The pain threshold of high-threshold mechanosensitive receptors subsequent to maximal eccentric exercise is a potential marker in the prediction of DOMS associated impairment
The pain threshold of high-threshold mechanosensitive receptors subsequent to maximal eccentric exercise is a potential marker in the prediction of DOMS associated impairment
Johannes Fleckenstein 1
Matthias KoÈ nig 0 1
Lutz Vogt 1
Winfried Banzer 1
Editor: GaeÈl Guilhem
0 Sport and Exercise Science Research Centre, School of Applied Sciences, London South Bank University , London , United Kingdom , 4 Institute of Movement and Sport Gerontology, German Sport University Cologne , Am Sportpark MuÈ ngersdorf 6, Cologne , Germany
1 Department of Sports Medicine, Institute of Sports Sciences, Goethe-University Frankfurt , Frankfurt am Main, Germany , 2 Department of Sports Medicine, Johannes Gutenberg-University Mainz , Mainz , Germany
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: This study was funded in part by a grant
by the Vereinigung von Freunden und FoÈrderern
der Goethe-UniversitaÈt [Association of friends and
sponsors of the Goethe-University Frankfurt]
awarded to JF assuring independent research and
publication of the data.
Competing interests: The authors have declared
that no competing interests exist.
Twenty volunteers (9 female and 11 male, age 25.2 ± 3.2 years, weight 70.5 ± 10.8 kg,
height 177.4 ± 9.4 cm) participated in the study. DOMS reduced the PPT (at baseline 5.9 ±
0.4 kg/cm2) by a maximum of 1.5 ± 1.4 kg/cm2 (-24%) at 48 hours (p < 0.001). This
correlated with the decrease in MIVF (r = -0.48, p = 0.033). Whereas subjective pain was an
indicator of the early 48 hours, the PPT was still present after 72 hours (r = 0.48, p = 0.036).
Other mechanical thresholds altered significantly due to DOMS, but did show no clinically or physiologically remarkable changes.
Functional impairment following DOMS seems related to the increased excitability of highthreshold mechanosensitive nociceptors. The PPT was the most valid mechanical threshold to quantify the extent of dysfunction. Thus PPT rather than pain intensity should be considered a possible marker indicating the athletes' potential risk of injury.
Delayed Onset Muscle Soreness (DOMS) has been subject to many studies investigating
mechanism or treatments in exercise-related muscle pain, [
] and is a common state in elite and
recreational athletes [
]. Mechanically-induced microtraumata, i.e. grade 1 muscle strain injuries,
result in the perception of muscle soreness associated with pain and weakness [
symptomology should be restricted to dull pain and discomfort, manifesting itself usually 6 to 12
hours and peaking 48 to 72 hours post-exercise [
]. Often, people go to bed with mild
discomfort and wake up the next morning with severe pain . Longer lasting impairment and
muscular dysfunction may be a consequence of DOMS [
]. Generally accepted epidemiologic
data regarding its incidence and prevalence is missing.
The physiological basis of muscle contraction and damage draws upon the relationship
between force, speed and tension in a muscle fibre. Constant velocity lengthening produces a
complex tension record, leading to a continued increase in tension throughout a given
]. Beyond the plateau of the length tension curve, stretching the muscle works
non-uniformly, elongating the weakest sarcomeres first, which are those with the smallest number of
]. As a consequence, disturbances of the cross-striated band pattern of the
sarcomere can be observed. Biopsies taken after repetitive eccentric muscle actions have revealed
broadening, streaming, and at times, total disruption of Z-discs [
]. Eccentric exercise led to a
dramatic change in the arrangement of the t-tubule network and the disposition of the triads,
which is thought to be a primary reason for disorders of the membrane systems involved in
excitation-contraction coupling failure [
]. Microscopic disruptions are also thought to lead to
other damaged cell membranes and, therefore, a loss of intracellular calcium homeostasis [
Several inflammatory processes are initiated, which in turn lead to fiber damage and cell death
]. Exercise induced muscle damage (EIMD) is variable in severity in muscles with different
architecture, and is exacerbated by inflammation after the initial injury [
Still, the debate about why this pathophysiologic response mediates pain remains
controversial. There is no doubt that excessive exercise, triggered by frequency or load, can be painful
]. However, there is no consensus regarding the origin of pain. From a clinical point of
view, this understanding is crucial in order to choose adequate preventive and rehabilitative
Whereas some researchers suggest e.g. muscular fascia to cause pain [
], others showed
the presence of cutaneous allodynia [
]. Whilst muscular fascia would just need to induce
local nociceptors (peripheral sensitivity), it is also conceivable that both observations are the
result of an increased spinal sensitivity [
]. In addition, the breakdown products of the
impaired muscle tissue excites nociceptors. Specifically, the transient receptor potential
channels of the vanilloid type TRPV1 and acid sensing ion channels ASICs have been suggested to
play a central role in the processing of the stimuli [
]. In combination with an augmented
mechanical response in muscle thin-fibre sensory receptors [
], these neurophysiological
observations could be related to muscle tenderness and soreness.
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Pain is initiated through the activation of nociceptors by noxious thermal, mechanical and
chemical stimuli [
]. There are two classes of nociceptors, myelinated Aδ fibres that mediate
acute, well-localized ªfirstº or fast pain, and unmyelinated C fibres mediating poorly localised,
ªsecondº or slow pain [
]. Whereas C-fibres develop mechanical sensitivity only in the setting
of injury [
], Aδ nociceptors also respond to chemical and thermal as well as mechanical
stimuli. A nociceptor response is primarily linked to the occurrence of a tissue injury, and can be
considered at least partially as the result of modification of the extracellular milieu by
intracellular contents released from injured cells, such as protons, potassium ions or ATP [
]. On the
muscular cellular level, almost half of the muscle fibres present low threshold
mechanosensitive units (LTM, on Aδ fibres) which respond to weak stimuli such as deformation of the
muscle tissue and fascia [
]. They have been implicated as the primary afferents transmitting
signals to or maintaining sensitization of wide dynamic range neurons [
] which are likely
involved in deep, spread and referral pain. Muscle nociception is supposed to involve
highthreshold mechanosensitive receptors (HTM, on C and Aδ-fibres). Their membrane may be
equipped with transient receptor potential channels that seem to play pivotal roles in the
processing of the stimuli [
16, 24, 25
]. Other candidates of mechanotransducers include members
of the degenerin/epithelial Na+ channel (DEG/ENaC) families, involving above mentioned
]. Hoheisel et al. showed that the activation of these HTM units is pressure
dependent and requires a certain pressure threshold to be exceeded [
]. The receptors are supposed
to be first hyper-sensitized by chemical mediators like bradykinin and prostaglandin-2, and
secondly to be activated by the increased interstitial pressure caused by the development of
intramuscular swelling due to DOMS-related oedema [
]. Once activated, the pain signal is
transduced by the activation of a variety of voltage-gated ion channels, with the critical role of
sodium and potassium channels to convey the signal to the dorsal horn [
]. The signal is
mediated to the CNS, place of the sensory, emotional and affective assessment, leading to
enhanced processing of nociceptive messages . In persistent pain, it is assumed that the
mechanism of peripheral sensitisation results in alteration in the properties of peripheral
nerves. This second phase of pain results from inflammation-associated changes in the
chemical environment of the nerve fibres [
]. An important role has been contributed to the nerve
growth factor NGF, producing hypersensitivity to heat and mechanical stimuli via two
temporally distinct mechanisms. First, the sensitivity of the nociceptor is changed, as target proteins
functionally potentiate at the peripheral nociceptor terminal; most notably TRPV1, leading
to a rapid change in cellular and behavioural heat sensitivity [
]. In addition to this first
response, NGF promotes increased expression of pro-nociceptive proteins in the nucleus of
the nociceptor (for review [
]). Together, these changes in gene expression enhance
excitability of the nociceptor and amplify the neurogenic inflammatory response.
To investigate different mechanical pain thresholds, standardised methods of quantitative
mechanical sensory testing have been established [
], allowing to distinguish cutaneous
perception (A-beta fibres assessed with thin filaments) from superficial (LTM-evoked, A-delta
fibre mediated hyperalgesia to pinprick stimuli) or deep tissue nociception (HTM evoked,
Cand A-delta fibre mediated pain to pressure). The present study has been designed to test the
hypothesis if the HTM units represent the primarily involved nociceptor in DOMS.
A single-centre, randomised study at the Sports Campus, Goethe-University Frankfurt to
investigate mechanical pain and detection thresholds of the non-dominant biceps brachii
muscle following DOMS in healthy adults. Participants were assessed for study eligibility using the
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following exclusion criteria: DOMS within last 7 days, pregnancy and lactation, severe illness
limiting physical or psychological health, and frequent intake of analgesics. Participants signed
a written informed consent to participate in the study, which has been approved by the Ethics
Committee FB05 of the Goethe University of Frankfurt, Germany (reference 2015±157) and is
in agreement with the Declaration of Helsinki (Version Fortaleza 2012). After enrolment,
participants were subsequently randomised to either Group 1 or Group 2. Groups differed
regarding the sequence of the threshold assessments, i.e.
Group 1: Mechanical Detection Threshold (MDT) ! Mechanical Pain Threshold (MPT) !
Pressure Pain Threshold
Group 2: Pressure Pain Threshold ! Mechanical Detection Threshold (MDT) ! Mechanical
Pain Threshold (MPT)
The rationale behind allocating the participants into two groups focuses on the possible
role of spinal pain inhibiting/enhancing mechanisms. The alternation of the sequence of
measures might reveal possible between-measure mechanism.
After the initial baseline measures, DOMS was induced and measures were repeated
immediately thereafter and every 24 hours, up to 72 hours post induction. The main outcome
measure was the PPT over the biceps muscle belly. Secondary outcome measures were the MDT
and MPT, the pain intensity as rated on a visual analogue scale (VAS), the pain perception as
assessed with the McGill-short form questionnaire and the maximum isometric voluntary
force (MIVF) of the elbow flexors. Participants were told not to exercise during participation
in the study and not to use DOMS alleviating treatments.
Participants were randomly assigned to one of the two study groups using the smartphone-based
application Certified True Randomizers (Integer Generator, Random.org, Dublin, Ireland).
Sample size estimation
Sample size was estimated using the software G Power (Version 3.15, University of DuÈsseldorf,
Germany). With α set at 5%, 18 participants are required to have 80% power to detect a
difference in pressure pain threshold of 11% from baseline between groups [
]. Taken a drop out
ratio of 10% into account, twenty participants were estimated to be included into the study.
Induction of DOMS
At baseline, DOMS of the non-dominant elbow flexors was experimentally induced adhering to a
standardised protocol [
]. All participants were seated at a preacher's bench (multi muscle
machine m3, Diagnos+,Schnell TrainingsgeraÈte GmbH, Peutenhausen, Germany), with the hand
in supination and with the upper arm, wrist, and shoulder fixed in a way allowing to perform
standardised, isolated and controlled biceps curls. Following a standardised warm-up exercise for
3 minutes, i.e. eccentric and concentric movements of the arm without loads, individual one
repetition maximum (1 RM; i.e., the maximum weight lifted with one concentric contraction), was
determined for the elbow flexors within a maximum of five trials by loading the dumbbell with
free weights in 0.5 kg increments. Participants were encouraged verbally to elicit their maximal
effort. Ninety percent of the concentric 1 RM was then used to provoke DOMS through eccentric
contractions. For this, the dumbbell was lifted by the experimenter, until the participant's elbow
was flexed approximately 120Ê, and the participant then had to lower the weight eccentrically
over a time span of 5 seconds, controlled by a typical metronome, until the elbow was extended
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(~0±5Ê). Participants completed a maximum of 6 sets, each comprising 5 repetitions and 2
minutes resting time between sets. The procedure was stopped if the participants could not control
lowering the weight in time more than twice in a row in two consecutive sets.
Demographics included height (in cm), weight (kg), level of activity (hours), time spent with
training (hours), etc.), as well as the previous experience of DOMS on a 4-fold Likert scale (1±
2 per year; monthly; weekly; >2 per week).
Mechanical Testing was performed according to the recommendations of the German
Research Network on Neuropathic Pain [
], comprising mechanical detection thresholds
(MDT), mechanical pain thresholds (MPT), and pressure pain thresholds (PPT). A
comprehensive summary of the mechanical measures of the somatosensory system has been described
]. Testing was performed at five equidistant points, perpendicular to the
individuals' belly of the biceps brachii muscle. On a thought line between the tuberositas radii and the
coracoid prominence, seven sections were determined by using a tape measure and dividing
the belly into seven sections. The beginning of the first (tendon) and the end of the last section
(insertion) were not considered being muscle points. Distance between points was according
to individual anthropometrical characteristics. Points were marked with a waterproof and skin
tolerant pen to ensure the same spots of measurement during the study, as previously reported
]. Testing always started proximally.
MDT was measured with a set of von Frey filaments, incrementing by a factor of 2 from
0.25 mN to 512 mN (Marstock-nervtest Ltd., Marburg, Germany). The geometric mean of 5
ascending and 5 descending series of stimuli (1-second duration per stimulus) generated the
mechanical detection threshold.
MPT was measured with a set of 7 weighted pinprick stimulators each with a blunt contact
area of 25 μm diameter (MRC Systems GmbH, Heidelberg, Germany) [
]. The intensity of
the punctate stimulators is incremented by a factor of 2 from 8 to 512 mN. The method of
limits was used to determine the intensity at which participants distinguished between prick and
The PPT was assessed with a mechanical pressure algometer (pdt, Rome, Italy; range 2±20
kg/cm2, diameter 1 cm). The algometer was applied to each of the above described points with
increasing force at a rate of approximately 1 kg/cm2 per second until the participant reported a
painful sensation and the force value was recorded (kg/cm2). We explained to each participant
to differentiate between tenderness and the feeling of pressure versus real pain. After the
muscle was investigated at all five points (from proximal to distant), the subjects were allowed to
rest for 5 min. This procedure was repeated a total of 3 times, following the protocol as
proposed by Park [
Maximum isometric voluntary force (MIVF) of the biceps muscle was measured using the
m3 (multi muscle machine; Diagnos+, Schnell TrainingsgeraÈte GmbH, Peutenhausen,
Germany) with the elbow flexed at 90Ê and pressing the wrist against a bar connected to a force
transducer (100 Hz sampling rate). Three trials were performed with contractions lasting 5
seconds, separated by 2 minute rest intervals. Participants were encouraged verbally to elicit
their maximal effort and force was displayed on a visual display in real time providing
immediate feedback. Peak force values (N) were recorded, and the highest of the three repetitions was
used for statistical analysis.
Pain intensity at rest and during active movement (flexion and extension) of the biceps
muscle was assessed using a visual analogue scale VAS ranging from 0 to 10 cm (with 0
indicating no pain and 10 experiencing the worst imaginable pain).
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Participants completed the Short Form McGill Pain Questionnaire (SF-MPQ) for
sensations experienced in the non-dominant biceps muscle. The SF-MPQ was adapted to German
language and we used ten sensory and four affective pain descriptors that could be ranked in
intensity from 0 = none to 3 = severe [
]. The sum of ranked values provides a sensory (SPRI;
0±30), an affective (APRI; 0±12) and a total pain score (TPRI; 0±42).
Statistical analysis was conducted for comparison of the main and secondary outcome
measures between the study groups. After testing for normal distribution, the following parametric
methods were used: 1) unpaired t-tests for the comparisons between both study groups and 2)
repeated measures analysis to analyse effects over time in the overall group. Sphericity of the
data was tested with Mauchly's test and if assumption of sphericity was been violated,
Greenhouse-Geisser was applied for correction. Post hoc tests to compare the different points in
time were done with paired t-tests. The Bonferroni test was applied to compensate for multiple
measurements (in total n = 6), with p < 0:605 = 0.0083 for intragroup analysis. Correlations were
calculated according to Pearson for parametric data. Demographic data are presented as
mean ± standard deviation and outcome measures as mean ± standard error of the mean. We
calculate the value of Cohen's d using the means and standard deviations of two groups to
estimate the effect size of the greatest change to baseline.
Data analysis was performed with the SPSS statistical software system, version 23.0 (SPSS
Inc., Chicago, IL, USA).
Twenty participants (9 female and 11 male, age 25.2 ± 3.2 years, weight 70.5 ± 10.8 kg, height
177.4 ± 9.4 cm) were included in the study (for details see Table 1). One dropout occurred at
the last visit (72 hours) due to scheduling conflicts.
DOMS was induced in both groups with no difference in eccentric load (Group 1:
10.8 ± 6.5 kg; Group 2: 9.3 ± 6.4 kg; p = 0.613). In both groups there was one subject being
exhausted after 5 sets, and all others completing the whole protocol. We found significant time
effects for all pain related outcome measures as well as for the MIVF, indicating that we had
been able to provoke the development of DOMS (see below, and S1 Table).
There were no significant differences as a consequence of the sequence of threshold
detection, nor depending on the sites of measure (see S2 Table). Therefore, data was pooled for the
Pressure pain threshold
The two-way repeated-measure ANOVA revealed a significant effect for time (F = 175.528
p < 0.001) but no time × sequence of pressure pain threshold assessment (F = 0.667 p = 0.43).
Post hoc test revealed significant decrease to baseline at 24 hours (paired t-test p = 0.002), at
48 hours (p < 0.001) and at 72 hours (p = 0.001; Fig 1A). The maximum change in PPT was
achieved at 48 hours: -1.5 ± 1.4 kg/cm2 (-24%; Cohen's d = 0.86).
Mechanical detection threshold
The two-way repeated-measure ANOVA revealed a significant effect for time (F = 7.980
p = 0.012) but no time × sequence of mechanical detection threshold assessment (F = 1.295
p = 0.27). Post hoc test revealed no significant differences to baseline (Fig 1B).
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All (n = 20)
Mechanical pain threshold
The two-way repeated-measure ANOVA revealed a significant effect for time (F = 110.707
p < 0.001) but no time × sequence of mechanical pain threshold assessment (F = 0.061
p = 0.81). Post hoc test revealed a statistical trend towards an increase to baseline at 48 hours
(-15.9 ± 82.9 mN; paired t-test p = 0.012; Cohen's d = 0.15; Fig 1C).
The pain intensity (VAS) during movement (F = 35.268 p = 0.001) and at rest (F = 14.913
p = 0.002) significantly increased over time with no differences between groups. ªPain at restº
was significantly increased comparing baseline to 24 and 48 hours (both p = 0.001) and when
comparing 72 to 24 hours (p = 0.002). Differences to baseline at 72 hours (p = 0.018), and
when comparing 24 to 48 hours (p = 0.015; Fig 1D) were not significant. ªPain during
movementº was significantly different to baseline at 24 and 48 hours (both p < 0.001) and at the
limit of the level of significance at 72 hours (p = 0.008; Fig 1E). The maximum pain intensity
during movement was 2.2 ± 1.4 cm VAS after 24 hours (Cohen's d = -2.1) and at rest 1.1 ± 1.2
cm VAS after 48 hours (Cohen's d = -1.2).
Mean isometric voluntary force
The two-way repeated-measure ANOVA revealed a significant effect for time (df1 F = 100.006
p < 0.001), but not for time × sequence for the assessment of mean isometric voluntary force (F =
0.701 p = 0.41; Fig 1B). The reduction of MIVF was close to significance at 48 hours (p = 0.012),
and significantly reduced at 24 (p < 0.001) and 72 hours (p = 0.004; Fig 1F) when compared to
baseline. The maximum decrease in force was -16.8 ± 21.1 N after 72 hours (Cohen's d = 0.72).
Correlation between mechanical sensory thresholds and pain intensity or voluntary force
Linking pain to mechanical thresholds indicated a correlation between the maximum change
in PPT and the respective change in pain intensity (r = 0.48, p = 0.036, Fig 2A). No correlations
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p = 0.012
Fig 1. A-C display the mechanical thresholds at baseline and 24, 48 and 72 hours after induction of DOMS. Mean change ± SEM of the PPT in kg/cm2 (A),
the MDT in mN (B) and the MPT in mN (C). D-F display pain and DOMS-related dysfunction. Mean change ± SEM of pain at rest (A) and during movement
(B) in cm VAS and maximum isometric voluntary force (C). Black lines with p-values indicate the post-hoc tests between two times in case that repeated
measures ANOVA detected significant effects x time. No between group differences (i.e. sequence of sensory testings) could be observed (refer to the text).
between the maximum change in MDT (r = -0.1, p = 0.68) or MPT (r = -0.28, p = 0.23) and
the respective change in pain intensity could be detected. Linking pain to function indicated a
negative correlation between the maximum change in MIVF and the respective change in PTT
(r = -0.48, p = 0.033; Fig 2B), but not MIVF and pain intensity (r = 0.04, p = 0.86).
Sensory description of DOMS
The SF-MPQ was used to assess the intensity and quality of sensations arising from the
induction of DOMS. Under baseline conditions, the total pain rating index (TPRI) was 0.6 ± 0.5
with a sensory (SPRI) and affective component (APRI) scores of 0.1 ± 0.1 and 1.0 ± 1.0
respectively (Fig 3A). The two-way repeated-measure ANOVA revealed a significant effect for time
for the TPRI and both subscores (all p < 0.001), but not for time × sequence (all p > 0.05).
One day after the induction of DOMS the total intensity rating significantly increased to
6.5 ± 3.7 (paired t-test, p < 0.001; Cohen's d = -1.9), and was significantly increased at 48
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Fig 2. Displays the correlation between the change in PPT (in kg/cm2, with negative numbers indicating an
increase in pressure pain) and the change in maximum pain intensity (in cm VAS, A) or MIVF (in N, B).
(p < 0.001), but not at 72 hours (p = 0.048). The SPRI and the APRI did significantly increase
in this regard, Fig 3B and 3C).
The SF-MPQ offers descriptors to qualitatively describe sensations. Under baseline
conditions, none of the ratings was reasonably affected. Following DOMS, it were the sensory
descriptors stabbing, gnawing, heavy and tender aching the descriptors most likely to be
categorised `mild painful'. The average rating of `throbbing', `shooting', `stabbing', `sharp' and
`hot-burning' during ischemia was mild-moderate. The affective descriptors,
`tiring-exhausting' were rated mild, too (Fig 3D).
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Fig 3. A-D display the rating of pain perception on the short-form MQP. (A)-(C) shows the mean change ± SEM at baseline and 24, 48 and 72 hours after
induction of DOMS of the Total (A), Sensory (B) and Affective (C) Pain Score. D lists the used descriptors ranging from not to strong at the 4 time points.
Descriptors at baseline and after 24 hours were connected with lines for a better visualization. Black lines with p-values indicate the post-hoc tests between
two times in case that repeated measures ANOVA detected significant effects x time. No between group differences (i.e. sequence of sensory testings)
could be observed (refer to the text).
Effects of gender
As there were no sequence effects neither for male or female participants, data was
consequently pooled. Pain and DOMS-related dysfunction significantly occurred independently of
gender (female n = 9). However, two-way repeated-measure ANOVA revealed a significant
effect for time x gender of PPT (df1 F = 30.447 p < 0.001) and MIVF (df1 F = 57.480 p <
0.001), with a more pronounced decrease in PPT in female, and of MIVF in male participants.
Post-hoc tests did not reveal significant differences at the respective times.
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We present the results of a study investigating the effects of DOMS on different sensory and
functional outcomes. Our DOMS model was successfully applied as evidenced by the increase
in pain threshold, pain intensity and functional impairment. The results are in line with
previous investigations, showing a similar increase in pain and loss of function in the subsequent 48
hours following exercise [
12, 33, 35, 39, 40
]. In contrast to previous studies, we implemented
different mechanical pain thresholds, to differentiate the origin of perceived pain. Thus, we
were able to demonstrate that the PPT was the only mechanical pain measurement that
correlated significantly with the perceived participative muscle pain intensity. The PPT showed the
largest effect regarding the quantification of pain. All results together consolidate the
hypothesis of an intramuscular pain origin.
In view of our results, the decrease in PPT of approximately 24% supports the idea that
muscular HTM receptors play a primary role in the induction of pain. The proportion of
HTM receptors is increased in type IV (non myelinated nerve fibres) when compared to type
III (myelinated) fibres [
]. A high mechanical threshold (e.g. strong pressure) is required to
evoke a receptor potential [
]. In contrast, LTM units respond to any form of innocuous
muscle sensations. Several conditions have been shown to increase the mechanical sensitivity
of the HTM nociceptors. First, the spread of endogenous substances (bradykinin, nerve growth
factor NGF, TNF-α and others) following mechanical tissue damage [
]. This increase is
maximised when substances act in concert [
]. Second, a subpopulation of nociceptors can
be sensitised and activated during muscle work under ischemic conditions [
inflammation causes receptors to become more susceptible to weak stimuli [
]. Strong or
long-lasting inflammation is supposed to alter the proportion of HTM receptors towards LTM units,
indicating a lowered mechanical threshold in inflamed muscle.
We could demonstrate that a decrease in PPT (i.e. facilitated elicitation of pressure pain)
strongly correlates with a reduced perceived pain intensity. This is astounding, as many studies
thought PPT and VAS express the same characteristics of pain in DOMS. However, a decrease
in PPT strongly correlates with reduced maximum isometric voluntary force. One possible
conclusion from these observations is that the typical discomfort as described in DOMS [
is more likely evoked in low threshold mechanosensitive units as a response to weak stimuli
such as deformation of the muscle tissue and fascia . This assumption could not be
confirmed from our results, as there is no correlation between the maximum change in MPT and
the respective change in pain intensity, indicating that a reduced mechanical pain threshold
(addressing such LTMs) does not necessarily increase the pain intensity. The PPT in contrast
addresses other mechanism of muscle nociception, i.e. high-threshold mechanosensitive
receptors, which is more likely to be linked with muscular dysfunction. From an athlete's
point of view, this differentiation may be crucial. In daily routine, athletes complain more
often about muscular dysfunction and interruption of training or competition, than about
general discomfort. The differentiation between superficial and deep pain may thus
substantially change the therapeutic strategy. DOMS is classically considered a self-limiting condition
that usually requires no treatment [
]. Still, the role of inflammation -a major factor
sensitising HTMs- has been postulated being responsible for further EIMD [
]. Whereas subjective
pain is an indicator of the early 48 hours, the PPT is still present after 72 hours, which is in line
with concepts in EIMD prevention, proposing that the timing of DOMS disappearance occurs
prior to complete structural and functional recoveries according to the eccentric and
stretchshortening cycle [
]. The sensory and affective descriptors of DOMS; as assessed in this
study, also match the proposed concept of pathophysiology. One could hypothesise from
the data, that the first 24 hours are dominated by heavy, sharp discomfort (which would
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correspond to an activation of Aδ-afferents), whereas the upcoming hours carry dull and
diffuse pain (i.e. afferent C-fibres; [
]). DOMS has for long been considered a protective
mechanism that already disappears too early. Our data suggest that PPT could be the better
diagnostic marker to assess the potential risk of severe EIMD.
The stimuli arising from muscle causing pain are normally projected to spinal neurons of
ascending nociceptive pathways to sites in the brain stem and thalamus, e.g. the spinothalamic
]. In addition, the activation of a complex neuronal networks in the dorsal horn
contributes to the development of secondary hyperalgesia, i.e. lamina I cells which respond to
noxious mechanical or thermal stimuli and lamina IV-V cells receiving polysynaptic nociceptive
input from muscle receptors as well as other tissues. These multireceptive neurons (wide
dynamic range neurons, WDR) combine input from Aδ and C fibres and can respond to both,
low-threshold superficial stimuli and high-threshold noxious stimuli [
]. WDR neurons
react to noxious stimuli with a graded increase in discharge .
Our results suggest that the spinal multireceptive network modifying and spreading the
stimuli in the sense of secondary hyperalgesia (see above) are of subsidiary importance. The
MPT was reduced over time by approximately 10%. This is a probable correlate of the
combined input from low- and high-threshold noxious stimuli to the spinal horn neurons. The
lack of remarkable effects on the MDT makes major excitation of other sensory pathways via
spinal pathways less probable. The lack of cutaneous allodynia suggests that DOMS is not a
strong enough stimulus to elicit `central sensitization', i.e. an increased responsiveness of
nociceptive neurons in the central nervous system. The absolute lack of between-group effects, i.e.
the sequence of threshold measures implies that pain arising from HTM receptors is primarily
projected to brain sites where pain is perceived.
However, other recent research assumes a contribution of C-tactile fibres to cutaneous
allodynia in participants with experimentally induced DOMS at the lower leg [
suppose that vibration caused cutaneous allodynia as intradermal anaesthesia abolished this effect.
This is not in contrast with our data, showing some minor effects on cutaneous Aβ fibres
(MDT). This is in accordance with Nagi and Mahns who showed the intensity of allodynia to
be 1.7 ± 0.2 cm VAS, which is of minor clinical relevance. At this point it remains unclear
whether segmental irritation or anaesthesia may induce mechanism of segmental inhibition to
the muscular pain perceived in DOMS. However, a shortcoming of this study is that authors
did not investigate the impact of cutaneous anaesthesia on muscular PPT. Thus, mechanical
hyperalgesia can be regarded a fortiori the cardinal symptom in DOMS [
We are aware that gender differences could potentially influence the findings in sensory
]. In the present investigation, we did not find differences concerning the outcomes
indicating the onset of DOMS. We could show that the PPT had a significantly greater
decrease in women, as did force in men. Thus, it might be possible that the sensory and
functional response to the experimental model might slightly differ. This could potentially
influence the primary outcome when PPT or MIVF are chosen. However these observations need
to be carefully interpreted due to the small sample size and further research is necessary for
A limitation of our investigation might be that we did not use the full range of the sensory
assessment tools as provided by the German Research Network on Neuropathic Pain [
However, Queme et al. clearly identified DOMS to influence mechanical but not thermal
]. Thus, in our opinion our methods are appropriate to assess the most relevant
mechanical thresholds in DOMS.
The current model applies experiments and measures at the biceps brachii as previous
studies could demonstrate its principle role in DOMS. Several factors could influence this model.
In regard to the eccentric exercise, the magnitude of contraction-induced EIMD can be
12 / 17
influenced by multiple variables, such as fibre length [
], fibre type distribution [
peak force [
], average force [
], work during the stretch [
], or strain defined as the
relative change in length [60±62]. As these factors vary among muscles, assumptions made in this
study should be primarily limited to the biceps muscle.
In addition, we are aware that the brachialis muscle is systematically involved with the
biceps brachii, and we cannot fully rule out contributing factors in the generation and cure of
DOMS. Therefore it could have provided additional valuable data, if e.g. we would have
assessed not only the long but also the short head of the biceps muscle. Finally, the role of
DOMS-related edema can be a possible contributing factor, however we did not assess
intramuscle pressure or muscle swelling.
In this study we did not assess molecular adaptations on the level of the HTMs and
potential inflammatory factors triggering adaptations (e.g. NGF, as well as bradykinin, TNFα, IL-6,
or BDNF). To better understand the sensitisation of HTMs, further functional studies should
be encouraged to assess these associations. However, these studies will most likely require
transgenic animal models to demonstrate cause and effect.
Finally, our study does not answer the question whether treatments addressing the HTMs
would be beneficial in the prevention of further damage. Reducing the degree of inflammation
and the amount of cytokines irritating the muscular tissue could shorten the period needed to
recovery. However, one should also be aware of the potentially delayed structuro-functional
recovery when attenuating the inflammatory process [
]. To this point, it could not yet be
determined if pain therapy desensitizing the HTM units, i.e. preferentially local deep
intramuscular techniques or anti-inflammatory approaches, are beneficial (e.g. enhanced healing)
or harmful (e.g. increased risk of EIMD) for the athlete.
The sensitization of HTM receptors in the muscle seems to be a primary mechanism in the
facilitation of DOMS. The PPT is a reliable method to adequately determine the degree of
pain. Other spinal or central mechanisms of pain are of subsidiary importance, but could still
contribute to the appearance of prolonged states of DOMS. The PPT rather than pain intensity
might thus present a potential marker to assess the risk of overloading to early (at a stage of
incomplete regeneration) after EIMD.
S1 Table. Outcome measures. Indicates the measures at baseline with no significant
differences between groups, and following 24, 48 and 72 hours after the induction of DOMS. Data is
indicated as mean ± SD (95%-CI). PPT pressure pain threshold; MDT mechanical detection
threshold; MPT mechanical pain threshold; VAS visual analogue scale; MPQ McGill Pain
Questionnaire; TPRI: total pain rating index (range 0±42); SPRI sensory pain rating index (0±
30); APRI affective pain rating index (0±12); MIVF maximum isometric voluntary force.
post-hoc tests revealed no significant differences between times.
S2 Table. Measure sites. Testing was performed at five equidistant points, perpendicular to
the individuals' belly of the biceps brachii muscle. On a thought line between the tuberositas
radii and the coracoid prominence, seven sections were determined by using a tape measure
and dividing the belly into seven sections. The beginning of the first (tendon) and the end of
the last section (insertion) were not considered being muscle points. The table indicates the
measures at baseline with no significant differences between groups, and following 24, 48 and
13 / 17
72 hours after the induction of DOMS at the five measure sites. No differences in thresholds
between sites over time could be detected. Data is indicated as mean ± SD (95%-CI). PPT
pressure pain threshold; MDT mechanical detection threshold; MPT mechanical pain threshold.
This study has been conducted in parts with the assistance of the student class `Scientific Skills
Lab', Master of Sports Medical Training & Clinical Exercise Physiology, Institute of Sports
Sciences, Goethe-University Frankfurt, Germany. We thank Dr. Christian Koelbl, MD, PhD,
Assistant Professor at Columbia University Division at Mount Sinai Medical Center, Miami
Beach, USA to revise our manuscript.
Conceptualization: Johannes Fleckenstein, Lutz Vogt, Winfried Banzer.
Data curation: Johannes Fleckenstein, Perikles Simon.
Formal analysis: Johannes Fleckenstein, Perikles Simon.
Funding acquisition: Johannes Fleckenstein.
Investigation: Johannes Fleckenstein, Matthias KoÈnig.
Methodology: Johannes Fleckenstein, Lutz Vogt, Winfried Banzer.
Project administration: Johannes Fleckenstein.
Resources: Johannes Fleckenstein.
Software: Johannes Fleckenstein.
Supervision: Johannes Fleckenstein, Perikles Simon, Lutz Vogt, Winfried Banzer.
Validation: Johannes Fleckenstein, Perikles Simon, Matthias KoÈnig.
Visualization: Johannes Fleckenstein, Perikles Simon, Matthias KoÈnig.
Writing ± original draft: Perikles Simon, Matthias KoÈnig.
Writing ± review & editing: Johannes Fleckenstein, Perikles Simon, Matthias KoÈnig, Lutz
Vogt, Winfried Banzer.
14 / 17
15 / 17
16 / 17
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