The perception of painful and nonpainful stimuli during voluntary motor activity in man

Previous studies have shown that voluntary movement diminishes the transmission of cutaneous afferent input through the dorsal column-medial lemniscal system, and also raises the threshold for detecting nonpainful, cutaneous stimuli (electrical shocks). Although there is some evidence that pain elicited by electrical stimulation is diminished during movement, no studies have tested the effect of movement on the perception of pain produced by natural stimulation. For this reason, we tested the effects of voluntary motor activity on the perception of noxious thermal stimuli in human volunteers. We first developed a motor paradigm in which the thermal stimulation could be applied to the immobile limb (isometric elbow flexion-extension). Both isometric and isotonic muscle contractions about the elbow increased the threshold for detecting weak cutaneous stimuli (electrical shocks) applied to the forearm, and to a lesser extent the detection of stimuli applied to the dorsum of the hand. Afterwards, noxious and innocuous heat stimuli were applied to the forearm during isometric contractions and at rest. Magnitude estimates for the intensity of the pain, as well as latency measures of the onset of pain, were recorded. We found no evidence that isometric motor activity diminished either the threshold for pain or the subjective intensity of the noxious and innocuous thermal stimuli. Thus, motor activity decreases the ability to detect weak low-threshold cutaneous inputs, but has no effect on the perception of warmth and heat pain.     

Cutaneous vascular responses to isometric handgrip exercise during local heating and hyperthermia.

The dramatic increase in skin blood flow and sweating observed during heat stress is mediated by poorly understood sympathetic cholinergic mechanisms. One theory suggests that a single sympathetic cholinergic nerve mediates cutaneous active vasodilation (AVD) and sweating via cotransmission of separate neurotransmitters, because AVD and sweating track temporally and directionally when activated during passive whole body heat stress. It has also been suggested that these responses are regulated independently, because cutaneous vascular conductance (CVC) has been shown to decrease, whereas sweat rate increases, during combined hyperthermia and isometric handgrip exercise. We tested the hypothesis that CVC decreases during isometric handgrip exercise if skin blood flow is elevated using local heating to levels similar to that induced by pronounced hyperthermia but that this does not occur at lower levels of skin blood flow. Subjects performed isometric handgrip exercise as CVC was elevated at selected sites to varying levels by local heating (which is independent of AVD) in thermoneutral and hyperthermic conditions. During thermoneutral isometric handgrip exercise, CVC decreased at sites in which blood flow was significantly elevated before exercise (-6.5 +/- 1.8% of maximal CVC at 41 degrees C and -10.5 +/- 2.0% of maximal CVC at 43 degrees C; P < 0.05 vs. preexercise). During isometric handgrip exercise in the hyperthermic condition, an observed decrease in CVC was associated with the level of CVC before exercise. Taken together, these findings argue against withdrawal of AVD to explain the decrease in CVC observed during isometric handgrip exercise in hyperthermic conditions.     

Afferent Modulation of Warmth Sensation and Heat Pain in the Human Hand

The hands of 14 normal humans were used to determine the somatotopic organization of the modulation of warmth sensation and heat pain by different forms of cutaneous stimuli. Test stimuli were 5-sec heat pulses ranging from 36° to 51°C, delivered to the fingerpads of digits 1, 2, 4, and 5 with a contact thermode. Conditioning stimuli (15 sec) bracketed the test stimuli and included vibration, noxious and innocuous heat, cold, and electrical pulses delivered to the fingerpads of digits that were adjacent or nonadjacent to the tested digits. Noxious (48° ± 1.3°C), but not innocuous (43°C), heat stimuli increased the perceived magnitude estimation of innocuous test stimuli (36–43°C) by 20–37% when delivered to adjacent, but not to nonadjacent, digits. No other conditioning stimuli had any effect on the intensity of warmth perception. In contrast, both noxious and innocuous heat or electrical conditioning reduced the magnitude estimation of noxious (50–5°C), but not innocuous, test pulses by 12–22% when delivered to adjacent digits. Conditioning of nonadjacent digits was significantly less effective. The analgesic effects of noxious and innocuous conditioning were approximately equal. Vibratory (120 Hz, 3.5 μm) and cold (15°C) conditioning stimuli were ineffective. The results are consistent with a dermatomal somatotopic organization of tactile and heat modulatory influences on warmth sensation and heat pain. The results further suggest that the neural mechanisms subserving warmth mediate a negative feedback influence on heat pain intensity.     

Comparison of skin sympathetic nerve responses to isometric arm and leg exercise.

Measurement of skin sympathetic nerve activity (SSNA) during isometric exercise has been previously limited to handgrip. We hypothesized that isometric leg exercise due to the greater muscle mass of the leg would elicit greater SSNA responses than arm exercise because of presumably greater central command and muscle mechanoreceptor activation. To compare the effect of isometric arm and leg exercise on SSNA and cutaneous end-organ responses, 10 subjects performed 2 min of isometric knee extension (IKE) and handgrip (IHG) at 30% of maximal voluntary contraction followed by 2 min of postexercise muscle ischemia (PEMI) in a normothermic environment. SSNA was recorded from the peroneal nerve. Cutaneous vascular conductance (laser-Doppler flux/mean arterial pressure) and electrodermal activity were measured within the field of cutaneous afferent discharge. Heart rate and mean arterial pressure significantly increased by 16 +/- 3 and 23 +/- 3 beats/min and by 22 +/- 2 and 27 +/- 3 mmHg from baseline during IHG and IKE, respectively. Heart rate and mean arterial pressure responses were significantly greater during IKE compared with IHG. SSNA increased significantly and comparably during IHG and IKE (52 +/- 20 and 50 +/- 13%, respectively). During PEMI, SSNA and heart rate returned to baseline, whereas mean arterial pressure remained significantly elevated (Delta12 +/- 2 and Delta13 +/- 2 mmHg from baseline for IHG and IKE, respectively). Neither cutaneous vascular conductance nor electrodermal activity was significantly altered by either exercise or PEMI. These results indicate that, despite cardiovascular differences in response to IHG and IKE, SSNA responses are similar at the same exercise intensity. Therefore, the findings suggest that relative effort and not muscle mass is the main determinant of exercise-induced SSNA responses in humans.     

Determinants of skin sympathetic nerve responses to isometric exercise.

Exercise-induced increases in skin sympathetic nerve activity (SSNA) are similar between isometric handgrip (IHG) and leg extension (IKE) performed at 30% of maximal voluntary contraction (MVC). However, the precise effect of exercise intensity and level of fatigue on this relationship is unclear. This study tested the following hypotheses: 1) exercise intensity and fatigue level would not affect the magnitude of exercise-induced increase in SSNA between IHG and IKE, and 2) altering IHG muscle mass would also not affect the magnitude of exercise-induced increase in SSNA. In protocol 1, SSNA (peroneal microneurography) was measured during baseline and during the initial and last 30 s of isometric exercise to volitional fatigue in 12 subjects who randomly performed IHG and IKE bouts at 15, 30, and 45% MVC. In protocol 2, SSNA was measured in eight subjects who performed one-arm IHG at 30% MVC with the addition of IHG of the contralateral arm in 10-s intervals for 1 min. Exercise intensity significantly increased SSNA responses during the first 30 s of IHG (34+/-13, 70+/-11, and 92+/-13% change from baseline) and IKE (30+/-17, 69+/-12, and 76+/-13% change from baseline) for 15, 30, and 45% MVC. During the last 30 s of exercise to volitional fatigue, there were no significant differences in SSNA between exercise intensities or limb. SSNA did not significantly change between one-arm and two-arm IHG. Combined, these data indicate that exercise-induced increases in SSNA are intensity dependent in the initial portion of isometric exercise, but these differences are eliminated with the development of fatigue. Moreover, the magnitude of exercise-induced increase in SSNA responses is not dependent on either muscle mass involved or exercising limb.     

Baroreceptor modulation of active cutaneous vasodilation during dynamic exercise in humans.

The hypothesis that baroreceptor unloading during dynamic limits cutaneous vasodilation by withdrawal of active vasodilator activity was tested in seven human subjects. Increases in forearm skin blood flow (laser-Doppler velocimetry) at skin sites with (control) and without alpha-adrenergic vasoconstrictor activity (vasodilator only) and in arterial blood pressure (noninvasive) were measured and used to calculate cutaneous vascular conductance (CVC). Subjects performed two similar dynamic exercise (119 +/- 8 W) protocols with and without baroreceptor unloading induced by application of -40 mmHg lower body negative pressure (LBNP). The LBNP condition was reversed (i.e., either removed or applied) after 15 min while exercise continued for an additional 15 min. During exercise without LBNP, the increase in body core temperature (esophageal temperature) required to elicit active cutaneous vasodilation averaged 0.25 +/- 0.08 and 0.31 +/- 0.10 degrees C (SE) at control and vasodilator-only skin sites, respectively, and increased to 0.44 +/- 0.10 and 0.50 +/- 0.10 degrees C (P < 0.05 compared with without LBNP) during exercise with LBNP. During exercise baroreceptor unloading delayed the onset of cutaneous vasodilation and limited peak CVC at vasodilator-only skin sites. These data support the hypothesis that during exercise baroreceptor unloading modulates active cutaneous vasodilation.     

Glycine inhibitory dysfunction turns touch into pain through PKCgamma interneurons

Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. During tactile allodynia, activation of the sensory fibers which normally detect touch elicits pain. Here we provide a new behavioral investigation into the dynamic component of tactile allodynia that developed in rats after segmental removal of glycine inhibition. Using in vivo electrophysiological recordings, we show that in this condition innocuous mechanical stimuli could activate superficial dorsal horn nociceptive specific neurons. These neurons do not normally respond to touch. We anatomically show that the activation was mediated through a local circuit involving neurons expressing the gamma isoform of protein kinase C (PKCgamma). Selective inhibition of PKCgamma as well as selective blockade of glutamate NMDA receptors in the superficial dorsal horn prevented both activation of the circuit and allodynia. Thus, our data demonstrates that a normally inactive circuit in the dorsal horn can be recruited to convert touch into pain. It also provides evidence that glycine inhibitory dysfunction gates tactile input to nociceptive specific neurons through PKCgamma-dependent activation of a local, excitatory, NMDA receptor-dependent, circuit. As a consequence of these findings, we suggest that pharmacological inhibition of PKCgamma might provide a new tool for alleviating allodynia in the clinical setting.     

Effects of muscle metaboreceptor stimulation on cutaneous blood flow from glabrous and nonglabrous skin in mildly heated humans.

Given differences in sympathetic innervation to glabrous and nonglabrous skin, we tested the hypothesis that muscle metaboreceptor regulation of cutaneous vascular conductance (CVC) differs between these skin regions. Subjects (n = 21) performed isometric handgrip exercise (IHG; 50% maximal voluntary contraction for 60 s), followed by 2 min of postexercise ischemia. Throughout IHG and postexercise ischemia, CVC was measured from glabrous (palm) and nonglabrous (forearm and chest) regions contralateral to the exercising arm. These procedures were conducted after the subjects had been exposed to an ambient temperature of 35 degrees C and a relative humidity of 50% for 60 min. These thermal conditions were intended to cause slight increases in cutaneous blood flow via sympathetic withdrawal. Esophageal, sublingual, and mean skin temperatures did not change markedly during IHG or postexercise ischemia. During IHG, forearm CVC did not change, chest CVC increased slightly, and palm CVC decreased substantially (from 100 to 34.8 +/- 3.5%; P = 0.001). During muscle metaboreceptor stimulation due to postexercise ischemia, CVC from nonglabrous regions returned to preexercise baselines, whereas CVC at the palm remained below preexercise baseline (68.2 +/- 4.2%; P = 0.001 relative to preexercise baseline). These results indicate that in mildly heated humans muscle metaboreflex stimulation is capable of modulating CVC in glabrous, but not in nonglabrous, skin.     

Cutaneous vascular responses to isometric handgrip exercise

Cutaneous vascular responses to dynamic exercise have been well characterized, but it is not known whether that response pattern applies to isometric handgrip exercise. We examined cutaneous vascular responses to isometric handgrip and dynamic leg exercise in five supine men. Skin blood flow was measured by laser-Doppler velocimetry and expressed as laser-Doppler flow (LDF). Arterial blood pressure was measured noninvasively once each minute. Cutaneous vascular conductance (CVC) was calculated as LDF/mean arterial pressure. LDF and CVC responses were measured at the forearm and chest during two 3-min periods of isometric handgrip at 30% of maximum voluntary contraction and expressed as percent changes from the preexercise levels. The skin was normothermic (32 degrees C) for the first period of handgrip and was locally warmed to 39 degrees C for the second handgrip. Finally, responses were observed during 5 min of dynamic two-leg bicycle exercise (150-175 W) at a local skin temperature of 39 degrees C. Arm LDF increased 24.5 +/- 18.9% during isometric handgrip in normothermia and 64.8 +/- 14.1% during isometric handgrip at 39 degrees C (P less than 0.05). Arm CVC did not significantly change at 32 degrees C but significantly increased 18.1 +/- 6.5% during isometric handgrip at 39 degrees C (P less than 0.05). Arm LDF decreased 12.2 +/- 7.9% during dynamic exercise at 39 degrees C, whereas arm CVC fell by 35.3 +/- 4.6% (in each case P less than 0.05). Chest LDF and CVC showed similar responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise thermoregulation after prolonged wakefulness

The effect of 33 h of wakefulness on the control of forearm cutaneous blood flow and forearm sweating during exercise was studied in three men and three women. Subjects exercised for 30 min at 60% peak O2 consumption while seated behind a cycle ergometer (Ta = 35 degrees C, Pw = 1.0 kPa). We measured esophageal temperature (Tes), mean skin temperature, and arm sweating continuously and forearm blood flow (FBF) as an index of skin blood flow, twice each minute by venous occlusion plethysmography. During steady-state exercise, Tes was unchanged by sleep loss. The sensitivity of FBF to Tes was depressed an average of 30% (P less than 0.05) after 33 h of wakefulness with a slight decrease (-0.15 degrees C, P less than 0.05) in the core temperature threshold for vasodilatory onset. Sleep loss did not alter the Tes at which the onset of sweating occurred; however, sensitivity of arm sweating to Tes tended to be lower but was not significant. Arm skin temperature was not different between control and sleep loss experiments. Reflex cutaneous vasodilation during exercise appeared to be reduced by both central and local factors after 33 h of wakefulness.     

Tactile and thermal detection thresholds of the scalp skin

The tactile and thermal sensitivity of diverse regions of the human body have been documented extensively, with one exception being the scalp. Additionally, sensory changes may accompany the hair loss from the scalp in androgen-related alopecia (ARA), but formal quantitative sensory testing (QST) has not been reported in respect of this. Therefore, light touch detection thresholds were obtained at nine scalp sites and one forehead site, using Semmes–Weinstein filaments (Von Frey hairs), and for warming and cooling from skin baseline temperature, using 28 and 256?mm² thermodes. Affective, thermal, and nociceptive sensations experienced at thermal detection threshold were quantified. Thirty-two male participants were recruited, 10 of whom had normal hair coverage, 12 of whom had shaved scalp but with potentially normal hair coverage, and 10 of whom exhibited ARA to some extent. The scalp was relatively insensitive to tactile and thermal stimulation at all tested sites, especially so along the midline and near the apex of the skull. Threshold level warm stimuli were rated less pleasant, the less sensitive the test site. After correction for age-related changes in sensitivity, bald scalp sites were found more sensitive to cooling than the same sites when shaved, consistent with prior informal reports of increased sensitivity for some scalp sensations in ARA. QST on hair-covered sites was subject to methodological issues that render such testing non-ideal, such as bias in measurement of resting skin temperatures, and the near impossibility of delivering filament stimuli to the scalp skin without disturbing neighboring hairs.     

Tactile and thermal detection thresholds of the scalp skin

The tactile and thermal sensitivity of diverse regions of the human body have been documented extensively, with one exception being the scalp. Additionally, sensory changes may accompany the hair loss from the scalp in androgen-related alopecia (ARA), but formal quantitative sensory testing (QST) has not been reported in respect of this. Therefore, light touch detection thresholds were obtained at nine scalp sites and one forehead site, using Semmes-Weinstein filaments (Von Frey hairs), and for warming and cooling from skin baseline temperature, using 28 and 256 mm(2) thermodes. Affective, thermal, and nociceptive sensations experienced at thermal detection threshold were quantified. Thirty-two male participants were recruited, 10 of whom had normal hair coverage, 12 of whom had shaved scalp but with potentially normal hair coverage, and 10 of whom exhibited ARA to some extent. The scalp was relatively insensitive to tactile and thermal stimulation at all tested sites, especially so along the midline and near the apex of the skull. Threshold level warm stimuli were rated less pleasant, the less sensitive the test site. After correction for age-related changes in sensitivity, bald scalp sites were found more sensitive to cooling than the same sites when shaved, consistent with prior informal reports of increased sensitivity for some scalp sensations in ARA. QST on hair-covered sites was subject to methodological issues that render such testing non-ideal, such as bias in measurement of resting skin temperatures, and the near impossibility of delivering filament stimuli to the scalp skin without disturbing neighboring hairs.     

Seasonal changes in the function of mechanosensitive receptors in the rat skin

The effect of circannual rhythms on functional properties of the rat skin tactile receptors and nocireceptors, was studied. The effect proved to be quite significant for the cutaneous receptors threshold stimuli and for the parameters of their responses: the latency and AP duration. These changes seem to be determined by hormonal mechanisms.     

Topically applied capsaicin inhibits sensitivity to touch but not to warmth or heat-pain in the region of secondary mechanical hyperalgesia

The aim of this study was to investigate tactile sensitivity near the site of primary hyperalgesia evoked by capsaicin applied topically to the dorsolateral aspect of the hand. In the first experiment (N = 15), touch thresholds increased in the fifth finger ipsilateral to the topically applied capsaicin, but remained unchanged at greater distances from the site of capsaicin treatment. In a second experiment (N = 12), the effect of the capsaicin treatment on sensations evoked not only by light touch but also by warmth, heat-pain, and pressure-pain to a 2-mm diameter steel probe was investigated in the fifth finger. Again, tactile sensitivity was inhibited at the fifth finger, even though stimulation with a cotton bud evoked no discomfort; moreover, sensitivity to warmth and heat-pain were unimpaired. However, sensitivity to pressure-pain increased in the fifth finger after the capsaicin treatment, possibly due to activation of nociceptors sandwiched between the probe tip and bone that normally responded to sharp stimuli. These findings suggest that the central mechanisms that mediate secondary mechanical hyperalgesia suppress sensitivity to innocuous tactile sensations. This effect may contribute to tactile hypoesthesia in chronic pain conditions.     

Influence of isometric exercise on blood flow and sweating in glabrous and nonglabrous human skin.

The distribution of the reflex effects of isometric exercise on cutaneous vasomotor and sudomotor function is not clear. We examined the effects of isometric exercise by different muscle masses on skin blood flow (SkBF) and sweat rate (SR) in nonglabrous skin and in glabrous skin. The latter contains arteriovenous anastomoses (AVAs), which cause large fluctuations in SkBF. SkBF was measured by laser-Doppler flowmetry (LDF) and reported as cutaneous vascular conductance (CVC; LDF/mean arterial pressure). SR was measured by capacitance hygrometry. LDF and SR were measured at the sole, palm, forearm, and ventral leg during separate bouts of isometric handgrip (IHG) and isometric leg extension (ILE). CVC and its standard deviation decreased significantly during IHG and ILE in the palm and sole (P < 0.05) but not in the forearm or leg (P > 0.05). Only palmar SR increased significantly during IHG and ILE (P < 0.05). We conclude that the major reflex influences of isometric exercise on the skin include AVAs and palmar sweat glands and that this is true for both arm and leg exercise.     

Roles of absolute and relative load in skin vasoconstrictor responses to exercise

Systemic hemodynamic responses to exercise (e.g., heart rate, blood pressure) depend on the relative intensity, the active muscle mass, and the mode of exercise. It is not known whether regional vasomotor responses follow the same pattern. To answer this question, in five men we examined cutaneous vascular responses to dynamic and isometric exercise of two legs, one leg, one arm, and one hand, each at high and low work loads. Skin blood flow was monitored by laser-Doppler flowmetry (LDF) at the forearm. Mean arterial pressure (MAP) was measured each minute. Cutaneous vascular conductance (CVC) was indexed as LDF/MAP. Reductions in CVC during the 1st min of dynamic exercise were statistically significant for two-leg exercise at either level and for one-leg exercise at the higher level. Dynamic exercise of smaller muscle groups at either intensity was not associated with significant changes in CVC. The reduction in CVC correlated with external work load (r = 0.75). Work load relative to the capacity of a given muscle group had no identifiable role in the response of CVC to dynamic exercise but did have a role in the increase in MAP at the beginning of exercise. Isometric exercise did not have a measurable effect on CVC regardless of the muscle group or the intensity of the exercise. We conclude that the level of external work determines the redistribution of blood flow from skin to active muscle. Furthermore, absolute rather than relative work and dynamic rather than isometric modes of exercise are the dominant factors.     

Skin potential and EMG changes induced by cutaneous electrical stimulation. I. Normal man in arousing and non-arousing environment.

Skin potential and EMG responses induced in normal man by electrical stimuli applied to the skin were recorded in the four limbs in order to study somato-sympathetic and somato-motor reflexes. Different patterns of responses were observed in different conditions: alarm, habituation, sensitization and arousal. During alarm, sensitization and arousal, the responses were present in the four limbs; during habituation, the responses were only present in the stimulated and in the contralateral limb. Three sensory thresholds to cutaneous electrical stimulation were identified in habituated subjects: tactile, tingling and pain. Cutaneous and EMG responses appeared at tingling threshold. A relationship between skin potential level and skin potential response was observed.     

The effects of stimulus location on the gating of touch by heat- and cold-induced pain

The influence of heat- and cold-induced pain on tactile sensitivity, a "touch gate", was measured under conditions in which the location of the noxious stimuli was varied with respect to the tactile stimulus applied to the thenar eminence of humans. Vibrotactile thresholds were measured in the absence of pain and during administration of a painful stimulus, with the stimulus frequencies selected to activate independently the four psychophysical channels hypothesized to exist in human glabrous skin. Heat-induced pain produced by spatially co-localizing the noxious stimuli with the tactile stimuli was found, on average, to elevate threshold amplitude by 2.2 times (6.7 dB). Co-localized, cold-induced pain raised the average thresholds by about 1.5 times (3.6 dB). Heat-induced pain presented contralaterally produced no change in vibrotactile sensitivity indicating that the effect is probably not due to attentional mechanisms. Ipsilateral heat-induced pain caused an elevation in tactile thresholds even when the noxious and non-noxious stimuli were not co-localized, and the effect may seem to require that the painful stimulus be within the somatosensory region defined possibly in terms of dermatomal organization. Thus the effect is probably related to somatotopic organization and is not peripherally mediated. A brief discussion as to the possible locus of the touch gate within the nervous system is also given.     

The effects of stimulus location on the gating of touch by heat- and cold-induced pain

The influence of heat- and cold-induced pain on tactile sensitivity, a "touch gate", was measured under conditions in which the location of the noxious stimuli was varied with respect to the tactile stimulus applied to the thenar eminence of humans. Vibrotactile thresholds were measured in the absence of pain and during administration of a painful stimulus, with the stimulus frequencies selected to activate independently the four psychophysical channels hypothesized to exist in human glabrous skin. Heat-induced pain produced by spatially co-localizing the noxious stimuli with the tactile stimuli was found, on average, to elevate threshold amplitude by 2.2 times (6.7 dB). Co-localized, cold-induced pain raised the average thresholds by about 1.5 times (3.6 dB). Heat-induced pain presented contralaterally produced no change in vibrotactile sensitivity indicating that the effect is probably not due to attentional mechanisms. Ipsilateral heat-induced pain caused an elevation in tactile thresholds even when the noxious and non-noxious stimuli were not co-localized, and the effect may seem to require that the painful stimulus be within the somatosensory region defined possibly in terms of dermatomal organization. Thus the effect is probably related to somatotopic organization and is not peripherally mediated. A brief discussion as to the possible locus of the touch gate within the nervous system is also given.     

Muscle sympathetic nerve responses to physiological changes in prostaglandin production in humans.

Previous studies suggest that prostaglandins may contribute to exercise-induced increases in muscle sympathetic nerve activity (MSNA). To test this hypothesis, MSNA was measured at rest and during exercise before and after oral administration of ketoprofen, a cyclooxygenase inhibitor, or placebo. Twenty-one subjects completed two bouts of graded dynamic and isometric handgrip to fatigue. Each exercise bout was followed by 2 min of postexercise muscle ischemia. The second exercise bouts were performed after 60 min of rest in which 11 subjects were given ketoprofen (300 mg) and 10 subjects received a placebo. Ketoprofen significantly lowered plasma thromboxane B(2) in the drug group (from 36 +/- 6 to 22 +/- 3 pg/ml, P < 0.04), whereas thromboxane B(2) in the placebo group increased from 40 +/- 5 to 61 +/- 9 pg/ml from trial 1 to trial 2 (P < 0.008). Ketoprofen and placebo did not change sympathetic and cardiovascular responses to dynamic handgrip, isometric handgrip, and postexercise muscle ischemia. There was no relationship between thromboxane B(2) concentrations and MSNA or arterial pressure responses during both exercise modes. The data indicate that physiological increases or decreases in prostaglandins do not alter exercise-induced increases in MSNA and arterial pressure in humans. These findings suggest that contraction-induced metabolites other than prostaglandins mediate MSNA responses to exercise in humans.