1. health and fitness
2. exercise

The Journal of Pain, Vol 8, No 12 (December), 2007: pp 989-997
Available online at www.sciencedirect.com
Extended Swimming Exercise Reduces Inflammatory and
Peripheral Neuropathic Pain in Rodents
Karen E. Kuphal,*,† Eugene E. Fibuch,‡ and Bradley K. Taylor†,§
*Department of Physical Therapy and Rehabilitation Science, Kansas University Medical Center, Kansas City, Kansas.
†
Division of Pharmacology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Kansas.
‡
Department of Anesthesiology, School of Medicine, St. Luke’s Hospital, University of Missouri-Kansas City, Kansas
City, Kansas.
§
Department of Pharmacology, School of Medicine, Tulane University, New Orleans, Louisiana.
Abstract: Physical exercise is often recommended to patients who have chronic pain. However, only a
small number of studies report exercise-induced analgesia in the setting of inflammatory pain, and even
fewer relate long-term exercise to reductions in neuropathic pain. To address these questions, we
evaluated the effect of extended swimming exercise in animal models of inflammatory (intraplantar
injection of dilute formalin) and neuropathic (partial peripheral nerve injury) pain. We found that 9 days
of swimming exercise in 37°C water for 90 min/d decreased licking and flinching responses to formalin,
as compared with nonexercised control animals. In addition, 18 to 25 days of swimming decreased nerve
injury–induced cold allodynia and thermal hyperalgesia in rats, and 7 days of swimming decreased nerve
injury–induced thermal hyperalgesia in mice. Our data indicate that swimming exercise reduces behavioral hypersensitivity in formalin- and nerve injury–induced animal models of persistent pain.
Perspective: Surprisingly, few animal studies have investigated the effects of extended exercise on
chronic pain. Our results support the use of exercise as a nonpharmacological approach for the management of peripheral neuropathic pain.
© 2007 by the American Pain Society
Key words: Formalin, allodynia, hyperalgesia, rat, mouse.
N
ociception provides an early warning system that
serves to minimize tissue damage in the face of
potential bodily harm. The resulting acute or transient pain elicits a coordinated escape response from the
threatening stimulus.50 Chronic pain, on the other hand,
serves no useful purpose and instead reduces the patient’s ability to work, walk, or sleep56 and is associated
with many deleterious physiological effects. Although
an arsenal of analgesic drugs is readily available for the
treatment of acute pain, these drugs do not provide sufficient efficacy for chronic pain in the absence of serious
side effects.
Numerous studies indicate that exercise decreases signs
of acute pain in nonpathological conditions.22,27,30,36 HowReceived December 7, 2006; Revised August 6, 2007; Accepted August 12,
2007.
Supported by NIH grant NS45954 to B.K.T. and St. Luke’s Foundation
funds to E.E.F.
Address reprint requests to Dr. Bradley K. Taylor, Department Pharmacology, SL83, Tulane University Health Sciences Center, New Orleans, LA
70112. E-mail: [email protected]
1526-5900/$32.00
© 2007 by the American Pain Society
doi:10.1016/j.jpain.2007.08.001
ever, as reviewed by Koltyn,30 most animal studies linking exercise and pain evaluated the immediate effects of
short-term exercise on transient nociceptive pain. The
exceptions, using models of more persistent inflammatory pain, have yielded mixed results. Whereas Carmody
and Cooper5 found that one 3-minute session of swimming in 20°C water reduced formalin-induced nociception in the mouse, Quintero et al39 found that 3 swimming sessions in warmer 24 to 26°C water increased
formalin-induced nociception. The frequency and duration of swimming in these studies do not, however, reflect human exercise regimens, eg, that involve exercise
training. To test the hypothesis that exercise training
regimens would reduce behavioral signs of inflammatory pain, rats swam for 7 days for up to 90 min/d and
were then evaluated for behavioral signs of pain in the
formalin model of ongoing inflammatory nociception.13
The distinction of the effects of exercise on acute versus chronic pain is quite important, as the mechanisms
underlying their control are vastly different.50 Despite
this, far fewer studies have investigated the effects of
exercise (particularly long-term, extended periods of exercise) on chronic pain, and the results of these studies
989
990
Extended Swimming Exercise Reduces Inflammatory and Peripheral Neuropathic Pain
are mixed. Although some clinical studies suggest that
exercise reduces chronic pain syndromes such as fibromyalgia, chronic low back pain, osteoporosis pain, myofascial pain, cancer treatment–related pain, and neck
pain,6,14,17,20,31,33,40 others report that exercise increases
the pain associated with fibromyalgia55 and chronic fatigue syndrome.57 Thus, further studies are needed to
justify the widely prescribed recommendation of physical exercise (particularly long-term, extended periods of
exercise) in patients who have chronic pain syndromes
such as fibromyalgia, chronic low back pain, myofascial
pain, and neuropathic pain.32,53,59 Specifically, there are
no studies that have evaluated the effects of extended
exercise in patients with a clear diagnosis of peripheral
neuropathic pain. To address this gap, and to gain insight into the potential benefits of extended exercise, we
evaluated the effects of repeated swimming exercise in
the partial sciatic nerve injury model of peripheral neuropathic pain.43
Materials and Methods
Animals
Forty-four male Sprague-Dawley rats (weight range,
250 –300 g) and 33 male CD1 mice (weight range, 30 –35
g) were purchased from Charles River Laboratories (Boston, MA). For all experiments, animals were exposed to a
12-hour light/dark cycle and were given food and water
ad libitum. Animals were transported daily to our laboratory for acclimation to the exercise and testing environment. All Animal Use protocols were approved by the
Institutional Animal Care and Use Committee (IACUC) of
University of Missouri-Kansas City (UMKC).
Swimming Exercise Protocols
Rodents were individually placed in 17-inch-long ⫻ 10inch-wide ⫻ 17-inch-high plastic containers filled with
approximately 15 inches of water maintained at 37°C. A
drop of soap was added to reduce surface tension; this
reduced the frequency of “floating” behavior. In the
rare instance of such behavior, animals were mildly stimulated to swim by nudging the nape with a pen. This
ensured a full session of exercise conditioning. After
each exercise session, animals were gently dried with a
cloth towel. Control (nonexercised) rats and mice were
allowed to swim for just 30 seconds each day and were
then gently dried.
Rat Studies
We developed a swimming exercise training protocol
in rats, as illustrated in Table 1. Our preliminary studies
revealed that initial exercise sessions led to rapid fatigue,
in agreement with previous studies showing that laboratory rats can continuously swim in warm water for approximately 60 minutes or less.10 Therefore, to produce
an exercise training effect, we began with short 10minute bouts of exercise interspersed with several rest
periods. Over the course of 7 days, the number of rest
periods gradually decreased to 0, and the duration of
Table 1.
Graded Exercise Protocols
DAY(S)
EXERCISE
DURATION
(MIN)
REST
DURATION
(MIN)
SESSIONS*
TOTAL EXERCISE
DURATION
(MIN)
1
2
3
4
5
6
7-9†
10-39‡§
10
15
30
45
60, 30
75, 15
90
90
15
15
15
15
15
15
0
0
9
6
3
2
2
2
1
1
90
90
90
90
90
90
90
90
*Equivalent to the number of sessions performed (exercise plus rest
component).
†Formalin experiment animals swam for 9 days only; behavioral assessment
was performed on day 10.
‡Hot plate experiment animals swam for a total 25 days; behavioral
assessment was performed on day 14 (before nerve injury) and at 11 days
after nerve injury only.
§Nerve injury animals swam for total 39 days; partial sciatic nerve ligation
(PSNL) surgery was performed on day 14, and behavioral assessments were
performed at baseline (day 14 [before PSNL surgery]), on day 21 (7 days after
injury), day 25 (11 days after injury), day 32 (18 days after injury), and 39
(25 days after injury).
each swimming session was increased to 90 minutes. For
the formalin studies of Fig 1, rats were randomly assigned to a control (n ⫽ 8) or treatment group involving
9 days of swimming (n ⫽ 8), followed 1 day later with
formalin testing. For the partial sciatic nerve ligation
(PSNL) studies (Fig 2), rats were randomly assigned to a
control or exercise group. Rats in the exercise group
swam up to 90 min/d for 13 days (Table 1). On day 14,
which we term “baseline,” we evaluated behavioral
signs of reflex responses to cold or heat stimuli (see “Cold
Allodynia” and “Heat Hyperalgesia,” below). Immediately afterward, PSNL surgery was performed. Every day
thereafter, the treatment group swam 90 min/d. Cold
allodynia and heat hyperalgesia testing was repeated on
day 21 (7 days after PSNL), day 25, day 32, and day 39. For
the hotplate studies of Fig 3, rats were tested on day 25
(11 days after PSNL).
Mouse Studies
For the PSNL studies (Fig 4), 20 mice were randomized
into a control (n ⫽ 10) or an exercise (n ⫽ 10) group. Mice
in the exercise group swam 30 minutes per day for 5 days.
On day 6, mice were tested for behavioral responses to
heat and then underwent PSNL surgery. Every day thereafter for 6 days, the treatment group swam 30 minutes.
The next day (7 days after PSNL), thermal hyperalgesia
was assessed. For the control studies (Fig 5), 13 mice were
randomized into groups that either underwent brief
handling but did not swim (control; n ⫽ 4), swam once
for 30 minutes in 37° water (n ⫽ 5), or swam once for 30
minutes in 20° water (n ⫽ 4). Latency to paw withdrawal
from radiant heat was assessed before and 18 hours after
treatment.
ORIGINAL REPORT/Kuphal et al
991
Days 18 and 32 represent 2½ and 4½ weeks after injury.
The latter is essentially identical to a key study in the
literature by Hutchinson et al,24 who evaluated behavior
31 days after spinal cord injury.
Each exercise training session was conducted in the
afternoon. Behavioral testing sessions occurred in the
morning, thus providing an 18-hour rest period. This
time interval minimized the potentially confounding factor of stress-induced antinociception (SIA), which occurs
on the order of minutes, not hours.42
Formalin Test
Rats were placed in plexiglas containers (15 inches
cubed) in a small, quiet room. After 1 hour of habituation, a syringe and 30 gauge needle were used to inject
fresh formalin (5% of 37% formaldehyde diluted in saline; 50 ␮L) into the plantar subcutaneous space at the
center of the tori of the right hind paw. As previously
described,46,48 the number of flinches and time spent
licking the injected paw during the second, third, fourth,
and fifth minutes after injection were evaluated during
phase 1 (time points 1–5). After phase 1, flinches and
time spent licking were counted in 2-minute intervals.
With this method, behavior in 2 animals was simultaneously recorded by one observer for 70 minutes after
the formalin injection.
Cold Allodynia
Figure 1. Exercise reduces persistent pain in the formalin test.
Compared with the formalin-treated group that did not exercise (control), the formalin-treated group that did exercise (exercise) exhibited significantly less licking (A) and flinching behavior (B). Error bars ⫽ SEM. 夝P ⬍ .05 exercise vs control on the
ipsilateral side, post hoc Bonferroni subsequent to repeatedmeasures ANOVA.
Nerve Injury Surgery
Rats and mice were anesthetized with a combination
of ketamine (64 mg·kg⫺1, i.p.; Fort Dodge Laboratories,
Fort Dodge, IA) and xylazine (5.3 mg·kg⫺1; i.p.) for PSNL.
As previously described,43 an incision was made at the
skin overlying the lateral femur, exposing the sciatic
nerve. The nerve was dissected from surrounding connective tissue near the trocanter, just distal to the
branching point of the posterior biceps semitendinosus
nerve. A tight ligature was tied around one-third to onehalf the diameter of the nerve with 8-0 (rat) or 9-0
(mouse) silk suture. After ligation, the muscle was loosely
sutured in layers with absorbable 4-0 and the skin was
closed with 3-0 suture. Sham surgery was produced by
skin incision and exposure of the sciatic distal trifurcation
without ligation. After surgery, animals were housed individually to prevent damage to the sutures from cagemates.
Behavioral Testing
We chose to evaluate behavior at the following time
points after nerve injury: 1, 1½, 2½, 3½, and 4½ weeks.
Rats were acclimated for 1 hour within an inverted
plexiglas box on top of an elevated one-quarter inch
stainless steel mesh floor. Using a syringe connected to
PE-90 tubing, flared at the tip to a diameter of 3.5 mm, a
drop of acetone was applied to the plantar surface of the
paw. Surface tension maintained the volume of the drop
to 10 to 12 ␮L. The length of time the animal lifted or
shook its paw was recorded. The duration of paw withdrawal was recorded up to 30 seconds and 3 observations, with an interstimulus interval of 10 minutes, were
averaged for subsequent analyses.
Thermal Hyperalgesia (Radiant Heat)
Rats or mice were acclimated for 2 hours within inverted transparent enclosures, 1 day before testing.
These cages rested on a thermal paw stimulator system,11 modified from the original design.19 This device
consisted of a glass surface maintained at a constant
temperature of 25.0oC; underneath the glass lies a radiant heat source. An attached, angled mirror facilitated
visualization of the footpad and positioning of the radiant heat. On the day of testing, animals were acclimated
for an additional hour on the glass floor. Next, the radiant light was activated and paw withdrawal latency
(PWL) was obtained from each hind paw (with a minimum of 2 minutes between each test). Voltage intensity
was adjusted such that (pre-injury) baseline latency was
12.5 ⫾ 0.5 seconds. The first 3 measurements were discarded (they tend to be unusually high and variable), and
the 5 subsequent measurements were averaged for subsequent analysis and presentation. If the animal did not
992
Extended Swimming Exercise Reduces Inflammatory and Peripheral Neuropathic Pain
Figure 2. Exercise reduces nerve injury-induced cold allodynia and thermal hyperalgesia in rats. Exercise reduced cold allodynia
(A and B) and heat hyperalgesia (C and D) in animals with partial sciatic nerve ligation (PSNL). Line graphs in A and C illustrate time
course data. Histograms in B and D summarize data averaged across days 7 to 25 at either the ipsilateral or contralateral sides. There
were no significant differences at the contralateral paw. Data are presented as mean ⫾ SEM. 夝P ⬍ .05, repeated-measures ANOVA
followed by post hoc Bonferroni. n ⫽ 6 to 8.
respond within 20 seconds, the heat was discontinued to
prevent damage to the paw.
imum of 10 minutes between each, was averaged for
subsequent analysis.
Thermal Hyperalgesia (Hot Plate)
Data Analysis
Rats were gently placed on a 52°C hot plate (Columbus
Instruments, Columbus, OH). Rats were removed when
they either licked the hind paw of the injured side,
jumped, or a 20-sec cutoff had been reached. Latency
was recorded and the average of 3 sessions, with a min-
Differences between means were analyzed by 2-way
repeated-measures ANOVA. Exercise treatment was the
between-subjects factor and time was the repeated measure. For the formalin studies, all data were analyzed
with a global ANOVA. Next, the data were binned into
phase I (time points 1–5) and phase II (time points 20
Figure 3. Exercise reduces nerve injury–induced thermal hyper-
Figure 4. Exercise decreases nerve injury-induced thermal hyperalgesia in mice. Latency to heat was assessed both before
(Pre) and 1 week after (Post) partial sciatic nerve ligation. Neither PSNL nor exercise altered latency at the contralateral paw.
Data are presented as mean ⫾ SEM. n ⫽ 10.
algesia in the hotplate test. Partial sciatic nerve ligation (PSNL)
reduced paw withdrawal latency to heat in control rats but not
in exercised rats. Data are presented as mean ⫾ SEM. 夝P ⬍ .05 vs
PSNL-exercise group. n ⫽ 7 to 9.
ORIGINAL REPORT/Kuphal et al
993
To confirm exercise-induced reversal of heat hyperalgesia, we used the hotplate test as a second measure of
thermal latency in sham and nerve-injured rats. Fig 3
illustrates that in control (no swim) rats, nerve injury decreased hotplate latency from 13.7 ⫾ 1.1 to 11.0 ⫾ 1.1
seconds. This heat hypersensitivity was not observed in
the exercise group (control-PSNL vs exercise-PSNL: 11.0 ⫾
1.1 vs 13.6 ⫾ 0.9 seconds, P ⫽ .049).
Nerve Injury Studies in the Mouse
Figure 5. Swimming in 37° water does not increase paw withdrawal latency (PWL) in uninjured mice. PWL was assessed both
before and 18 hours after swimming in warm water (37°) or
after a brief dip in water (controls). Data are presented as mean ⫾
SEM. n ⫽ 4 to 5.
through 60) and then further analyzed by ANOVA. If
significant (P ⬍ .05), the analyses were followed by post
hoc t tests with Bonferroni correction to evaluate group
differences at specific time points. Data are presented as
mean ⫾ SEM.
Results
Inflammatory Pain
To test the hypothesis that extended exercise reduces acute inflammatory pain, we evaluated formalininduced behavioral responses after 90 minutes ⫻ 9 days
of swimming. As illustrated in Fig 1, the control group
displayed the expected biphasic formalin response profile: An early phase 1 of flinching and licking responses
during the first 5 minutes after formalin injection, followed by a quiescent interphase, and then a later phase
2 response during time points 20 to 60. Exercise did not
change licking (F1,68 ⫽ 0.7) or flinching (F1,68 ⫽ 1.0) behavior during phase 1. We did find during phase 2, compared with control, that exercise decreased the magnitude of both licking (15.9 ⫾ 1.4 vs 8.4 ⫾ 1.7, F1,153 ⫽ 33,
P ⬍ .0001) and flinching (8.9 ⫾ 1.7 vs 5.4 ⫾ 0.7, F1,153 ⫽
23, P ⬍ .0001).
Nerve Injury Studies in the Rat
To test the hypothesis that extended exercise reduces
peripheral neuropathic pain, we evaluated the effect of
swimming on paw withdrawal responses to cold and hot
stimuli after PSNL. As illustrated in Fig 2, A and B, PSNL
increased cold responses at the ipsilateral hind paw. This
resolved more quickly in the exercise group from days 10
to 25 (F1,35 ⫽ 6.5, P ⫽ .015), and post hoc analysis revealed significant differences between control and exercise groups on day 18 and day 25 after nerve injury (P ⬍
.05). As illustrated in Fig 2, C and D, PSNL reduced thermal latency at the ipsilateral paw. This sign of heat hyperalgesia was reduced in the exercise group from days 7
to 25 (F1,47 ⫽ 6.8, P ⫽ .012). Exercise had no effect on the
contralateral paw.
To extend our findings in the rat to a second species,
we evaluated the effects of swimming exercise on injuryinduced thermal hyperalgesia in mice. Fig 4 illustrates
that exercise decreased hyperalgesia at the ipsilateral
side (F1,36 ⫽ 23, P ⬍ .0001), without altering heat latency
at the contralateral side (P ⬎ .05). On the ipsilateral side,
the decrease in PWL in the exercise group was significantly less than the control group (8.5 ⫾ 0.8 vs 10.4 ⫾ 0.6,
P ⫽ .044).
Control Studies in the Absence of Injury
Our swimming protocol is forced and therefore inherently stressful. Because a single stress event can alter
nociceptive thresholds,51 we next asked whether one
bout of swimming alters heat withdrawal latency in the
absence of injury. As illustrated in Fig 5, we evaluated
latency both before and 18 hours after swimming in
warm water (37°). Swimming did not change thermal
PWL, arguing against an effect of swimming or swim
stress on nociceptive thresholds.
Discussion
Our studies are the first to report the effects of longterm exercise in the formalin model of ongoing inflammatory pain13 and the partial sciatic nerve injury model
of peripheral neuropathic pain.43 We found that longterm swimming exercise decreased formalin-induced
and nerve injury–induced behavioral signs of persistent
pain. Our data support the hypothesis that long-term
exercise reduces acute and chronic pain.
Exercise Reduces Inflammatory Pain
Carmody and Cooper5 suggested that short-term cold
swim exercise reduces formalin-induced nociception in
the mouse. We extend these findings to more clinically
relevant swim times (9 consecutive days of 90 min/d
swimming), to warm water swim protocols that avoid
SIA,51 and to a second species, the rat. On the other
hand, our results contrast with Quintero et al,39 who
reported three, 10- to 20-minute, forced swim sessions in
cool (24 to 26°) water increased formalin nociception,
particularly during the interphase. They termed this
stress-induced hyperalgesia, or SIH. At least 3 differences
in protocol can explain such opposite results. First, the
intensity of SIH may inversely correlate with water temperature. Thus, swimming in cooler water may facilitate
SIH, whereas swimming in warmer water facilitates exercise-induced antinociception. Second, the mechanisms
underlying SIH may develop during the first 20 minutes
994
Extended Swimming Exercise Reduces Inflammatory and Peripheral Neuropathic Pain
might subside during our 90-minute swimming protocol.
Third, the severe stress during our initial swim sessions
might induce SIH; we speculate that these would dissipate as the animal habituates. Indeed, we observed a
dramatic decline in feces in the water over the first few
swim sessions.
The intraplantar injection of dilute formalin directly
stimulates nociceptors, resulting in a barrage of primary
afferent fiber activity that lasts about 5 minutes (phase 1).
Our results indicate that exercise does not reduce this.
Instead, exercise reduced phase 2. Overwhelming evidence with peripherally acting local anesthetics, neonatal capsaicin treatment, and isolated peripheral nerve
recordings demonstrate that ongoing C-fiber activity,
rather than central sensitization, predominantly drives
nociceptive responses during phase 2 in the formalin
test.34,37,38,47-49 This ongoing activity is probably driven
by multiple factors, including (1) direct stimulation of
peripheral afferent terminals by formalin; and (2) formalin-evoked neurogenic and non-neurogenic release of
inflammatory mediators and other chemicals that produce peripheral sensitization. We do not believe that
exercise reduced the former factor, because exercise did
not reduce phase 1. Instead, we favor the hypothesis that
long-term exercise prevents peripheral sensitization in
the setting of acute inflammatory pain.
Exercise Reduces Neuropathic Pain
Our studies are among the first to demonstrate that
extended exercise reduces behavioral signs of peripheral
neuropathic pain. We found that 18 to 25 days of swimming after PSNL decreased nerve injury–induced cold allodynia and thermal hyperalgesia in rats, and 7 days of
swimming decreased nerve injury–induced thermal hyperalgesia in mice.
In contrast to the prophylactic effect of exercise on
formalin-induced nociception, 7 days of exercise before
PNSL did not prevent the development of neuropathic
pain. One possibility is that SIH operates during the earlier time points, as Quintero et al39 found that 3 days of
swimming in cool water decreased paw withdrawal latency to heat. Alternatively, exercise may recruit inhibitory mechanism involved in the maintenance, but not
the induction, of neuropathic pain. We can only speculate that this mechanism involves the rostral ventral medulla (RVM). For example, Porreca et al found that microinjection of lidocaine into the RVM blocked the
maintenance but not the induction of neuropathic
pain.3,54 Whether the RVM serves as a target for the
anti-allodynic actions of exercise remains an interesting
question. We conclude that exercise recruits different
mechanisms to inhibit acute inflammatory vs neuropathic pain.
Certain features of our experimental design and results are quite similar to those of Hutchinson et al,24 who
reported that both treadmill running and swimming exercise reduced mechanical allodynia in a model of central
neuropathic pain involving spinal cord injury (SCI). For
example, the exercise parameters (20 minutes per day, 5
days per week for 7 weeks) were quite similar to our
study. Also, the time from initiation of exercise to the
appearance of reduced allodynia was 31 to 32 days in
both studies. They reported that swim training reduced
allodynia 5 to 6 weeks after injury; this anti-allodynic
effect was over by 7 weeks. We also observed a transient
effect on our measure of heat hypersensitivity; we found
that exercise reduced hyperalgesia until at least 18 days
after PSNL, and this effect was over by 25 days. It is important to note that unlike Hutchinson et al, our study
did not evaluate mechanical allodynia. Because mechanical allodynia and hyperalgesia are significant clinical
problems in chronic pain patients,58 further studies are
needed.
Mechanisms of Exercise-Induced
Analgesia
Bement and Sluka2 recently reported that low-intensity treadmill exercise (treadmill speed ⫽ 3.05 m/min for
30 min/d) for 5 consecutive days reduced the chronic bilateral mechanical hyperalgesia in a rat model of noninflammatory chronic muscle pain involving 2 injections of
acid (pH ⫽ 4.0) into the gastrocnemius muscle. Treadmill
exercise-induced reductions in mechanical hyperalgesia
were reversed by systemic administration of the opioid
receptor antagonist naloxone. These results suggest that
endogenous opioids mediate, in part, an inverse relationship between exercise and chronic muscle pain. Indeed, as reviewed by Koltyn et al,30 exercised-induced
increases in circulating levels of endogenous opioids
may feedback/inhibit acute pain at peripheral, spinal,
or supraspinal sites.5,7,8,12,26,45,52 Further studies are
needed to determine whether a similar relationship
holds true between exercise and chronic neuropathic
pain.
Swimming (particularly in cold water) produces the
well-known phenomenon of SIA, which is mediated by
both opioid and nonopioid mechanisms,51 the latter of
which include corticosteroid or endocannabinoid mediators.23 It is unlikely, however, that such stress-induced
mechanisms operate in our experimental model, because
we observed long-lasting reduction of inflammatory and
neuropathic pain (eg, after 18 hours of rest, after exercise). Any more subtle effect, not detectable in our
model, would have likely habituated across the repeated
swimming sessions. We conclude that long-term exercise
rather than SIA reduces the development of a neuropathic pain state in rodents.
Exercise Does Not Produce Extended
Antinociception in a Model of
Transient Pain
At the uninjured, contralateral paw, we found that
exercise changed neither PWL to radiant heat or to the
hotplate when measured 18 hours after the final exercise
session. These results suggest that swimming exercise
does not produce extended changes in acute nociception.
Although Tierney et al52 reported that swimming
produced antinociception in the tail-flick test in mice
ORIGINAL REPORT/Kuphal et al
45
and Shyu et al reported that 4 weeks of wheelrunning produced antinociception evidenced by increased squeak thresholds (from controlled electrical
stimuli of varying intensity) in rats, both studies measured nociception soon after exercise (12 and 60 minutes,
respectively), and in the latter study nociception steadily
returned to baseline.
In agreement with our results, numerous studies in
healthy humans demonstrate that exercise produces
short-lasting analgesic effects. For example, activities
such as running,21,25,41 cycling,28 stair-stepping,18 resistance training,29 and mixed resistance training and aerobic exercise1 increased pain threshold or reduced sensitivity to a variety of noxious stimuli, including cold25 and
pressure.1,18,21,28,29 Our results emphasize that the effects of exercise on acute nociception are likely to be
short-lasting, with nociception returning to baseline
within 18 hr of rest.
Clinical Implications
Aquatic exercise is commonly prescribed to patients
who must avoid weight-bearing activities such as walking or running. This includes patients with complex regional pain syndrome (CRPS), who often experience hypersensitivity of the feet. Our studies provide important
initial results with a rodent swimming exercise paradigm. We must keep in mind, however, that swimming
exercise in rodents is forced, whereas aquatic exercise in
humans is voluntary. Further studies incorporating voluntary exercise paradigms (eg, voluntary wheel-running), will be useful in translating rodent data to therapies for chronic pain patients.
References
1. Bartholomew JB, Lewis BP, Linder DE, Cook DB: Post-exercise analgesia: replication and extension. J Sports Sci 14:
329-334, 1996
2. Bement MK, Sluka KA: Low-intensity exercise reverses
chronic muscle pain in the rat in a naloxone-dependent
manner. Arch Phys Med Rehabil 86:1736-1740, 2005
3. Burgess SE, Gardell LR, Ossipov MH, Malan TP Jr, Vanderah TW, Lai J, Porreca F: Time-dependent descending facilitation from the rostral ventromedial medulla maintains,
but does not initiate, neuropathic pain. J Neurosci 22:51295136, 2002
995
Our results support the idea that long-term exercise, in
addition to its well-known benefits to general health,9
can be an effective strategy for the management of clinical inflammatory or neuropathic pain.15,35 A limited
number of clinical studies indicate that moderate exercise decreases pain ratings in humans with established
musculoskeletal disease14 or fibromyalgia.16,17,32,33 Exercise also enhances outcome in chronic pain patients with
lower back pain,22,35,53 osteoporosis,31 and other chronic
pain conditions that may have a neuropathic component.9,15 Still, several factors should be considered when
prescribing exercise for chronic pain patients. First, Butler et al4 reported that swimming exercise exacerbated
hyperalgesia in rats during the early stages of arthritis.
This raises the important point that exercise therapy perhaps should be reserved for patients with established
chronic pain, after acute inflammation has stabilized.44
Second, strenuous exercise can increase experimentally
induced pain in individuals with fibromyalgia,55 demonstrating the importance of intensity as it relates to exercise prescription. Future animal and human studies are
clearly warranted to determine the biological mechanisms that integrate exercise and pain, and future clinical
studies are needed to determine the importance of timing and intensity of exercise in terms of injury onset and
therapeutic effectiveness for chronic pain.
Acknowledgments
We thank Melissa Mena Vu, MD, for her assistance with
the rat nerve injury studies.
7. Cooper K, Carmody J: The characteristics of the opioidrelated analgesia induced by the stress of swimming in the
mouse. Neurosci Lett 31:165-170, 1982
8. D’Anci KE, Gerstein AV, Kanarek RB: Long-term voluntary
access to running wheels decreases kappa-opioid antinociception. Pharmacol Biochem Behav 66:343-346, 2000
9. Davis VP, Fillingim RB, Doleys DM, Davis MP: Assessment
of aerobic power in chronic pain patients before and after a
multi-disciplinary treatment program. Arch Phys Med Rehabil 73:726-729, 1992
10. Dawson CA, Horvath SM: Swimming in small laboratory
animals. Med Sci Sports 2:51-78, 1970
4. Butler SH, Godefroy F, Besson JM, Weil-Fugazza J: Increase in “pain sensitivity” induced by exercise applied during the onset of arthritis in a model of monoarthritis in the
rat. Int J Tissue React 13:299-303, 1991
11. Dirig DM, Salami A, Rathbun ML, Ozaki GT, Yaksh TL:
Characterization of variables defining hindpaw withdrawal
latency evoked by radiant thermal stimuli. J Neurosci Methods 76:183-191, 1997
5. Carmody J, Cooper K: Swim stress reduces chronic pain in
mice through an opioid mechanism. Neurosci Lett 74:358363, 1987
12. Droste C, Greenlee MW, Schreck M, Roskamm H: Experimental pain thresholds and plasma beta-endorphin
levels during exercise. Med Sci Sports Exerc 23:334-342,
1991
6. Chatzitheodorou D, Kabitsis C, Malliou P, Mougios V: A
pilot study of the effects of high-intensity aerobic exercise
versus passive interventions on pain, disability, psychological strain, and serum cortisol concentrations in people with
chronic low back pain. Phys Ther 87:304-312, 2007
13. Dubuisson D, Dennis SG: The formalin test: a quantitative study of the analgesic effects of morphine, meperidine,
and brain stem stimulation in rats and cats. Pain 4:161-174,
1977
996
Extended Swimming Exercise Reduces Inflammatory and Peripheral Neuropathic Pain
14. Ferrell BA, Josephson KR, Pollan AM, Loy S, Ferrell BR:
A randomized trial of walking versus physical methods
for chronic pain management. Aging (Milano) 9:99-105,
1997
32. Mannerkorpi K, Ahlmen M, Ekdahl C: Six- and 24-month
follow-up of pool exercise therapy and education for patients with fibromyalgia. Scand J Rheumatol 31:306-310,
2002
15. Fordyce W, McMahon R, Rainwater G, Jackins S, Questad
K, Murphy T, De Lateur B: Pain complaint– exercise performance relationship in chronic pain. Pain 10:311-321, 1981
33. McCain GA, Bell DA, Mai FM, Halliday PD: A controlled
study of the effects of a supervised cardiovascular fitness
training program on the manifestations of primary fibromyalgia. Arthritis Rheum 31:1135-1141, 1988
16. Gowans SE, deHueck A: Effectiveness of exercise in management of fibromyalgia. Curr Opin Rheumatol 16:138-142,
2004
17. Gowans SE, Dehueck A, Voss S, Silaj A, Abbey SE: Sixmonth and one-year followup of 23 weeks of aerobic exercise for individuals with fibromyalgia. Arthritis Rheum 51:
890-898, 2004
18. Gurevich M, Kohn PM, Davis C: Exercise-induced analgesia and the role of reactivity in pain sensitivity. J Sports Sci
12:549-559, 1994
19. Hargreaves K, Dubner R, Brown F, Flores C, Joris J: A new
and sensitive method for measuring thermal nociception in
cutaneous hyperalgesia. Pain 32:77-88, 1988
20. Hayden JA, van Tulder MW, Malmivaara AV, Koes BW:
Meta-analysis: Exercise therapy for nonspecific low back
pain. Ann Intern Med 142:765-775, 2005
21. Hoffman MD, Shepanski MA, Ruble SB, Valic Z, Buckwalter JB, Clifford PS: Intensity and duration threshold for
aerobic exercise-induced analgesia to pressure pain. Arch
Phys Med Rehabil 85:1183-1187, 2004
22. Hoffman MD, Shepanski MA, Mackenzie SP, Clifford PS:
Experimentally induced pain perception is acutely reduced
by aerobic exercise in people with chronic low back pain.
J Rehabil Res Dev 42:183-190, 2005
23. Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley
D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD,
Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D: An endocannabinoid mechanism for stress-induced analgesia. Nature 435:1108-1112, 2005
24. Hutchinson KJ, Gomez-Pinilla F, Crowe MJ, Ying Z, Basso
DM: Three exercise paradigms differentially improve sensory recovery after spinal cord contusion in rats. Brain 127:
1403-1414, 2004
25. Janal MN, Glusman M, Kuhl JP, Clark WC: Are runners
stoical? An examination of pain sensitivity in habitual runners and normally active controls. Pain 58:109-116, 1994
26. Kanarek RB, Gerstein AV, Wildman RP, Mathes WF,
D’Anci KE: Chronic running-wheel activity decreases sensitivity to morphine-induced analgesia in male and female
rats. Pharmacol Biochem Behav 61:19-27, 1998
34. McCall WD, Tanner KD, Levine JD: Formalin induces biphasic activity in C-fibers in the rat. Neurosci Lett 208:45-48,
1996
35. Nielens H, Plaghki L: Perception of pain and exertion
during exercise on a cycle ergometer in chronic pain patients. Clin J Pain 10:204-209, 1994
36. O’Connor PJ, Cook DB: Exercise and pain: The neurobiology, measurement, and laboratory study of pain in relation to exercise in humans. Exerc Sport Sci Rev 27:119-166,
1999
37. Peterson MA, Basbaum AI, Abbadie C, Rohde DS, McKay
WR, Taylor BK: The differential contribution of capsaicinsensitive afferents to behavioral and cardiovascular measures of brief and persistent nociception and to Fos expression in the formalin test. Brain Res 755:9-16, 1997
38. Puig S, Rivot JP, Besson JM: Effect of subcutaneous administration of the chemical algogen formalin, on 5-HT metabolism in the nucleus raphe magnus and the medullary
dorsal horn: A voltametric study in freely moving rats. Brain
Res 590:250-254, 1992
39. Quintero L, Moreno M, Avila C, Arcaya J, Maixner W,
Suarez-Roca H: Long-lasting delayed hyperalgesia after subchronic swim stress. Pharmacol Biochem Behav 67:449-458,
2000
40. Robb KA, Williams JE, Duvivier V, Newham DJ: A pain
management program for chronic cancer-treatment-related
pain: A preliminary study. J Pain 7:82-90, 2006
41. Ruble SB, Hoffman MD, Shepanski MA, Valic Z, Buckwalter JB, Clifford PS: Thermal pain perception after aerobic
exercise. Arch Phys Med Rehabil 86:1019-1023, 2005
42. Schwarz L, Kindermann W: Changes in beta-endorphin
levels in response to aerobic and anaerobic exercise. Sports
Med 13:25-36, 1992
43. Seltzer Z, Dubner R, Shir Y: A novel behavioral model of
neuropathic pain disorders produced in rats by partial sciatic
nerve injury. Pain 43:205-218, 1990
44. Semble EL, Loeser RF, Wise CM: Therapeutic exercise for
rheumatoid arthritis and osteoarthritis. Semin Arthritis
Rheum 20:32-40, 1990
27. Kemppainen P, Hamalainen O, Kononen M: Different
effects of physical exercise on cold pain sensitivity in fighter
pilots with and without the history of acute in-flight neck
pain attacks. Med Sci Sports Exerc 30:577-582, 1998
45. Shyu BC, Andersson SA, Thoren P: Endorphin mediated
increase in pain threshold induced by long-lasting exercise
in rats. Life Sci 30:833-840, 1982
28. Koltyn KF, Garvin AW, Gardiner RL, Nelson TF: Perception of pain following aerobic exercise. Med Sci Sports Exerc
28:1418-1421, 1996
46. Taylor BK, Peterson MA, Basbaum AI: Exaggerated cardiovascular and behavioral nociceptive responses to subcutaneous formalin in the spontaneously hypertensive rat.
Neurosci Lett 201:9-12, 1995
29. Koltyn KF, Arbogast RW: Perception of pain after resistance exercise. Br J Sports Med 32:20-24, 1998
30. Koltyn KF: Analgesia following exercise: A review.
Sports Med 29:85-98, 2000
47. Taylor BK, Peterson MA, Basbaum AI: Persistent cardiovascular and behavioral nociceptive responses to subcutaneous formalin require peripheral nerve input. J Neurosci 15:
7575-7584, 1995
31. Malmros B, Mortensen L, Jensen MB, Charles P: Positive
effects of physiotherapy on chronic pain and performance in
osteoporosis. Osteoporos Int 8:215-221, 1998
48. Taylor BK, Peterson MA, Basbaum AI: Early nociceptive
events influence the temporal profile, but not the magnitude, of the tonic response to subcutaneous formalin: Ef-
ORIGINAL REPORT/Kuphal et al
fects with remifentanil. J Pharmacol Exp Ther 280:876-883,
1997
49. Taylor BK, Basbaum AI: Early antinociception delays
edema but does not reduce the magnitude of persistent
pain in the formalin test. J Pain 1:218-228, 2000
50. Taylor BK: Pathophysiologic mechanisms of neuropathic
pain. Curr Pain Headache Rep 5:151-161, 2001
51. Terman GW, Morgan MJ, Liebeskind JC: Opioid and
non-opioid stress analgesia from cold water swim: Importance of stress severity. Brain Res 372:167-171, 1986
52. Tierney G, Carmody J, Jamieson D: Stress analgesia: the
opioid analgesia of long swims suppresses the non-opioid
analgesia induced by short swims in mice. Pain 46:89-95,
1991
53. van Tulder MW, Koes BW, Bouter LM: Conservative
treatment of acute and chronic nonspecific low back pain:
A systematic review of randomized controlled trials of the
most common interventions. Spine 22:2128-2156, 1997
997
54. Vera-Portocarrero LP, Zhang ET, Ossipov MH, Xie JY,
King T, Lai J, Porreca F: Descending facilitation from the
rostral ventromedial medulla maintains nerve injuryinduced central sensitization. Neuroscience 140:1311-1320,
2006
55. Vierck CJ Jr, Staud R, Price DD, Cannon RL, Mauderli AP,
Martin AD: The effect of maximal exercise on temporal summation of second pain (windup) in patients with fibromyalgia syndrome. J Pain 2:334-344, 2001
56. Wall PD, Melzack R, eds: Textbook of Pain. New York,
NY, Churchill Livingstone, 1999
57. Whiteside A, Hansen S, Chaudhuri A: Exercise lowers
pain threshold in chronic fatigue syndrome. Pain 109:497499, 2004
58. Woolf CJ, Mannion RJ: Neuropathic pain: aetiology,
symptoms, mechanisms, and management. Lancet 353:19591964, 1999
59. Wright A, Sluka KA: Nonpharmacological treatments
for musculoskeletal pain. Clin J Pain 17:33-46, 2001