with a
sterile saline (0.9%) flush (5 ml) following delivery. As this
experiment was designed to evaluate fully the possibility
that these non-thermal stimuli might elicit sweating, even
in the presence of this blockade, two further (local)
blockades were planned. Firstly, bretylium tosylate was to
be used to block local noradrenaline release. Secondly, if
non-thermal sweating still persisted, botulinum toxin was
to be administered locally to exclude the cotransmission
of other sudorific agents. However, in our hands,
systemic atropine totally suppressed both thermal and
non-thermal sweating in every subject during thermal
clamping, obviating the need for these supplementary
blockades.

Standardization. Subjects acted as their own controls

within a single trial, with ambient conditions stable
throughout. Subjects were instructed to refrain from
strenuous exercise on the day preceding testing, not
to consume caffeine or alcohol for 12 h preceding the
experiment, and to present in a well-hydrated state,
following a high-carbohydrate breakfast. On arrival, urine
specific gravity was measured (Clinical Refractometer,
model 140; Shibuya Optical, Tokyo, Japan) to confirm
hydration state [mean = 1.016 (SD 0.007)]. Neither food
nor liquid was consumed during testing, and subjects were
blindfolded throughout the experiment, except during
the cognitive and exercise challenges. The use of 3min interstimulus recovery periods ensured that the
sudorific effect of each non-thermal treatment was not
carried through into the subsequent treatments. This was
established through pilot testing, and verified within every
trial by the return to pretreatment sweating baselines
(where present). It was therefore felt that a randomized
presentation order of these stimuli was not required,
and as the time between subsequent reapplications of
any one stimulus was at least 30 min, the residual
effects would not be carried into the next experimental
phase. At the completion of every experiment, recovery
was medically supervised, and subjects were driven
home.

Exp Physiol 97.8 (2012) pp 930942

Measurements

Auditory canal temperature was monitored using an earmoulded plug with a thermistor protruding 1 cm (Edale
Instruments Ltd, Cambridge, UK), and positioned within
the external auditory meatus and insulated with cotton
wool. The water-perfusion garment did not contact facial
tissues. These procedures isolate the auditory canal from
thermal artefacts, permitting auditory canal temperature
to track oesophageal temperature faithfully and rapidly in
these conditions (Cotter et al. 1995). Skin temperatures
were measured from eight skin sites (forehead, chest,
scapula, upper arm, forearm, dorsal hand, thigh and calf;
Type EU; Yellow Springs Instruments Co. Ltd, Yellow
Springs, OH, USA). All thermistors were calibrated against
a certified reference thermometer in a stirred water-bath
(Dobros total immersion; Dobbie Instruments, Sydney,
NSW, Australia). These data were collected at 5-s intervals
(1206 Series Squirrel; Grant Instruments (Cambridge)
Ltd). Mean skin temperature was derived from a weighted
summation of the eight local temperatures (ISO 9886,
1992), with mean body temperature taken as 80% of the
core plus 20% of the mean skin temperature (Hardy &
DuBois, 1938). Heart rate was monitored continuously
(5-s intervals) from ventricular depolarization (Vantage
NV, Polar Electro Sport Tester; Kempele, Finland).
Local surface sweat rates (discharged sweat) were
measured simultaneously from two glabrous [hairless
sites; forehead and volar (palmar) surface of the right
hand] and three non-glabrous skin surfaces (hairy sites;
dorsal surface of the right forearm, dorsal surface of the
right hand and upper medial surface of the right calf).
These measurements were performed using ventilated
sweat capsules (3.16 cm2 ) glued to the skin to prevent
leakage and pressure-induced artefacts (Collodion USP;
Mavidon Medical Products, FL, Lake Worth, USA). Lowhumidity air was obtained by passing room air over
an enclosed, saturated, lithium chloride solution housed
outside the chamber, with local air temperature measured.
Air collected above this solution remains at 12% relative
humidity over a broad range of temperatures. This air was
pumped through each sweat capsule at a flow that ensured
complete evaporation (600 ml min1 ), and through tubes
long enough to guarantee thermal equilibration with
the internal air temperature. Postcapsular (exhaust) air
temperatures (thermistors) and humidities (capacitance
hygrometers) were continuously sampled downstream
(1-m) as part of an integrated sweat monitor system
(Clinical Engineering Solutions, NSW, Sydney, Australia).
Temperature and humidity sensors were equilibrated with
ambient conditions prior to each trial. Data were recorded
at 1-s intervals (DAS1602; Keithley Instruments, Inc.,
Cleveland, OH, USA) and used to derive local sweat
rates (Taylor et al. 1997). Hygrometer calibration, using
saturated solution standards, preceded experimentation.

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Cholinergic modulation of non-thermal sweating

Sweat capsules can only be used to measure surface

(discharged) sweat, and low production rates of precursor
(primary) sweat can result in complete fluid reabsorption
within the sweat duct (Bullard, 1971). Such sweat would
not be evident at the skin surface, nor could it be detected
gravimetrically. As it was also necessary to evaluate
sweat production during non-thermal stimulations in
thermoneutral conditions, which are known to elicit lowlevel sudomotor responses, a technique was required
that could detect precursor sweat secretion. Changes in
skin conductance have long been used for this purpose
(Veraguth, 1908; Thomas & Korr, 1957; Machado-Moreira
et al. 2009), and this method was particularly important
during the thermoneutral and systemic blockade phases.
In the latter phase, an absence of surface (discharged)
sweat would not have been sufficient evidence to justify a
claim for complete sweat suppression (Machado-Moreira
et al. 2009). A pair of AgAgCl surface electrodes (1081
FG) was positioned adjacent to the sweat capsule on
the volar (glabrous) surface of the right hand, because
the probability of detecting psychological sweating in
thermoneutral individuals was much greater from that
site (Machado-Moreira & Taylor, 2012b). An electrolyte
of 0.05 M sodium chloride in an inert ointment base
provided the conductive medium, and a constant voltage
of 0.5 V was applied across each electrode pair. Data were
recorded at 10 Hz (UFI Bioderm model SC2000/4-SCL
Simple Scope Data Collection System; UFI, Morro Bay,
CA, USA; connected to a computer).
Analysis

The effect of each stimulus was evaluated by expressing

sweat flow and skin conductance as change scores
relative to prestimulus baselines, and averaged across each
stimulation. The dynamics of the atropine-induced sweat
suppression were derived assuming exponential decays
(Machado-Moreira et al. 2010). One-way ANOVA, with
repeated measures, was used to evaluate intercondition
differences (control, passive heating and blockade).
Tukeys honestly significant difference post hoc tests were
used to isolate sources of significant differences. Within
the same condition, Students paired t tests were used to
compare sweat rates immediately prior to, and during each
non-thermal stimulus, and also sweating and temperature
data before and after removing the thermal clamp. For all
analyses, was set at the 0.05 level. Data are presented as
means SEM and standard deviations (SD).
Results
Phase one: control (thermoneutral) state

During the control phase, the baseline thermal status of

each participant was clamped within the thermoneutral

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935

range, with the core, skin and mean body temperatures

averaging 36.6 (SD 0.2), 33.7 (SD 0.3) and 36.0 C (SD
0.3), respectively. The corresponding mean pretreatment
heart rate was 58 beats min1 (SD 8), which increased
to average 78 beats min1 across the three non-thermal
stimuli (SD 11; P < 0.05). However, none of the thermal
variables changed significantly during these challenges
(P > 0.05). It was therefore assumed that all sudomotor
responses during this phase could be attributed to neural
events associated with these stimulations, and were not
associated with an altered thermal state.
When subjects were thermoneutral, the application of
each non-thermal stimulus resulted in significant sweat
secretion from the volar (glabrous) surface of the hand
(P < 0.05; Fig. 2), as evidenced by changes in both skin
conductance and discharged sweat. However, minimal
sudomotor activity was apparent from each of the other
sites (P > 0.05; Fig. 2).

Phase two: passively heated state

Passive heating [26 min (SD 6)] resulted in significant

elevations in core [0.5 C (SD 0.2); P < 0.05], mean skin
[2.5 C (SD 0.4); P < 0.05] and mean body temperatures
[0.9 C (SD 0.2); P < 0.05]. As the feet and lower legs
were immersed in hot water, the calf skin temperature
increased from 33.1 (SD 0.5; phase one) to 36.7 C (SD 2.0;
phase two; P < 0.05). Thermal clamping sustained this
state, with core temperatures changing non-significantly
thereafter (<0.1 C; P > 0.05). Heart rate increased from
its thermoneutral, pretreatment baseline to 76 beats min1
(SD 12; P < 0.05) after the thermal clamp had been
established. In this state, discharged sweating was evident
from every glabrous and non-glabrous site, which
displayed steady-state baselines of 1.40 0.14 (forehead),
0.78 0.18 (calf), 0.74 0.08 (dorsal hand), 0.20 0.04
(volar hand) and 0.33 0.05 mg cm2 min1 (forearm).
From these data, it was concluded that the thermal
clamp was successful, and it was further assumed that
subsequent sudomotor responses would be the result
of superimposing the non-thermal stimuli onto this
background of steady-state (primed) thermal sweating.
Significantly more sweat was discharged from most
sites in all subjects, relative to both the control and
primed steady-state conditions, when exposed to the three
non-thermal challenges (P < 0.05; Fig. 2). Thus, none of
these stimulations inhibited thermal sweating (P > 0.05;
Fig. 2), although discharged sweat from the calf during
mental arithmetic, and from the volar hand during each
stimulation, did not differ significantly from the control
phase (P > 0.05). Sweating and the electrodermal changes
in response to these stimulations, measured from the volar
(glabrous) hand surfaces, were large, but were equivalent
to responses observed within the control phase (P > 0.05;

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Exp Physiol 97.8 (2012) pp 930942

Figure 2. Changes in local sweat rates and skin conductance (volar hand) accompanying a painful
stimulus (A; 15 s), mental arithmetic (B; 2-min) and static exercise (C; 2-min)
These non-thermal stimuli were applied in the thermoneutral (control) state, following passive heating and finally
after establishing a systemic cholinergic blockade (atropine) in the presence of a thermal clamp. Baseline sweat
rates (in milligrams per square centimetre per minute) appear in parentheses next to the abscissa labels of Fig. 2C.
Significantly different from the control and blockade conditions (P < 0.05); and significantly different from the
blockade phase (P < 0.05). Data are means SEM, with the sample size being nine for all variables except for
forehead sweating (n = 7) and volar hand skin conductance (n = 8).

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Cholinergic modulation of non-thermal sweating

Fig. 2). Therefore, thermal loading did not inhibit these

non-thermal sudomotor responses (P > 0.05; Fig. 2).
Heart rate was again significantly elevated in response
to these stimuli (P < 0.05), averaging 94 beats min1
(SD 12) across these challenges. Following the ensuing
stimulus, baseline sweating was restored during each
recovery period, to be not significantly different from the
immediate pretreatment levels (P > 0.05). This was an
important standardization strategy.
Phase three: systemic blockade condition

Application of the systemic cholinergic blockade almost

immediately released the parasympathetic brake on heart
rate (Fig. 3A). As a consequence, heart rate increased
by 40 4 beats min1 (P < 0.05) relative to its heated
and clamped baseline, prior to the first non-thermal
stimulation, and now averaged 119 beats min1 (SD 12).
It took 510 min to suppress sweating from all sites
completely, which, on average, returned to preheated

baselines 4.9 0.2-min after injection (Fig. 3B). Indeed,

the time constant of this decay was 2.4 0.1 min across
sites, with no significant intersite variations (P > 0.05).
These changes verified the whole-body nature of the
blockade. Throughout the non-thermal stimulations, the
thermal clamp prevented body temperature elevation,
with core temperature changes kept <0.1 C (P > 0.05;
Fig. 3A). Likewise, skin and mean body temperatures
varied by <0.1 C (both P > 0.05). Collectively, these
procedures established the physiological conditions
necessary to test the working hypothesis.
From this state, it was assumed that non-thermal
sudomotor responses, if present, could be attributable
to non-cholinergic mechanisms. However, each stimulus
failed to elicit significant precursor or discharged sweat
from either the glabrous or the non-glabrous skin surfaces
(P > 0.05; Fig. 2). Nevertheless, the chronotropic response
to each non-thermal stimulus remained and was again
significantly elevated, albeit less so. When averaged across
these stimuli, the heart rate was now 130 beats min1

Figure 3. Core temperature, heart rate (A) and local sweating responses (B) during thermoneutral
rest (control baseline) and for the 5 min of thermal clamping prior to initiating a systemic cholinergic
blockade (atropine infusion at time 0), and for 15 min afterwards
Data are mean curves, with means and SEMs indicated by the symbols.

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C. A. Machado-Moreira and others

(SD 12; P < 0.05). That is, even in the presence of an

atropine-induced tachycardia, these psychological and
exercise challenges were able to elicit cardiac, but not
sudomotor responses.

Phase four: thermal clamp removed

At the end of each trial, water-bath temperatures were

increased to equal those used during passive heating (phase
two). Restoring these temperatures, in conjunction with
reduced evaporation due to the blockade, led to increases
in core (0.4 0.1 C; P < 0.05), mean skin (1.1 0.2 C;
P < 0.05) and mean body temperatures (0.5 0.1 C;
P < 0.05) over the next 15 min. In these conditions, calf
skin temperature increased from 36.0 (SD 0.9; phase three)
to 37.7 C (SD 1.0; phase four; P < 0.05). These changes
were accompanied by significant increases in discharged
sweating from every site (Fig. 4; P < 0.05) except for
the volar surface of the hand (P > 0.05), even though
subjects were still under the influence of atropine. This
was consistent with the breakthrough of a competitive
blockade, and it was hypothesized to be due to the
increased sympathetic drive that accompanied the gradual
elevation in mean body temperature. This temperature
dependence was evident in every subject (Fig. 5).

Discussion
Firstly, this four-phase experiment has confirmed
observations that, when each of these non-thermal
treatments is applied to passively heated individuals,

Exp Physiol 97.8 (2012) pp 930942

increments in eccrine sweating are not restricted to the

glabrous skin surfaces (Kuno, 1956; Kennard, 1963; Allen
et al. 1973; Machado-Moreira & Taylor, 2012a). Secondly,
these data show no evidence for a reciprocal inhibition
between the thermal and non-thermal drives for sweating,
as had been postulated by Kuno (1956) and accepted by
others (Ogawa, 1975; Ogawa et al. 1977; Quinton, 1987;
Iwase et al. 1997). Thirdly, during a systemic cholinergic
blockade, it was demonstrated that none of the three
non-thermal stimuli could evoke either precursor or
discharged sweating when body tissue temperatures were
prevented from rising. These observations are, in the
first instance, consistent with the universally accepted
cholinergic mediation of thermal sweating (Chalmers &
Keele, 1951, 1952; Foster & Weiner, 1970). Moreover, they
now comprehensively extend this sudomotor control to
include the non-thermal sudomotor responses from both
the glabrous and non-glabrous skin surfaces, as noted by
Allen et al. (1973). This evidence rebuts the postulated
participation of noradrenergic efferents in the control of
psychological sweating from the glabrous skin surfaces
(Robertshaw, 1977; Noppen et al. 1997; Nakazato et al.
2004; Weihe et al. 2005), even in the absence of thermal
sweating. Finally, thermal clamping has revealed that,
when a competitive blockade of this form is employed,
residual sudomotor activity is not necessarily evidence
for the existence of other participating neurotransmitters.
Indeed, it may simply represent an increased thermal load
leading to a blockade breakthrough.
Atropine crosses the bloodbrain barrier, making it
imperfect for evaluating sudomotor function, because
one cannot exclude the possibility of central interactions

Figure 4. Local sudomotor and average core temperature responses prior to, and following the removal
of the thermal clamp, but with subjects under the influence of atropine
The vertical line indicates removal of the clamp (0 min). Data are mean curves, with means and SEMs indicated by
the symbols.

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Exp Physiol 97.8 (2012) pp 930942

Cholinergic modulation of non-thermal sweating

in the control of sweating, or thermoregulation in

general. Central muscarinic receptor activation can
modify thermoregulation (Takahashi et al. 2001).
However, the small drug-induced body temperature
displacements in animals (Gordon, 1994) are preventable
(thermal clamping). Moreover, the systemic effects
of atropine match changes observed following its
intramuscular administration (Matthew et al. 1988).
Indeed, Craig (1970) demonstrated, using three systemic
infusions (atropine sulphate, atropine methyl nitrate and
scopolamine hydrobromide), that the sudomotor effects
were indistinguishable. Thus, the antagonistic thermal
actions were almost exclusively peripheral in nature,
because only atropine could cross the bloodbrain barrier.
This stands in contrast to their different central nervous
system potencies (Cheshire & Fealey, 2008). It is also
notable that the inhibition of sweating by atropine is
transient (Mirakhur & Dundee, 1980; Ellinwood et al.
1990), in contrast to its prolonged inhibitory effects
on cognition and psychomotor performance (Ellinwood
et al. 1990). Furthermore, the acute, centrally mediated
tachycardia during each non-thermal stimulus was
unimpeded, revealing that only the peripheral sudomotor
component of the sympathetic response was blocked. The
potential for a peripheral ganglionic blockade can equally
be excluded, because atropine did not inhibit the heart rate
responses. Therefore, whilst a central sudorific influence
cannot absolutely be excluded, no evidence was found to
suggest such an action, and several pieces of circumstantial
evidence strongly suggest that the inhibition of sweating
was peripherally mediated, and at the end-organ level.
Several groups have previously reported incomplete
sweat suppression during cholinergic blockades applied

to resting, heated subjects (Rodman, 1952; Cummings

& Craig, 1967; Allen et al. 1972; Gibinski et al. 1973;
Shastry et al. 2000) and also during exercise (Craig, 1952;
Goldsmith et al. 1967; Sawka et al. 1984; Kolka et al.
1986, 1989). Some of these studies had methodological
limitations, leading one to question the veracity of the
blockade. For instance, the following four factors may lead
to an incomplete or transient blockade: the choice of a less
effective blocking agent (e.g. hyoscine; Goldsmith et al.
1967); the use of local, rather than systemic, drug delivery
(e.g. electrophoresis; Gibinski et al. 1973); intramuscular
injection (Wolf & Maibach, 1974; Kolka et al. 1986, 1989);
and the use of an insufficient dose (Gibinski et al. 1973;
Wolf & Maibach, 1974; Shastry et al. 2000). However,
one cannot dispute either the reported reappearance or
the residual presence of discharged sweat during such
blockades within experiments that do not have these
limitations. Why is it, therefore, that some previous
researchers have failed to achieve complete and sustained
sweat suppression during a cholinergic blockade?
Based on the present evidence (Figs 4 and 5), it is
now clear that residual sweating, or its reappearance,
as seen within the pilot trials, was dependent upon
the concomitant rise in tissue temperatures in the
absence of thermal clamping. This increased the thermal
stimulus and facilitated a blockade breakthrough. Indeed,
such a systemic blockade transposes an otherwise
physiologically compensable thermal load into an
uncompensable state, simply by reducing heat loss.
Therefore, without a thermal clamp, one has no control
over thermoreceptor feedback, with the ensuing elevation
in body temperature stimulating sympathetic activity and
increasing acetylcholine release. As competitive receptor

Figure 5. The relationship between dorsal hand sweat secretion and mean body temperature for
atropinized individuals before and after removal of the thermal clamp

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C. A. Machado-Moreira and others

binding is a dynamic process, the probability of either

the agonist (acetylcholine) or its antagonist (atropine)
interacting with these muscarinic receptors is a simple
function of their affinity for the receptor and their
relative concentrations. With the atropine concentration
approximating a state of equilibrium, at least over the time
frame in question, heightened sympathetic activity will
increase the probability of acetylcholine activating sweat
gland receptors, and if this body temperature elevation
persists, then blockade breakthrough must eventuate.
Whilst the present atropine dose (0.04 mg kg1 ) was
sufficient to block steady-state sweating totally during
passive heating with superimposed non-thermal stimuli,
it is not a maximal blockade. This is illustrated in the
fourth phase of every trial by the rapid rise in core
(Fig. 4) and mean body temperatures (Fig. 5) when
participants were heated further. As this can readily
occur in resting conditions, it is certainly possible during
exercise. However, systemic adrenaline release, which may
occur during exercise and can stimulate eccrine sweat
glands (Sato & Sato, 1981; Maple et al. 1982), will increase
the probability of a second (humoral) agonist activating
the sweat gland. For these reasons, one must be cautious
when attempting to interpret the cause of eccrine sweating
during a cholinergic blockade alone.
The present experimental procedures resulted in the
complete and sustained suppression of eccrine sweating
when each non-thermal stimulus was applied in the
presence of a whole-body thermal clamp. Indeed,
clamping permitted the magnitude of the thermal
stimulus to be fixed and controlled, thereby isolating the
sudomotor responses to these non-thermal stimulations.
These conditions were critical to test the hypothesis that
psychological sweating is not of a noradrenergic (neural)
origin.
It is well recognized that eccrine sweat glands respond
to catecholamines (Allen & Roddie, 1972; Sato &
Sato, 1981; Maple et al. 1982; Reddy & Bell, 1996).
This is not contested. However, it has been suggested
that different neuroendocrine controls exist for the
thermal (cholinergic) and non-thermal [cholinergic and
adrenergic (both neural and humoral)] modulation of
sweating (Robertshaw, 1977; Mack et al. 1986; Shields et al.
1987; Noppen et al. 1997; Nakazato et al. 2004; Weihe et al.
2005). The present observations refute this hypothesis.
Indeed, these data demonstrate that sweating during these
thermal, psychological and static exercise stimulations
appeared to be exclusively of a cholinergic origin. Whilst
we were prepared to block local noradrenaline release,
had sweating persisted, there was no evidence for the
existence of either primary or discharged sweat following
systemic atropine administration. Therefore, the present
observations challenge the existence of functionally
relevant noradrenergic efferents for the control of human
eccrine sweating in general, at least in resting participants

Exp Physiol 97.8 (2012) pp 930942

who have experienced a mean body temperature elevation

of 1 C. More specifically, these data refute the possibility
that psychological stimulation provokes noradrenergically
mediated sweating from the glabrous skin surfaces
(Robertshaw, 1977).

Conclusion

Thermal clamping and a systemic cholinergic blockade

were combined to evaluate the neurotransmitter control
of eccrine sweating responses from glabrous and nonglabrous skin during non-thermal stimuli (palmar
pain, mental arithmetic and static exercise). No
evidence was found to support the physiologically
significant participation of neurotransmitters other than
acetylcholine. It is therefore concluded that, within
resting and mildly hyperthermic humans (mean body
temperature elevation 1 C), both thermally and
non-thermally mediated sweating are dependent upon
cholinergic mechanisms at the sweat gland. This evidence
challenges existing theories concerning the psychological
modulation of sweating. Nevertheless, the capacity of
progressively higher atropine doses to continue to block
such sweating with increments in body temperature has
not been demonstrated. No doubt within hyperadrenergic
states (neural and humoral) that may obtain in more
extreme conditions (Rowell, 1990), atropine may become
less effective, regardless of its dose. Therefore, until
such experiments have been performed, one cannot
absolutely exclude the possibility of noradrenergic neural
pathways influencing eccrine sweating in more stressful
states.
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Acknowledgements
C.A.M.-M. was supported by a doctoral scholarship from
Coordenacao de Aperfeicoamento de Pessoal de Nvel Superior
CAPES (Ministry of Education, Brazil). J.N.C. was supported by
an Australian Postgraduate Award (Department of Innovation,
Industry, Science and Research, Australia).


C 2012 The Authors. Experimental Physiology 
C 2012 The Physiological Society