Muscle hyperalgesia in postexercise muscle soreness assessed by single and repetitive ultrasound stimuli

Muscle Hyperalgesia in Postexercise Muscle Soreness Assessed by Single and Repetitive Ultrasound Stimuli Prem Bajaj, Thomas Graven-Nielsen, Anthony Wright, lolo ab lthel Davies, and Lars Arendt-Nielsen

Abstract: This study hypothesized

the presence of muscle hyperalgesia and central hyperexcitability in postexercise muscle soreness (PEMS). PEMS was induced by standardized eccentric exercise of the first dorsal interosseous (FDI) muscle of the right hand using a newly designed hand exerciser. The left-hand FDI served as a control. Concentric maximum voluntary contraction, pressure pain threshold (PPT), pain threshold to a single ultrasonic stimulus (USl), and pain summation threshold to a 2 Hz train of five ultrasonic stimuli (US5) were used to assess the FDI. Measurements were performed at intervals up to 48 hours after exercise. The PPT in the test hand was minimum after 24 hours. US1 was not significantly different in the test and control hands at any time before or after the exercise, whereas US5 was significantly lower than control after 24 hours (P = .03). Facilitation of the temporal summation pain threshold, calculated as a ratio between US1 and US5, was maximum at 24 hours compared with the control hand (P = .005). This indicates that temporal summation was facilitated as a component of the muscle hyperalgesia and the ultrasonic stimuli can be used as a noninvasive method to determine central mechanisms of muscle hyperalgeisa. Key words: Eccentric exercise, muscle hyperalgesia, postexercise muscle soreness, pressure pain threshold, ultrasound stimulation, temporal summation.

ostexercise muscle soreness (PEMS) is a symptom that is usually present after eccentric exercise (lengthening contractions) and rarely after concentric exercise (shortening contractions).’ PEMS is described as a dull, aching pain associated with stiffness in response to motion or palpation. *s3 Hyperalgesia (primary or secondary) has been defined as an altered state of sensitivity characterized by a decrease in pain threshold and an increase in perceived pain intensity induced by suprathreshold stimuli. Central hyperexcitability is manifested as increased spontaneous impulse discharges, increased responsiveness to nociceptive and nonnociceptive peripheral stimuli, and expanded receptive fields of dorsal horn nociceptive neurons.4,5 Hyperexcitability of dorsal horn neurons

P

Received November 29, 1999; Revised January 14, 2000; Accepted January 14, 2000 From the Laboratory For Experimental Pain Research, Center for Sensory-Motor Interaction (SMI), Aalborg University, Denmark; the School of Medical Rehabilitation, University of Manitoba, Canada; and the School of Pharmacy, The Queen’s University of Belfast, Northern Ireland. Supported in part by the Danish National Research Foundation. Address reprint requests to Prem Bajaj, MBBS,.MPM(UK), FCGP, MMEDSCI(UK), Center for Sensory-Motor Interactron, Aalborg University, Frederik Bajers Vej 7 D-3, DK-9220, Aalborg 0, Denmark. E-mail: [email protected] 0 2000 by the American Pain Society 1526-5900/00/0102-0007$8.00/O doi:10.1054/xb.2000.6061

The

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develops in animals following noxious stimulation of muscle and deep tissues.6-g Studies with experimental pain models in humans are also suggestive of involvement of central pain mechanisms in muscle hyperalgesia.lO,” Temporal summation causes exaggerated pain perceptions in humans and results from repetitive noxious stimulation. Temporal summation in humans has been measured by pain perception/tolerance thresholds and nociceptive withdrawl reflex.‘* Arendt-Nielsen et all3 studied temporal summation in cutaneous hyperalgesia and found that the summation pain thresholds to repetitive laser and electrical stimuli were reduced compared with single laser and electrical stimuli. ArendtNielsen et allo also proposed that central hyperexcitability can facilitate temporal summation. Moreover, drugs that reduce central hyperexcitability, for example, N-methyl D-aspartate (NMDA) antagonists have been shown to be effective in reducing facilitated pain caused by repetitive nociceptive stimuli in healthy humans.14-16 Temporal summation has been shown experimentally in firbromyalgia patients by the presence of facilitated pain to repetitive muscle pain stimuli and not to a single stimulus compared with controls.17 Fibromyalgia patients also have been shown to obtain significant pain relief in response to intravenous ketamine (an NMDA-antagonist).18,1g 2 (Summer),

2000;

pp 111-121

111

Figure 1. Illustration of the hand exerciser: (A) adjustableheight platform, (B) index finger splint, (D) pulley system, (0) oaenina for flexina finaers, (w) weiuhts. (F) foot medal, and (i) sprkg. (B’) Enikgei vikk bf the fin&r split-k showing placements of bearings underneath it.

Because of the easy accessibility of the skin, underlying mechanisms of superficial tissue hyperalgesia are widely studied in humans. Recently, ultrasound stimuli have been used as a noninvasive method to study temporal summation of cutaneous, muscle, and joint pain.20,21 No studies to date have investigated if temporal summation is facilitated in PEMS in healthy volunteers. The showing of changes in ultrasonic temporal summation pain thresholds might elucidate the role of central hyperexciability in PEMS. It is likely that pressure pain thresholds will express the degree of sensitization of nociceptors following the release of sensitizing substances caused by tissue damageZ2 or the central factors contributing to changes in pressure thresholds.17,23 Therefore, the presence of similarities between the time course of ultrasonic temporal summation pain thresholds, pressure pain thresholds and PEMS might elucidate the role of peripheral and central components of muscle hyperalgesia in PEMS. The aim of this study was to assess muscle hyperalgesia in PEMS by single and repeated (temporal summation) ultrasound stimuli and by measurement of pressure pain thresholds. The results from this study have been previously presented in abstract form.24

Material and Methods Subjects Twelve students from Aalborg University participated in the study; 11 were males and 1 was female. The students were aged 24.8 +- 4.3 years;

height 175 f 3 cm; weight 71.5 f. 4.1 kg (mean + S.E.M.). All the students signed an informed consent form and could withdraw from the experiment at any time. They did not participate in any unaccustomed exercise or intake of any drug, alcohol, or coffee during the experiment. Coffee was avoided because of the caffiene content,25 which might act as an antinociceptive agent and interfere with muscle functioning during fatigue.26-28 All subjects were healthy and had no past history of any neuromuscular or orthopedic disorder of the upper extremities. All the subjects were right-handed (test hand), and their left hand served as a control hand. The study was conducted according to the 1975 Declaration of Helsinki and was approved by the local ethics committee. The same examiner (PB) assessed the subjects at all times before and after exercise. Subjects received monetary compensation for their participation in the study.

Hand

Exercise

Apparatus

The hand exerciser (Fig 1) consisted of an adjustable height platform (A) with an opening (0) for flexing the third, fourth, and fifth fingers, and a custom-fitted splint for the index finger (B). Ball bearings were located underneath the splint (B‘) to reduce surface friction. The weights were connected to the splint by a wire and a pulley system (D). Another wire connected the same weights to a foot pedal (F). The weights were adjusted to the specific requirements for each subject. The subject sat beside the apparatus in a comfortable chair. The right hand was placed palm down on the platform with the upper arm abducted at a right angle and the elbow flexed to 90”. The arm, wrist, forearm, and elbow were strapped to the exerciser and the last 3 fingers were fully flexed in an opening in the table to minimize the cocontraction from extensors and palmar interossei muscles. The index finger was strapped in the finger splint. The first dorsal interosseous muscle (FDI) was held at maximum length by fixing the thumb at an angle nearly 90”.

Induction

of PEMS

After positioning the hand, the subject was asked to press the foot pedal to avoid any load on the FDI during the first step (ie, concentric contraction) when the index finger was brought into the fully abducted position. The examiner then gradually added increasing weights (100 to 300 g at a time) to the pulley. The subject then released the foot pedal and tried to resist the adduction movement of the finger produced by the weights (lengthening contraction or eccentric exercise). The weight at which the FDI could

ORIGINAL REPORT/Bajaj et al

not resist any adduction without any special effort was recorded as the concentric maximum voluntary contraction (MVC) weight. A total of 125% MVC weight was then added to the pulley for performing the eccentric contractions. For those subjects who were unable to bear this weight, the exercise was carried out with lesser weights than 125% MVC. To perform the eccentric exercise, the subject pressed the foot pedal and fully abducted the right index finger. On receiving a signal, he/she released the foot pedal and simultaneously resisted any adduction movement of the finger. The finger was allowed to come back to the neutral position over approximately 5 seconds (timed with a stopwatch). This process was continued repetitively by alternately pressing and releasing the foot pedal until the finger could not resist adduction and had fatigued. Following a rest for approximately 1 minute, the second bout of eccentric exercise was performed. Each subject carried out a total of 6 such bouts of exercises.

Pressure Pain Thresholds (PPT) Hyperalgesia was defined as a reduced pain threshold intensity to pressure algometry. 22,2g,30 A hand-held electronic pressure algometer (Somedic AB, Farsta, Sweden) with a probe of 1 cm2 diameter was used. Pressure pain threshold was measured in kilopascals (kPa). The probe was pressed at a point marked on the FDI (the point of intersection of perpendicular lines drawn at the level of the junction of the proximal one third and the distal two thirds of the first and second metacarpal bones, corresponding to the center of the FDI). A constant rate of pressure increase (30 kPa/sec) was applied until the subject pressed a button indicating the point where the pressure was first perceived as painful, that is, the pressure pain threshold (PPT). Three PPT measurements were taken and the mean value of the 3 was considered as the PPT.

Ultrasonic Stimulation The ultrasound generator consisted of 4 main components; a LabView (National Instruments, Austin, TX) control system, a function generator, an RF power amplifier and a focused piezoceramic transducer. The function generator (Phillips) produced 1.66 MHz sine-wave signals, which were used as an input to the broadband power amplifier (ENI, Rochester, NY). The duration, repetition and amplitude of sinewave signals from the function generator were modified using a LabView (National Instruments) software based control system specifically developed for this purpose. The output signal from the power

113

amplifier was applied to a focused piezoceramic transducer (1.66 MHz) (The Queen’s University of Belfast, Belfast, Northern Ireland, UK). The amplitude of the 1.66 MHz signal was varied from 0 to 1 arbitrary units (AU). The ultrasound transducer had a diameter of 5 cm and a focal length of 4 cm. A water-filled standoff attachment was placed above the ultrasound transducer and positioned so that the focal region of the beam would project in the FDI area. The thenar eminence was placed over the opening in the standoff, ensuring that the skin was always in contact with the water. The focal region of the beam was directed towards the center of the FDI and its position was adjusted up or down until the stimulus elicited a deep-seated diffuse pain, characteristic of muscle pain. Because the beam was focused in the tissues between the first and the second metacarpal bones, the ultrasound beam possibly elicited pain from deep tissues other than the periosteum. The duration of each ultrasonic stimulus (US) was fixed at 50 milliseconds and the interstimulus interval for each train of 5 stimuli was set at 500 milliseconds in accordance with earlier studies.21 This corresponded to a stimulus rate of 2 Hz. Ultrasound pain threshold was defined as the lowest stimulus intensity (AU) for a single stimulus (US’l) which evoked pain in the FDI. The temporal summation pain threshold was defined as the stimulus intensity causing the fifth stimulus in a train of 5 stimuli (US5) to be painful.‘O The intensity of the ultrasonic stimuli was increased in regular, prefixed steps (0.02 AU) until pain threshold was reached. Then using a staircase procedure that combines the up-down trials of the method of limits with the method of adjustment, intensity was varied to determine pain thresholds.31 The procedure was repeated to determine the minimum intensity required to elicit just noticeable clear and distinct pain. The pain threshold was calculated as the mean of the 3 readings for US1 or US5. Facilitation of temporal summation was calculated as the ratio between US1 and US5 before, immediately after, 24 hours after, and 48 hours after exercise in the test and control hands.

Study Protocol The first session consisted of preexercise assessments and eccentric exercise training. During the training the subjects were introduced to the use of the hand exerciser. Preexercise sensibility assessments were made by recording the PPT, USI, and US5 at the site corresponding to the center of the FDI. This site on FDI remained marked on each subject during the study period. During the second session, the concentric MVC

Mimic

114

Hyperalyesid

700 1

500 i s 400 4 c’ k 300 200 100 0

I

I

Pre-exer

lmm-after

24 h

7

48h

Time Figure

2. Time course of changes in PPT (mean * S.E.M; n = 12) in the test and control hand FDI before cise. * Indicates a significant difference between test hand compared with the control hand (Wilcoxon, nificant difference as compared with before exercise in the test hand (Friedman, P = 0.01; SNK, P < .05).

weight for the FDI was determined and the subject performed eccentric exercise on the hand exerciser. Immediately, 24 hours, and 48 hours after the exercise all sensory assessments were repeated using the same procedures as in the first session.

Statistical Analysis The data are expressed as means 1 S.E.M. The data were not suitable for analysis using 2-factor analysis of variance (ANOVA), because a majority of values could not pass the Kolmogorov-Smirnov nomality test. Accordingly, the nonparameteric Friedman’s test of variance (Friedman) was used. Significant results were further analysed using the nonparameteric Student-Newman-Keuls test (SNK) for multiple comparisons. The Wilcoxon signed rank test (Wilcoxon) also was used to compare paired samples. Spearman’s rank order correlation test was applied to measure the strength of correlation between ultrasonic pain thresholds and PPT. Significance was accepted at P < .05.

Results Eccentric Exercise Data The mean MVC of the finger in the fully abducted position was 1.61 f 0.12 kg and the weights selected for exercise were 1.87 f 0.11 kg (118% * 4 % of MVC weight). The endurance time for the 6 eccentric exercise bouts was 10.8 f

1 .I6 minutes and the number formed were 116.2 * 7.7.

and after eccentric P < .05). + Indicates

exera sig-

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per-

Pressure Pain Threshold The PPT was not different between the test and control hand before exercise. In the control hand, the PPT was not significantly decreased after exercise compared with that before exercise at all times (Fig 2). In the test hand, the PPT was reduced immediately 24 hours after, and 48 hours after exercise as compared with that before exercise (Friedman, P = .Ol; SNK, P c .05) and also when compared with the control hand (Wilcoxon, P < .04). PPT was also significantly reduced in the test hand at 24 hours and 48 hours as compared with immediately after exercise (SNK, P < .05).

Ultrasonic Stimulation US1 was not significantly different between test and control hands before and after the exercise. In the control hand, US1 was not decreased after the exercise compared to before the exercise (Fig 3). In the test hand, US1 was reduced immediately 24 hours after, and 48 hours after exercise compared with before the exercise (Friedman, P = .017; SNK, P < .05). Compared with the control hand, US5 in the test hand was significantly decreased immediately after and 24 hours after the exercise (Wilcoxon, P = .03) (Fig 3). In the test hand, US5 was significantly reduced immediately after and at 24 hours after as compared with before exer-

ORIGINAL REPORT/Bajaj et al

115

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.

Pre-exer

24 h

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b

48h

Time Figure

3. Time course changes of US1 and US5 in the test and control hands. compared with the control hand (Wilcoxon, P < .05). + Indicates a significant after exercise (Friedman, P < ,001; SNK, P < .05).

cise (Friedman, P = .Ol; SNK, P < .05). In the control hand, US5 was significantly reduced at 48 hours after exercise as compared with before exercise time (Friedman, P = .049; SNK, P < .05). The temporal summation ratio (USl/USS) was significantly higher in the test hand immediately after and at 24 hours after exercise as compared with the control hand (Wilocxon, P c .Ol) (Fig 4). In the test hand, the temporal summation ratio was also significantly higher immediately after and at 24 hours after compared with before exercise (Friedman, P = .lO; SNK, P c .05). In the control hand, there was an increased USl/US5 ratio over time (Friedman, P = .049), but no increase within session could be identified by the SNK method (Fig 4). There was a positive correlation between US1 and PPT in the test hand (R = 0.44; P = .002) and in the control hand (R = 0.35; P = .02). There was also a positive correlation between US5 and PPT in the test hand before and after exercise (R = 0.36; P = .Ol> (Fig 5). There was no significant correlation between US5 and PPT in the control hand (R = 0.2; P = 0.17). As shown in Fig 6, there was a negative correlation

* indicates decrease

a significant compared

difference between test hand with preexercise and 48 hours

between temporal summation ratio (USl/US5) and PPT in the test hand (R = -0.31; P = .03), but no correlation in the control hand (R = -0.14; P = .34).

Discussion For the first time, the present results show facilitation of temporal summation to noninvasive, repeated ultrasonic stimulation applied to the FDI after PEMS. Time course changes in PPT, USI, US5, and USl/US5 ratio suggest that PEMS might be caused by the combined effect of peripheral sensitisation and central hyperexcitability (facilitated temporal summation). Moreover, the correlation between the temporal summation pain threshold and PPT suggests a relationship between temporal summation and hyperalgesia due to PEMS.

PEMS The time course changes of the PPT in the present study showed that PEMS started immediately after the exercise and increased further at

116

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Time Figure 4. Time course of the temporal summation effect (USlAJS5) before and after eccentric exercise. USlIUS5 is significantly elevated at 24 hours after exercise in the test hand as compared with the control hand. (*Wilcoxon, P c .05). ). + Indicates a significant difference between preexercise and postexercise times in the test hand (SNK, P < .05).

24 and 48 hours. These results are consistent with the time course of soreness reported in PEMS studies on other muscle groups.32-34 However, some previous studies found no muscle soreness immediately after the eccentric exercise of elbow flexors, but a significant soreness at 24 to 48 hours.30 Smith et al35 and Teague and Schwane 36 also reported a significant increase in soreness at 24 and 48 hours in chest and elbow muscles respectively, but they did not measure soreness immediately after the eccentric exercise. Nussbaum and Gabison30 showed that PPT was at a minimum at 24 hours in the elbow flexors after eccentric exercise. Some variation in the results of the present study compared with the earlier studies might be caused by differences in the type of apparatus used for eccentric exercise and differences in the muscles involved in PEMS generation. Typically, muscles affected by eccentric exercise damage tend to have a high percentage of type II or fast-twitch fibers.37 Garrett et al37 suggested that these muscles might be predisposed to injury because of the intrinsic properties of type II fibers themselves. In the present study, it was possible to induce soreness in the FDI of the hand, which has a predominantly type I fiber content.38 Thus, it is possible that factors other than type II muscle fiber content are responsible for muscle damage following eccentric exercise. Armstrong* and Asmussen3g suggested that PEMS associated with eccentric exercise is probably caused by damage of muscle or connective tissue caused by overloading of these tissues.

Others have suggested inflammation as a cause of PEMS.30,40 Pressure applied by an algometer has been shown to first activate group II (AO) afferent cutaneous mechanoreceptors and, as the pressure is increased, group III (Ah) mechanoreceptors as well as group IV (C) polymodal nociceptors.41-43 In the present study, the reduced PPT immediately after the exercise might be a manifestation of muscle injury initiated by the mechanically induced cellular damage in the muscle caused by the high forces developed during eccentric exercise. Other factors, such as release of neuropeptides from nociceptors and sensitizing substances from muscle tissues caused by ischemia and/or low pH also are shown to be playing role in causing the muscle damage during the exercise in humans44-48 and animals.4g Further reduction in PPT at 24 to 48 hours could be caused by a secondary inflammatory process.50 Hellsten et a150 showed that within hours of eccentric exercise of quadriceps muscle there was an increase in plasma interleukin-6 (IL-6), indicating an onset of inflammation. They further proposed that IL-6 enhanced the xanthine oxidase levels in leucocytes infiltrating the muscle, which could injure tissues in the near vicinity by generation of reactive oxygen free radicals. 5o In addition, the current study suggests the involvement of central mechanisms in PEMS, as shown by facilitation of temporal summation. There appears to be a tendency of reduction in PPT in the control hand after the exercise, which might be an effect of the repeated noxious stimuli caused by the

ORIGINAL

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repeated measurements. Recently, Ray et a151 have shown that exercising one limb has an effect on the nonexercising limbs. In the present study, an addition of less than 20% weight to the MVC weight of FDI was sufficient to induce muscle soreness that was still present 48 hours after exercise. Teague and Schwane3‘j induced significant pain in the elbow flexor muscles using submaximal forces (60% MVC) that were repeated with a rest interval of up to 10 minutes between each contraction. In the present study, the exercise time was 10.8 + 1.16 minutes compared with extensive exercises performed for longer time periods in earlier studies.52-56 The fact that this eccentric work of short duration could induce soreness lasting for up to 48 hours suggests a disruptive nature of eccentric exercise and shows the effectiveness of this new model to induce muscle pain. Presently, isokinetic dynamometers are the most commonly used method to undertake eccentric exercise,57 but they are expensive, and the exercises performed (against fixed rates of constant resistance) are quite different from activities of daily life or sports activities.

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The current study is the first to show the presence of muscle hyperalgesia by a noninvasive method of repetitive ultrasonic muscle stimulation in PEMS. Previously, ultrasonic stimulation has been used to induce muscle pain in healthy subjects21,58 and has been used for analgesic testing in animals. 5g,60 The correlation of temporal summation of ultrasound stimuli and PPT suggests that the use of noninvasive focused ultrasound might serve as a new method of algometery for human pain studies. In the present study, as in Yanaura et al,61 no volunteers suffered from any side effects caused by ultrasonic stimuli. Pain in response to ultrasound is probably caused by the vibration effects of the ultrasonic waves. Davies et al62 reviewed the application of focused ultrasound for pain research and concluded that the main action of US waves was similar to the action of vibrations at the receptor structures. Pacinian corpuscles are responsible for perception of vibrations and these receptors are found in subcutaneous tissue, tendons and fascia of muscles, on the periosteum, and in joint capsules.63 Gavrilov et al64 have shown that Pacinian

Muscle

118

corpuscles were excited when stimulated with ultrasound. However, other receptors might also be recruited at higher stimulus intensities, and further research is required to determine which type of nociceptors might be involved in the pain evoked by ultrasonic stimulation

Temporal Summation Earlier studies have shown temporal summation in muscle by the use of intramuscular electrical stimulationlo and ultrasonic stimulation2’ in healthy individuals. Moreover, it has been suggested that temporal summation is probably caused by a central mechanism,14-l6 and it has been proposed that central hyperexcitability can facilitate temporal summation.1° In the present study, there was a correlation between ultrasonic temporal summation threshold and PPT in the test hand; it may be assumed that the facilitation of temporal summation seen was specifically caused by mechanisms associated with PEMS. Temporal summation has been shown to be facilitated in cutaneous secondary hyperalgesia induced by capsaicin.13,14,65 Sorensen et all7 used intramuscular electrical stimulation in fibromyalgia patients and also found facilitated temporal summation in this disorder with widespread pain.66 Facilitation of temporal summation in the present study was probably caused by the persistent barrage of nociceptive inputs from the damaged tissue after the eccentric exercise, resulting in hyperexcitability of spinal neurons. Myositis-induced functional reorganization of dorsal horn neurons (central hyperexcitability) has been shown after noxious stimulation of muscle and deep tissues6f8 Others have shown that tonic activity of nociceptive C-fibers after tissue injury and inflammation results in hyperexcitability of dorsal horn neurons.5,17,67 Weng et a160 studied the AB fiber-evoked responses of the knee flexor and foot plantar reflexes from cutaneous stimulation in normal and arthritic rat. Potentiation of the magnitude of the knee flexor reflex progressively increased for repetitive electrical stimulation of AB fibers only in the arthritic rat. The effect, was inhibited by the y-

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aminobutyric acid-A (GABA,) receptor antagonist, (+)bicuculline. They proposed that Aj3 fiber wind-up is a GABA,-mediated mechanism.68 However, the relationship between wind-up and temporal summation is not fully understood. In the present study, the temporal summation ratio (USlNS5) was significantly facilitated immediately after and at 24 hours after eccentric exercise in the test hand. This study also showed a correlation of temporal summation threshold (US5) and temporal summation ratio (USl/USS) with PPT in the test hand. This suggests that temporal summation and muscle hyperalgesia after eccentric exercise are related. The present study also suggests that FDI damage caused by eccentric exercise might firstly result in peripheral muscle hyperalgesia as evidenced by reduced PPT and this is then followed by central hyperexcitability that contributes to facilitation of temporal summation of ultrasonic stimuli in the FDI. The present postexercise soreness model induced muscle hyperalgesia with a peripheral and central components. Ultrasonic stimulation can be used as a noninvasive method to test muscle hyperalgesia. Unlike PPT, the ultrasonic stimulation could eliminate the influence of examiner as it is delivered from the transducer, which is not held by the examiner. Moreover, this study shows that the pain threshold assessments by ultrasonic and pressure algometer correlated with each other. However, the reliability of the study might be improved by repeating the study in such a way that the examiner is blind in regard to which hand received exercise. Postexercise soreness causes stronger facilitation of repeated rather than single ultrasonic stimulation, indicating a relation between muscle hyperalgesia and the mechanisms involved in temporal summation of muscle pain.

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