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Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation

Open AccessPublished:February 06, 2017DOI:https://doi.org/10.1016/j.jpain.2017.01.006

      Highlights

      • In rats, intra-articular Complete Freund's Adjuvant produced pain, stress, and ankle swelling.
      • Voluntary exercise reduced pain and stress, but not ankle swelling.
      • Inflamed rats voluntarily exercise as much as uninflamed sham rats.
      • The amount of exercise is unrelated to the level of reduction in pain and stress.
      • Self-regulated exercise may be more relevant than standardized activity goals.

      Abstract

      Aerobic exercise improves outcomes in a variety of chronic health conditions, yet the support for exercise-induced effects on chronic pain in humans is mixed. Although many rodent studies have examined the effects of exercise on persistent hypersensitivity, the most used forced exercise paradigms that are known to be highly stressful. Because stress can also produce analgesic effects, we studied how voluntary exercise, known to reduce stress in healthy subjects, alters hypersensitivity, stress, and swelling in a rat model of persistent hind paw inflammation. Our data indicate that voluntary exercise rapidly and effectively reduces hypersensitivity as well as stress-related outcomes without altering swelling. Moreover, the level of exercise is unrelated to the analgesic and stress-reducing effects, suggesting that even modest amounts of exercise may impart significant benefit in persistent inflammatory pain states.

      Perspective

      Modest levels of voluntary exercise reduce pain- and stress-related outcomes in a rat model of persistent inflammatory pain, independently of the amount of exercise. As such, consistent, self-regulated activity levels may be more relevant to health improvement in persistent pain states than standardized exercise goals.

      Key words

      Although physical activity is effective in preventing or delaying the onset of persistent pain in animal models
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      ; however, this approach does not address the potential therapeutic benefits of exercise initiated after injury. Moreover, housing rodents with the running wheel allows for higher levels of running behavior that may not necessarily reflect the level of exercise seen in most humans. To assess therapeutic effects of voluntary running while incorporating more modest levels of exercise, our rats were given limited access to running wheels (2 hours per day, 4 days per week, for 3 weeks) after intra-articular Complete Freund's Adjuvant (CFA), a rodent model of persistent inflammation.
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      Methods

      Animals

      Male Long Evans rats (Charles River, Raleigh, North Carolina) between 250 and 275 g were used for all experiments (n = 16–24 rats per group). Rats were kept on an inverted 12-hour/12-hour light/dark cycle (lights out at 9 am) and were only tested during the early portion of their waking cycle. All animals were housed in pairs and given free access to food and water. Each cage was randomly assigned to 1 of the 4 experimental conditions. All protocols were reviewed and approved by National Institute of Neurological Disorders and Stroke/National Institute on Deafness and other Communication Disorders Animal Care and Use Committee. Experiments were in accordance with the National Institute of Neurological Disorders and Stroke/National Institute on Deafness and other Communication Disorders Animal Care and Use Committee and the International Association for the Study of Pain guidelines for the care and use of experimental animals.

      Peripheral Inflammation

      A total of 25 μL of CFA (1 mg/mL Mycobacterium tuberculosis; Sigma Aldrich, St. Louis, Missouri) was injected into the tibial-tarsal joint of the left hind paw in isoflurane-anesthetized (5% in O2) rats according to the method described in Butler et al.
      • Butler S.H.
      • Godefroy F.
      • Besson J.M.
      • Weil-Fugazza J.
      A limited arthritic model for chronic pain studies in the rat.
      Control (sham) animals underwent the same procedure including needle insertion but without irritant injection in order to prevent potential volume-related damage to the ankle joint. Animals were immediately returned to their home cage for observation. Intra-articular CFA typically results in approximately 6 to 8 weeks of ankle/knee swelling and hypersensitivity,
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      • Besson J.M.
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      A limited arthritic model for chronic pain studies in the rat.
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      Chronic secondary hypersensitivity of dorsal horn neurones following inflammation of the knee joint.
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      but can reach 12 weeks depending on volume and concentration of CFA injection.
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      Joint swelling and hypersensitivity typically reach maximum levels within the first week post injection.
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      Changes in dorsal root ganglion CGRP expression in a chronic inflammatory model of the rat knee joint: Differential modulation by rofecoxib and paracetamol.
      • Uematsu T.
      • Sakai A.
      • Ito H.
      • Suzuki H.
      Intra-articular administration of tachykinin NK(1) receptor antagonists reduces hyperalgesia and cartilage destruction in the inflammatory joint in rats with adjuvant-induced arthritis.

      Experimental Design and Exercise Paradigm

      Four groups of rats were studied: 1) CFA and home cage sedentary that had no access to running wheels (n = 24), 2) CFA and locked wheel sedentary that spent 2 hours per day, 4 days per week for 3 weeks in the running wheel cages with locked wheels (n = 10), 3) CFA and exercise (CFA-RUN) that spent 2 hours per day, 4 days per week for 3 weeks in running wheel cages with functioning wheels (n = 24), and 4) sham and exercise that spent 2 hours per day, 4 days per week for 3 weeks in running wheel cages with functioning wheels (n = 16). No statistically significant differences were found between the inflamed home cage sedentary and inflamed locked wheel sedentary groups in body weight, ankle width, weight-bearing, thermal latency, plasma corticosterone, or heart rate variability (HRV), so data from these groups were pooled into a single group (CFA-SED). A total of 7 cohorts of animals were tested to achieve the desired sample sizes and ensure consistent results. Each cohort of 10 to 12 rats was comprised of animals from each experimental group. A sample size of n = 24 for the CFA-RUN group was chosen to expand upon on the sample sizes used in other published rodent exercise studies performing linear regression analysis (ie, n = 6–18 per group).
      • Grace P.M.
      • Fabisiak T.J.
      • Green-Fulgham S.M.
      • Anderson N.D.
      • Strand K.A.
      • Kwilasz A.J.
      • Galer E.L.
      • Walker F.R.
      • Greenwood B.N.
      • Maier S.F.
      • Fleshner M.
      • Watkins L.R.
      Prior voluntary wheel running attenuates neuropathic pain.
      • Herrera J.J.
      • Fedynska S.
      • Ghasem P.R.
      • Wieman T.
      • Clark P.J.
      • Gray N.
      • Loetz E.
      • Campeau S.
      • Fleshner M.
      • Greenwood B.N.
      Neurochemical and behavioural indices of exercise reward are independent of exercise controllability.
      • Sumiyoshi A.
      • Taki Y.
      • Nonaka H.
      • Takeuchi H.
      • Kawashima R.
      Regional gray matter volume increases following 7days of voluntary wheel running exercise: A longitudinal VBM study in rats.
      For the sham group, we chose to use a smaller group size (n = 16) because this was a control group that was not expected to exhibit any changes in hypersensitivity and would not be used for regression analysis. In addition, a smaller group size of n = 16 would minimize animal usage while maintaining satisfactory statistical power.
      Voluntary exercise was performed on stainless steel running wheels (diameter 34 cm; width 7 cm) in polycarbonate cages (48 × 31.5 × 47 cm; Bioseb, Boulogne, France). A computer connected to the wheels automatically recorded the distance traveled by each animal during the running session. Considering that peak running behavior in rats occurs in the early portion of their waking cycle,
      • Greenwood B.N.
      • Foley T.E.
      • Le T.V.
      • Strong P.V.
      • Loughridge A.B.
      • Day H.E.
      • Fleshner M.
      Long-term voluntary wheel running is rewarding and produces plasticity in the mesolimbic reward pathway.
      rats were always given access to wheels shortly after lights out (ie, 9:30–11:30 am). Each morning, all rodents were transported in their home cage to an adjacent room containing running wheels. Rats in the exercise groups were given individual access to running wheels for 2 hours per day, 4 days per week for 3 weeks beginning 3 days after induction of CFA-induced inflammation (Fig 1A). The total distance run per day was monitored for each rat. Rats were not pretrained on the running wheels. No experimenters were present during the running sessions. For all animals with running wheel access, the daily running distance was measured. The time spent running was also measured for a subset of animals. For analysis, running behavior was expressed either as distance (in meters) or average velocity (in meters per second) per time period.
      Figure thumbnail gr1
      Figure 1Voluntary running behavior is robust and highly variable in sham and CFA-injected rats. (A) Experimental time line. (B) In sham and CFA-RUN groups, no significant differences were observed in weekly running distance. (C) In terms of average weekly velocity, the average velocity was significantly higher in week 3 than in week 2 for the sham group, and week 3 was higher than week 1 for the CFA-RUN group. (D) No differences in the total running distance over the 3-week period were observed between groups. (E) No difference in average velocity for the entire 3-week time span were found between the sham and CFA-RUN groups. n = 12 to 24 per group. P < .05. Abbreviation: Cort, corticosterone.
      Baseline behavioral testing occurred 1 day before CFA injection and at post-injection days 7, 14, and 21 (Fig 1A). In all groups, post-CFA testing was always performed 24 hours after the last weekly exercise of the exercise groups. Similarly, plasma corticosterone was always harvested 48 hours after the last weekly exercise of the exercise groups. Access to running wheels and behavioral testing occurred under red light conditions to avoid interfering with rodents’ nocturnal waking cycle. Rodents were habituated to all testing apparatus on 3 separate days before baseline testing. Experimenters were blinded to active or sedentary condition, but were not blinded to inflamed versus sham groups because of obvious hind paw swelling in inflamed rodents. No animals were excluded from analyses.

      Hind Paw Swelling

      After behavioral testing, rats were lightly anesthetized with isoflurane. The widest point of the ankle joint, between the medial and the lateral malleolus, was measured with a digital micrometer for the ipsilateral and contralateral paw. Data are presented as the proportion of ipsilateral to contralateral paw width, in percent.

      Corticosterone

      Plasma corticosterone was assessed using an enzyme-linked immunosorbent assay (ELISA; kit #ADI-900-097; Enzo Life Sciences Inc, Farmingdale, NY). Rats were allowed to enter a soft folded towel where they were gently restrained. To minimize stress, rats were handled in a separate room using a new towel for each rat. A small volume of blood (20–30 μL) was harvested with heparin-treated capillary tubes from the tip of the tail via a .5-mm incision. The entire procedure lasted approximately 2 minutes. Blood samples were kept at 4°C until centrifugation (2 minutes at 16,000 rpm; Iris CritSpin; Beckman Coulter, Inc., Indianapolis, Indiana) to separate plasma from serum. Plasma was pipetted into individually labeled sample tubes and stored at −80°C until ELISA processing. Plasma levels of corticosterone were assessed according to the small sample volume instructions from Enzo Life Sciences kit #ADI-900-097. Briefly, samples were brought to room temperature and 10 μL of each sample was diluted (40:1) with assay buffer. One hundred milliliters of samples and standards were pipetted into the appropriate wells of the ELISA plate. Conjugate (50 μL) and antibody (50 μL) were added to each well and incubated in darkness for 2 hours on a shaker (500 rpm) at room temperature. The plate was then washed 3 times with washing buffer and gently tapped on an absorbent paper to remove remaining moisture. Two hundred milliliters of p-nitrophenyl phosphate substrate was added to each well and incubated in darkness for 1 hour at room temperature without shaking. Fifty milliliters of ‘stop’ solution was then added to each well and the absorbance was immediately measured with a Wallac 1420 model plate reader (PerkinElmer Inc., Waltham, Massachusetts) with a 405-nm filter. All samples, controls, and standards were measured in duplicate. Plasma levels of corticosterone were expressed in picograms per milliliter (pg/mL).

      HRV

      HRV reflects the change in the time intervals between successive heartbeats, an effect that is driven by various regulatory systems to adapt to stressors.
      • Thayer J.F.
      • Ahs F.
      • Fredrikson M.
      • Sollers 3rd, J.J.
      • Wager T.D.
      A meta-analysis of heart rate variability and neuroimaging studies: Implications for heart rate variability as a marker of stress and health.
      Reductions in HRV have been linked to deficits in stress adaptation that can result in overall poorer health and decreased longevity.
      • Dekker J.M.
      • Schouten E.G.
      • Klootwijk P.
      • Pool J.
      • Swenne C.A.
      • Kromhout D.
      Heart rate variability from short electrocardiographic recordings predicts mortality from all causes in middle-aged and elderly men. The Zutphen Study.
      • Kuo T.B.
      • Lin T.
      • Yang C.C.
      • Li C.L.
      • Chen C.F.
      • Chou P.
      Effect of aging on gender differences in neural control of heart rate.
      • Laing S.T.
      • Gluckman T.J.
      • Weinberg K.M.
      • Lahiri M.K.
      • Ng J.
      • Goldberger J.J.
      Autonomic effects of exercise-based cardiac rehabilitation.
      • Thayer J.F.
      • Ahs F.
      • Fredrikson M.
      • Sollers 3rd, J.J.
      • Wager T.D.
      A meta-analysis of heart rate variability and neuroimaging studies: Implications for heart rate variability as a marker of stress and health.
      • Tsuji H.
      • Venditti Jr., F.J.
      • Manders E.S.
      • Evans J.C.
      • Larson M.G.
      • Feldman C.L.
      • Levy D.
      Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study.
      In our study, HRV was assessed using a noninvasive approach whereby rats were placed on a small platform with three 5 × 5-cm disposable conductive plate electrodes (ECGenie; Mouse Specifics, Framingham, MA). Rats were free to explore the platform during recording. Only traces recorded during immobility on the platform were used for analysis. The electrocardiogram signal was recorded when 1 forepaw and the contralateral hind paw contacted 2 different electrodes. Only traces between 5 and 30 seconds long were used for analysis. Results from multiple traces were used to calculate a mean value for each rat. All rodents were habituated to the device before recording to minimize stress and movement artifact. Electrocardiogram signals were analyzed using LabChart software (ADInstruments, Colorado Springs, CO) to calculate standard deviation of the R-R interval (SDNN) as well as the root mean square of successive differences (RMSSD). As described elsewhere,
      • Farraj A.K.
      • Haykal-Coates N.
      • Winsett D.W.
      • Hazari M.S.
      • Carll A.P.
      • Rowan W.H.
      • Ledbetter A.D.
      • Cascio W.E.
      • Costa D.L.
      Increased non-conducted P-wave arrhythmias after a single oil fly ash inhalation exposure in hypertensive rats.
      • Mabe A.M.
      • Hoover D.B.
      Structural and functional cardiac cholinergic deficits in adult neurturin knockout mice.
      SDNN is considered to represent total variability in the recording and is calculated by determining the SDNNs in the given trace. RMSSD, however, is thought to reflect mainly the high frequency component of the given trace.
      • Balocchi R.
      • Cantini F.
      • Varanini M.
      • Raimondi G.
      • Legramante J.M.
      • Macerata A.
      Revisiting the potential of time-domain indexes in short-term HRV analysis.
      • Sollers 3rd, J.J.
      • Buchanan T.W.
      • Mowrer S.M.
      • Hill L.K.
      • Thayer J.F.
      Comparison of the ratio of the standard deviation of the R-R interval and the root mean squared successive differences (SD/rMSSD) to the low frequency-to-high frequency (LF/HF) ratio in a patient population and normal healthy controls.
      RMSSD is calculated as the square root of the mean of the squares of the successive differences between adjacent R-R intervals. Similar to other groups,
      • Arras M.
      • Rettich A.
      • Cinelli P.
      • Kasermann H.P.
      • Burki K.
      Assessment of post-laparotomy pain in laboratory mice by telemetric recording of heart rate and heart rate variability.
      we calculated delta scores for both SDNN and RMSSD by subtracting baseline from week 3 scores.

      Weight-Bearing and Thermal Hypersensitivity Measurements

      Static weight-bearing capacity was measured with an Incapacitance Meter (model 600; IITC Life Science, Woodland Hills, CA). Similar to humans with a painful injury to the ankle or knee, the static weight-bearing assay reflects the rodent's unwillingness or incapacity to bear weight on the injured limb. As such, it can be considered an ethologically relevant measure of mechanical hypersensitivity within the injured joint rather than on the skin. To measure static weight-bearing, we used a commercially available device (Incapacitance Meter, IITC Life Science, model 600) and used a commonly used approach.
      • Bove S.E.
      • Calcaterra S.L.
      • Brooker R.M.
      • Huber C.M.
      • Guzman R.E.
      • Juneau P.L.
      • Schrier D.J.
      • Kilgore K.S.
      Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis.
      Briefly, the rat was placed on an inclined plane within a small transparent Perspex enclosure where its tail was gently held to prevent excessive movement. When the animal had finished exploring the enclosure and hind paws were stably resting on the 2 strain gauges, the measurement was taken, expressed as the proportion of total weight placed on the left and right hind paws. Three measurements of 5 seconds each were recorded for each animal and a mean was calculated. The entire procedure lasted no more than approximately 2 minutes for each animal. For analysis, weight-bearing was expressed as the percent of contralateral scores.
      Thermal hypersensitivity was measured using the Plantar Test device (IITC Life Science, model 400), whereby the latency to withdraw from a radiant light beam directed at the plantar aspect of the hind paw was recorded. The intensity of the radiant light source was preset to produce withdrawal latencies of 10 to 12 seconds in naive rats. The glass surface was maintained at 30°C to reduce the potential influence of cold hypersensitivity on thermal responses. Rats were habituated to the testing enclosures for 30 minutes before testing. Each Perspex enclosure measured 10 × 20 cm with opaque side panels to prevent visual communication between rats. Three latencies were obtained for each rat with 2 to 3 minutes between measurements and a mean was calculated. For analysis, thermal latency was expressed as the percent of contralateral scores.

      Analysis

      All statistical analysis was performed with SPSS version 22 (IBM Corp, Armonk, NY). Data are represented graphically as mean ± standard error of the mean. To avoid non-normal distribution effects, logarithmic transformation of the data was performed before analysis. Unpaired t-tests, 1-way analysis of variance (ANOVA) or 2-way mixed design repeated measures ANOVA were used where indicated. Results of t-tests, 1- and 2-way ANOVAs are shown in Table 1. Post hoc tests were Bonferroni multiple comparisons tests. Analysis of nonspherical data was corrected using Greenhouse-Geisser adjustment. In all cases, P < .05 was considered significant. Linear regression analysis was used to assess the relationship between measures of voluntary running behavior (ie, total distance, average velocity) in the CFA-RUN group versus either week 3 scores in weight bearing, plasma corticosterone, or RMSSD or delta scores in weight-bearing, plasma corticosterone, or RMSSD (calculated as baseline scores subtracted from week 3 scores). To simplify statistical analysis, running behavior was binned into either weekly or total running scores over the 3 post-injection weeks.
      Table 1Description of Statistical Analysis and Results for Each Panel in Figure 1, Figure 2, Figure 3
      Figure and PanelComparisonStatisticResult
      1
       BWeekly running distanceTwo-way mixed design repeated measures ANOVAInteraction: F1.53,58.25 = 1.43, P = .247

      Groups: F1,38 = .197, P = .668

      Time: F1.53,58.25 = 1.38, P = .256
       CWeekly average velocityTwo-way mixed design repeated measures ANOVAInteraction: F2,44 = 1.68, P = .199

      Groups: F1,22 = .05, P = .819

      Time: F2,44 = 6.12, P = .005**
       DTotal running distanceUnpaired t-testt38 = .433, P = .668
       ETotal average velocityUnpaired t-testt22 = .231, P = .819
      2
       AWeight bearingTwo-way mixed design repeated measures ANOVAInteraction: F5.05,179.38 = 17.96, P < .0001***

      Groups: F2,71 = 83.67, P < .0001***

      Time: F2.53,179.38 = 49.79, P < .0001***
       BPlantar latencyTwo-way mixed design repeated measures ANOVAInteraction: F5.75,140.96 = 5.50, P < .0001***

      Groups: F2,49 = 29.03, P < .0001***

      Time: F2.88,140.96 = 6.55, P < .0001***
       CBody massTwo-way mixed design repeated measures ANOVAInteraction: F2.66,94.33 = 2.28, P = .092

      Groups: F2,71 = 1.23, P = .300

      Time: F1.33,94.33 = 245.91, P < .0001***
       DAnkle swellingTwo-way mixed design repeated measures ANOVAInteraction: F4.54,161.10 = 17.83, P < .0001***

      Groups: F2,71 = 24.81, P < .0001***

      Time: F2.27,161.10 = 86.45, P < .0001***
       EPlasma corticosteroneTwo-way mixed design repeated measures ANOVAInteraction: F6,204 = 1.27, P = .275

      Groups: F2,68 = 2.18, P < .0001***

      Time: F3,204 = 1.92, P = .128
      3
       AHeart rateTwo-way mixed design repeated measures ANOVAInteraction: F2,71 = 1.36, P = .262

      Groups: F2,71 = .976, P = .382

      Time: F1,71 = 1.88, P = .175
       BR-R intervalTwo-way mixed design repeated measures ANOVAInteraction: F2,71 = 2.05, P = .137

      Groups: F2,71 = .77, P = .465

      Time: F1,71 = 98, P = .326
       CSDNNTwo-way mixed design repeated measures ANOVAInteraction: F2,71 = 3.93, P = .024*

      Groups: F2,71 = .283, P = .754

      Time: F1,71 = .31, P = .581
       DRMSSDTwo-way mixed design repeated measures ANOVAInteraction: F2,71 = 4.29, P = .017*

      Groups: F2,71 = .055, P = .946

      Time: F1,71 = .52, P = .471
       EΔ SDNNOne-way ANOVAGroups: F2,71 = 4.36, P = .016*
       FΔ RMSSDOne-way ANOVAGroups: F2,71 = 3.92, P = .024*
      NOTE. Results of all post hoc analyses are displayed as */° in the relevant figure panel.
      P < .05.
      **P < .01.
      ***P < .0001.

      Results

      CFA-Inflamed and Sham-Injected Rodents Exhibit Robust Running Behavior

      Rats were given free access to running wheels for 2 hours per day, 4 days per week for 3 weeks, beginning 3 days post-CFA or sham injection (Fig 1A). Most rats from both groups engaged in robust running behavior within the first week of wheel access in terms of running distance (Fig 1B) as well as average velocity (Fig 1C). A 2-way mixed design repeated measures ANOVA for weekly running distance revealed no significant group, time, or interaction effects (Table 1). However, similar analysis of weekly average velocity showed a significant main effect for time (Table 1). Bonferroni post hoc analysis indicated a significant increase in average velocity between week 2 and week 3 in sham rats as well as an increase between week 1 and week 3 in the CFA-RUN group (Fig 1C). Although there was substantial inter-individual variability in total running distance and total average velocity among rats in the inflamed and sham conditions, both groups exhibited similar levels of overall running behavior (Figs 1D and E, Table 1).

      Voluntary Exercise Attenuates CFA-Induced Weight-Bearing Deficits and Thermal Hypersensitivity

      We tested static weight-bearing and thermal hypersensitivity at baseline and for each of the following 3 post-injection weeks. Two-way mixed design repeated measures ANOVA comparing the 3 treatment groups over the 4 time points revealed significant interaction, time, and group effects (Table 1). At baseline, all groups exhibited similar weight-bearing capacity (Fig 2A). Although the CFA-SED group exhibited severe weight-bearing deficits for all 3 post-injection weeks, the CFA-RUN group showed improved weight-bearing capacity from week 1. By week 3, weight-bearing capacity in the CFA-RUN group was indistinguishable from sham levels, whereas the CFA-SED group remained significantly lower than the sham group (Fig 2A).
      Figure thumbnail gr2
      Figure 2Voluntary exercise is antinociceptive. (A) Static weight-bearing on the CFA-injected paw remained significantly impaired in the CFA-SED group over the course of the study, whereas the CFA-RUN group improved from week 1 to be indistinguishable from sham animals by week 3. (B) In the CFA-SED group, withdrawal latencies to a radiant heat stimulus on the hind paw remained significantly lower than the sham group for the 3 post-CFA weeks. Thermal hypersensitivity was prevented in the CFA-RUN group. (C) All groups gained weight at a similar rate, with no statistically significant differences in body mass among the groups at any time point. (D) Ankle width in the CFA-RUN and the CFA-SED groups remained significantly wider than the sham group at all post-CFA time points. No differences between the CFA-RUN and the CFA-SED groups were observed at any time point. (E) Plasma corticosterone levels in the CFA-RUN group remained comparable with those in the sham group at all time points, whereas post-CFA levels were significantly higher in the CFA-SED group. *Significant comparisons with sham group; °significant comparisons with the CFA-RUN group. */°P < .05, **P < .01, ***/°°°P < .0001. n = 16 to 34 per group for weight-bearing and n = 12 to 28 for plantar test. Abbreviation: BL, baseline.
      In a subset of rats we also measured thermal withdrawal latencies to a beam of radiant light directed to the plantar aspect of the ipsilateral and contralateral paws (Fig 2B). Two-way mixed design repeated measures ANOVA comparing treatment groups over time revealed significant interaction, time, and group effects (Table 1). Although rats in the CFA-SED group exhibited ongoing latency reductions lasting the full 3 post-injection weeks, 1 week of access to running wheels prevented the development of thermal hypersensitivity in the CFA-RUN group (Fig 2B).

      Voluntary Exercise Does Not Alter Weight Gain or Swelling of the Inflamed Limb

      Body mass increased similarly over time in all 3 groups (Fig 2C), as indicated by a significant main effect for time but no group or interaction effects (Table 1). In terms of swelling of the ipsilateral ankle, intra-articular injection of CFA produced robust swelling in the CFA-SED and CFA-RUN groups (Fig 2D). Specifically, 2-way mixed design repeated measures ANOVA comparing the 3 treatment groups over the 4 time points revealed significant interaction, time, and group effects (Table 1). Post hoc Bonferroni multiple comparison tests revealed that ipsilateral ankle swelling was significantly greater than sham for both CFA-injected groups at all post-injection time points, with no significant differences between the 2 CFA-injected groups (Fig 2D).

      Voluntary Exercise Attenuates CFA-Induced Stress-Related Outcomes

      To account for the effect of stress, we measured plasma corticosterone in the 3 groups at baseline and at all 3 post-injection weeks (Fig 2E). Two-way mixed design repeated measures ANOVA yielded significant group effects, but no time or interaction effects (Table 1). At baseline, all groups exhibited similar levels of plasma corticosterone (Fig 2E). However, for all 3 post-injection weeks, plasma corticosterone levels in the CFA-SED group were significantly higher than the sham group and the CFA-RUN group. Corticosterone levels for the CFA-RUN group were indistinguishable from sham at all time points (Fig 2E). No significant differences were observed between baseline and post-injection time points for any group.
      Electrocardiographic data were collected noninvasively at baseline and at week 3 post-injection for all 3 groups. No significant interaction, group, or time effects were found (Table 1) for either heart rate (Fig 3A) or R-R interval (Fig 3B). We also measured how persistent inflammation and access to exercise altered HRV, measured as either SDNN or RMSSD. Two-way mixed design repeated measures ANOVAs comparing either SDNN or RMSSD for the 3 groups over 2 time points (baseline and week 3) revealed significant interaction effects but no main effects for time or groups (Table 1). Bonferroni post hoc analysis indicated that SDNN scores decreased over time for the CFA-SED group, whereas a trend toward an increased SDNN was found for the sham group (Fig 3C). Similarly, post hoc analyses showed that RMSSD scores increased over time for the sham group, whereas a trend for decreased RMSSD for the CFA-SED group was observed (Fig 3D). For SDNN and RMSSD measures, no significant group differences were observed in baseline or week 3 scores. We also calculated delta scores for SDNN (Fig 3E) and RMSSD (Fig 3F). One-way ANOVAs comparing the 3 groups were significant for SDNN and RMSSD (Table 1). Post hoc Bonferroni multiple comparison tests revealed a significant decrease in SDNN for the CFA-SED group compared with the sham group (Fig 3E). Similarly for RMSSD, post hoc testing revealed a significant decrease in RMSSD for the CFA-SED group compared with the sham group (Fig 3F).
      Figure thumbnail gr3
      Figure 3Voluntary exercise prevents CFA-induced reductions in HRV. (A) and (B) Neither heart rate nor R-R interval were significantly changed by CFA or access to running wheels. (C) However, a significant decrease in SDNN for the CFA-SED group along with a trend toward increased SDNN for the sham group were found. (D) Similarly, a trend toward a decrease in RMSSD for the CFA-SED group along with a significant increase in SDNN for the sham group were found. Delta scores for SDNN and RMSSD showed that CFA-induced decreases in SDNN (E) and RMSSD (F) were mitigated in the CFA-RUN group. *Significant comparisons with sham group. *P < .05, n = 16 to 34. Abbreviations: BPM, beats per minute; BL, baseline.

      The Level of Voluntary Running is Unrelated to the Amount of Analgesia or Stress Reduction

      We observed clear group-level benefits of voluntary exercise on pain- and stress-related outcomes, but no effects on ankle swelling, suggesting that the beneficial effects of exercise seen in our study may not be related to peripheral inflammatory processes that maintain swelling. Considering that intense exercise can yield short-term opioid-dependent euphoria (ie, ‘runners high’)
      • Boecker H.
      • Sprenger T.
      • Spilker M.E.
      • Henriksen G.
      • Koppenhoefer M.
      • Wagner K.J.
      • Valet M.
      • Berthele A.
      • Tolle T.R.
      The runner’s high: Opioidergic mechanisms in the human brain.
      and analgesia,
      • Koltyn K.F.
      Analgesia following exercise: A review.
      we hypothesized that rats exhibiting the highest level of running behavior would also have the greatest improvement in pain- and stress-related outcomes. Therefore, in the inflamed exercise group (CFA-RUN) we assessed the relationship between the level of exercise and outcomes including weight-bearing, plasma corticosterone, and RMSSD. Using linear regression analysis, we found no significant relationship between total running distance and weight-bearing scores (Fig 4A), plasma corticosterone levels (Fig 4B), or RMSSD measurements (Fig 4C) from week 3. Similarly, we found no significant relationship between average running velocity and weight-bearing scores (Fig 4D), plasma corticosterone levels (Fig 4E), or RMSSD measurements (Fig 4F) from week 3. We also assessed how either total running distance or average velocity relate to the delta scores between baseline and week 3 for weight-bearing capacity (Figs 4G and H), plasma corticosterone (Figs 4I and J), and RMSSD (Figs 4K and L). No significant correlations were found except for a positive correlation between Δ corticosterone and average velocity (Fig 4J), whereas increased overall velocity was associated with increased plasma corticosterone levels at week 3 post-CFA.
      Figure thumbnail gr4
      Figure 4Running measures are unrelated to degree of antinociception or reduction in stress-related outcomes. In the CFA-RUN group, linear regression analysis shows that total running distance is unrelated to week 3 weight-bearing (A), plasma corticosterone (B), and RMSSD (C). Similarly, average velocity is unrelated to week 3 weight-bearing (D), plasma corticosterone (E), and RMSSD (F). Change in weight-bearing between baseline and week 3 is not associated with either total running distance or average velocity (G) and (H). Similarly, change in corticosterone level between baseline and week 3 is not associated with total running distance (I), but is associated with average velocity (J). Change in RMSSD between baseline and week 3 is not associated with either total running distance or average velocity (K) and (L). **P < .01, n = 12 to 24.

      Discussion

      In this study, we have shown that regular but modest voluntary wheel running reduces CFA-induced pain- and stress-related outcomes without altering body weight gain or peripheral inflammation-induced swelling of the hind paw. Furthermore, we show that although the level of voluntary running is highly variable among individual rodents, the amount of running is unrelated to either the degree of analgesia or stress reduction in physically active CFA-inflamed rats.

      Weight-Bearing and Thermal Latency

      To better reflect the human weight-bearing deficits commonly seen after lower extremity injury or arthritis, our main outcome variable was static weight-bearing, or the proportion of body weight that the rodent can bear on its inflamed leg. Although sedentary inflamed rats experienced ongoing deficits in weight-bearing over the 3-week period, inflamed rats engaging in voluntary running exhibited a steady improvement in weight-bearing capacity of the ipsilateral paw, achieving basal levels by 3 weeks post-CFA. In studies using forced exercise paradigms, although not all groups describe complete exercise-induced reversal of hypersensitivity to von Frey stimulation, most produce progressive improvements over spans of a few days to more than 5 weeks.
      • Bement M.K.
      • Sluka K.A.
      Low-intensity exercise reverses chronic muscle pain in the rat in a naloxone-dependent manner.
      • Bobinski F.
      • Martins D.F.
      • Bratti T.
      • Mazzardo-Martins L.
      • Winkelmann-Duarte E.C.
      • Guglielmo L.G.
      • Santos A.R.
      Neuroprotective and neuroregenerative effects of low-intensity aerobic exercise on sciatic nerve crush injury in mice.
      • Chen Y.W.
      • Chiu C.C.
      • Hsieh P.L.
      • Hung C.H.
      • Wang J.J.
      Treadmill training combined with insulin suppresses diabetic nerve pain and cytokines in rat sciatic nerve.
      • Chen Y.W.
      • Hsieh P.L.
      • Chen Y.C.
      • Hung C.H.
      • Cheng J.T.
      Physical exercise induces excess hsp72 expression and delays the development of hyperalgesia and allodynia in painful diabetic neuropathy rats.
      • Chen Y.W.
      • Li Y.T.
      • Chen Y.C.
      • Li Z.Y.
      • Hung C.H.
      Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve.
      • Chen Y.W.
      • Tzeng J.I.
      • Lin M.F.
      • Hung C.H.
      • Wang J.J.
      Forced treadmill running suppresses postincisional pain and inhibits upregulation of substance P and cytokines in rat dorsal root ganglion.
      • Chuganji S.
      • Nakano J.
      • Sekino Y.
      • Hamaue Y.
      • Sakamoto J.
      • Okita M.
      Hyperalgesia in an immobilized rat hindlimb: effect of treadmill exercise using non-immobilized limbs.
      • Cobianchi S.
      • Casals-Diaz L.
      • Jaramillo J.
      • Navarro X.
      Differential effects of activity dependent treatments on axonal regeneration and neuropathic pain after peripheral nerve injury.
      • Cobianchi S.
      • Marinelli S.
      • Florenzano F.
      • Pavone F.
      • Luvisetto S.
      Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury.
      • Detloff M.R.
      • Smith E.J.
      • Quiros Molina D.
      • Ganzer P.D.
      • Houle J.D.
      Acute exercise prevents the development of neuropathic pain and the sprouting of non-peptidergic (GDNF- and artemin-responsive) c-fibers after spinal cord injury.
      • Hutchinson K.J.
      • Gomez-Pinilla F.
      • Crowe M.J.
      • Ying Z.
      • Basso D.M.
      Three exercise paradigms differentially improve sensory recovery after spinal cord contusion in rats.
      • Kim Y.J.
      • Byun J.H.
      • Choi I.S.
      Effect of exercise on micro-opioid receptor expression in the rostral ventromedial medulla in neuropathic pain rat model.
      • Korb A.
      • Bonetti L.V.
      • da Silva S.A.
      • Marcuzzo S.
      • Ilha J.
      • Bertagnolli M.
      • Partata W.A.
      • Faccioni-Heuser M.C.
      Effect of treadmill exercise on serotonin immunoreactivity in medullary raphe nuclei and spinal cord following sciatic nerve transection in rats.
      • Luan S.
      • Wan Q.
      • Luo H.
      • Li X.
      • Ke S.
      • Lin C.
      • Wu Y.
      • Wu S.
      • Ma C.
      Running exercise alleviates pain and promotes cell proliferation in a rat model of intervertebral disc degeneration.
      • Morimoto A.
      • Winaga H.
      • Sakurai H.
      • Ohmichi M.
      • Yoshimoto T.
      • Ohmichi Y.
      • Matsui T.
      • Ushida T.
      • Okada T.
      • Sato J.
      Treadmill running and static stretching improve long-lasting hyperalgesia, joint limitation, and muscle atrophy induced by cast immobilization in rats.
      • Shankarappa S.A.
      • Piedras-Renteria E.S.
      • Stubbs Jr., E.B.
      Forced-exercise delays neuropathic pain in experimental diabetes: Effects on voltage-activated calcium channels.
      • Sharma N.K.
      • Ryals J.M.
      • Gajewski B.J.
      • Wright D.E.
      Aerobic exercise alters analgesia and neurotrophin-3 synthesis in an animal model of chronic widespread pain.
      • Stagg N.J.
      • Mata H.P.
      • Ibrahim M.M.
      • Henriksen E.J.
      • Porreca F.
      • Vanderah T.W.
      • Philip Malan Jr., T.
      Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: Role of endogenous opioids.
      • Yoon H.
      • Thakur V.
      • Isham D.
      • Fayad M.
      • Chattopadhyay M.
      Moderate exercise training attenuates inflammatory mediators in DRG of Type 1 diabetic rats.
      Strikingly, development of the CFA-induced thermal hypersensitivity observed in the sedentary inflamed group was prevented by only 1 week of voluntary running. The 8 studies examining exercise-induced changes in thermal hypersensitivity all used neuropathic pain models, generally describing progressive attenuation or delayed onset of thermal hypersensitivity.
      • Chen Y.W.
      • Chiu C.C.
      • Hsieh P.L.
      • Hung C.H.
      • Wang J.J.
      Treadmill training combined with insulin suppresses diabetic nerve pain and cytokines in rat sciatic nerve.
      • Chen Y.W.
      • Hsieh P.L.
      • Chen Y.C.
      • Hung C.H.
      • Cheng J.T.
      Physical exercise induces excess hsp72 expression and delays the development of hyperalgesia and allodynia in painful diabetic neuropathy rats.
      • Chen Y.W.
      • Li Y.T.
      • Chen Y.C.
      • Li Z.Y.
      • Hung C.H.
      Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve.
      • Cobianchi S.
      • Casals-Diaz L.
      • Jaramillo J.
      • Navarro X.
      Differential effects of activity dependent treatments on axonal regeneration and neuropathic pain after peripheral nerve injury.
      • Detloff M.R.
      • Smith E.J.
      • Quiros Molina D.
      • Ganzer P.D.
      • Houle J.D.
      Acute exercise prevents the development of neuropathic pain and the sprouting of non-peptidergic (GDNF- and artemin-responsive) c-fibers after spinal cord injury.
      • Kim Y.J.
      • Byun J.H.
      • Choi I.S.
      Effect of exercise on micro-opioid receptor expression in the rostral ventromedial medulla in neuropathic pain rat model.
      • Lopez-Alvarez V.M.
      • Modol L.
      • Navarro X.
      • Cobianchi S.
      Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury.
      • Stagg N.J.
      • Mata H.P.
      • Ibrahim M.M.
      • Henriksen E.J.
      • Porreca F.
      • Vanderah T.W.
      • Philip Malan Jr., T.
      Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: Role of endogenous opioids.
      However, considering the differences between voluntary and forced exercise paradigms, the wide variability in exercise intensities used, the different pain models, and species/strain differences, it is difficult to directly compare study outcomes.
      In contrast to studies using exercise as a therapeutic tool, a number of studies have used voluntary running behavior as a diagnostic tool in persistent pain states.
      • Cobos E.J.
      • Ghasemlou N.
      • Araldi D.
      • Segal D.
      • Duong K.
      • Woolf C.J.
      Inflammation-induced decrease in voluntary wheel running in mice: A nonreflexive test for evaluating inflammatory pain and analgesia.
      • Grace P.M.
      • Loram L.C.
      • Christianson J.P.
      • Strand K.A.
      • Flyer-Adams J.G.
      • Penzkover K.R.
      • Forsayeth J.R.
      • van Dam A.M.
      • Mahoney M.J.
      • Maier S.F.
      • Chavez R.A.
      • Watkins L.R.
      Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy.
      • Kandasamy R.
      • Calsbeek J.J.
      • Morgan M.M.
      Analysis of inflammation-induced depression of home cage wheel running in rats reveals the difference between opioid antinociception and restoration of function.
      • Kandasamy R.
      • Calsbeek J.J.
      • Morgan M.M.
      Home cage wheel running is an objective and clinically relevant method to assess inflammatory pain in male and female rats.
      • Stevenson G.W.
      • Mercer H.
      • Cormier J.
      • Dunbar C.
      • Benoit L.
      • Adams C.
      • Jezierski J.
      • Luginbuhl A.
      • Bilsky E.J.
      Monosodium iodoacetate-induced osteoarthritis produces pain-depressed wheel running in rats: Implications for preclinical behavioral assessment of chronic pain.
      • Whitehead R.A.
      • Lam N.L.
      • Sun M.S.
      • Sanchez J.
      • Noor S.
      • Vanderwall A.G.
      • Petersen T.R.
      • Martin H.B.
      • Milligan E.D.
      Chronic sciatic neuropathy in rat reduces voluntary wheel-running activity with concurrent chronic mechanical allodynia.
      In studies using CFA-induced inflammation, wheel-running in rodents pretrained with running wheels is reduced for approximately 3 days postinjury.
      • Cobos E.J.
      • Ghasemlou N.
      • Araldi D.
      • Segal D.
      • Duong K.
      • Woolf C.J.
      Inflammation-induced decrease in voluntary wheel running in mice: A nonreflexive test for evaluating inflammatory pain and analgesia.
      • Kandasamy R.
      • Calsbeek J.J.
      • Morgan M.M.
      Analysis of inflammation-induced depression of home cage wheel running in rats reveals the difference between opioid antinociception and restoration of function.
      • Kandasamy R.
      • Calsbeek J.J.
      • Morgan M.M.
      Home cage wheel running is an objective and clinically relevant method to assess inflammatory pain in male and female rats.
      To avoid initiating exercise in this window of reduced activity, access to running wheels in our study was granted 3 days after CFA injection. As such, although we did not measure running behavior immediately after injury, no differences between sham and CFA-RUN groups were observed at later time points, which appears to be consistent with studies indicating relatively brief running deficits after CFA.
      • Cobos E.J.
      • Ghasemlou N.
      • Araldi D.
      • Segal D.
      • Duong K.
      • Woolf C.J.
      Inflammation-induced decrease in voluntary wheel running in mice: A nonreflexive test for evaluating inflammatory pain and analgesia.
      • Kandasamy R.
      • Calsbeek J.J.
      • Morgan M.M.
      Analysis of inflammation-induced depression of home cage wheel running in rats reveals the difference between opioid antinociception and restoration of function.
      • Kandasamy R.
      • Calsbeek J.J.
      • Morgan M.M.
      Home cage wheel running is an objective and clinically relevant method to assess inflammatory pain in male and female rats.
      • Stevenson G.W.
      • Mercer H.
      • Cormier J.
      • Dunbar C.
      • Benoit L.
      • Adams C.
      • Jezierski J.
      • Luginbuhl A.
      • Bilsky E.J.
      Monosodium iodoacetate-induced osteoarthritis produces pain-depressed wheel running in rats: Implications for preclinical behavioral assessment of chronic pain.

      Stress-Related Outcomes

      Plasma corticosterone is well known to reflect hypothalamic-pituitary-adrenal axis neuroendocrine responses to stressors, whereas HRV reflects the drive by various regulatory systems to adapt to stressors via fluctuations in the time intervals between successive heartbeats.
      • Thayer J.F.
      • Ahs F.
      • Fredrikson M.
      • Sollers 3rd, J.J.
      • Wager T.D.
      A meta-analysis of heart rate variability and neuroimaging studies: Implications for heart rate variability as a marker of stress and health.
      Although there is as yet no broad consensus on the optimal measure of HRV, higher levels of HRV are generally associated with improved health and stress adaptability, whereas reductions are associated with deficits in stress adaptation that can result in overall poorer health and decreased longevity.
      • Dekker J.M.
      • Schouten E.G.
      • Klootwijk P.
      • Pool J.
      • Swenne C.A.
      • Kromhout D.
      Heart rate variability from short electrocardiographic recordings predicts mortality from all causes in middle-aged and elderly men. The Zutphen Study.
      • Kuo T.B.
      • Lin T.
      • Yang C.C.
      • Li C.L.
      • Chen C.F.
      • Chou P.
      Effect of aging on gender differences in neural control of heart rate.
      • Laing S.T.
      • Gluckman T.J.
      • Weinberg K.M.
      • Lahiri M.K.
      • Ng J.
      • Goldberger J.J.
      Autonomic effects of exercise-based cardiac rehabilitation.
      • Thayer J.F.
      • Ahs F.
      • Fredrikson M.
      • Sollers 3rd, J.J.
      • Wager T.D.
      A meta-analysis of heart rate variability and neuroimaging studies: Implications for heart rate variability as a marker of stress and health.
      • Tsuji H.
      • Venditti Jr., F.J.
      • Manders E.S.
      • Evans J.C.
      • Larson M.G.
      • Feldman C.L.
      • Levy D.
      Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study.
      In our study, we analyzed electrocardiographic data as SDNN as well as RMSSD, well characterized measures that are understood to reflect total variability and the high frequency component of HRV, respectively.
      • Balocchi R.
      • Cantini F.
      • Varanini M.
      • Raimondi G.
      • Legramante J.M.
      • Macerata A.
      Revisiting the potential of time-domain indexes in short-term HRV analysis.
      • Sollers 3rd, J.J.
      • Buchanan T.W.
      • Mowrer S.M.
      • Hill L.K.
      • Thayer J.F.
      Comparison of the ratio of the standard deviation of the R-R interval and the root mean squared successive differences (SD/rMSSD) to the low frequency-to-high frequency (LF/HF) ratio in a patient population and normal healthy controls.
      Although preventative (preinjury) initiation of voluntary wheel-running has recently been demonstrated to produce beneficial results on mechanical hypersensitivity and HRV measures in a mouse model of chronic musculoskeletal pain,
      • Sabharwal R.
      • Rasmussen L.
      • Sluka K.A.
      • Chapleau M.W.
      Exercise prevents development of autonomic dysregulation and hyperalgesia in a mouse model of chronic muscle pain.
      our findings show that voluntary exercise initiated therapeutically (ie, after injury) also prevent the CFA-induced decreases in HRV. These findings are consistent with human studies showing that persistent pain reduces HRV,
      • Meeus M.
      • Goubert D.
      • De Backer F.
      • Struyf F.
      • Hermans L.
      • Coppieters I.
      • De Wandele I.
      • Da Silva H.
      • Calders P.
      Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: A systematic review.
      whereas aerobic exercise improves HRV in healthy individuals
      • Albinet C.T.
      • Boucard G.
      • Bouquet C.A.
      • Audiffren M.
      Increased heart rate variability and executive performance after aerobic training in the elderly.
      • De Meersman R.E.
      Heart rate variability and aerobic fitness.
      • Jurca R.
      • Church T.S.
      • Morss G.M.
      • Jordan A.N.
      • Earnest C.P.
      Eight weeks of moderate-intensity exercise training increases heart rate variability in sedentary postmenopausal women.
      • Lazoglu A.H.
      • Glace B.
      • Gleim G.W.
      • Coplan N.L.
      Exercise and heart rate variability.
      • Levy W.C.
      • Cerqueira M.D.
      • Harp G.D.
      • Johannessen K.A.
      • Abrass I.B.
      • Schwartz R.S.
      • Stratton J.R.
      Effect of endurance exercise training on heart rate variability at rest in healthy young and older men.
      • Sandercock G.R.
      • Bromley P.D.
      • Brodie D.A.
      Effects of exercise on heart rate variability: Inferences from meta-analysis.
      • Stein P.K.
      • Ehsani A.A.
      • Domitrovich P.P.
      • Kleiger R.E.
      • Rottman J.N.
      Effect of exercise training on heart rate variability in healthy older adults.
      as well as during persistent pain states
      • Sanudo B.
      • Carrasco L.
      • de Hoyo M.
      • Figueroa A.
      • Saxton J.M.
      Vagal modulation and symptomatology following a 6-month aerobic exercise program for women with fibromyalgia.
      (but also see Beaver et al
      • Bardal E.M.
      • Roeleveld K.
      • Mork P.J.
      Aerobic and cardiovascular autonomic adaptations to moderate intensity endurance exercise in patients with fibromyalgia.
      ).
      In addition to HRV, we also measured plasma corticosterone levels in the 3 groups. Similar to the elevated plasma cortisol levels seen in human chronic pain populations,
      • Van Uum S.H.
      • Sauve B.
      • Fraser L.A.
      • Morley-Forster P.
      • Paul T.L.
      • Koren G.
      Elevated content of cortisol in hair of patients with severe chronic pain: A novel biomarker for stress.
      our sedentary CFA-injected rats exhibited increased plasma corticosterone levels compared with the sham group. In CFA-injected rats with access to running wheels, however, we observed significantly lower corticosterone levels that were comparable with sham levels. Although no studies were found assessing voluntary exercise-induced effects on plasma corticosterone in persistent pain states, forced exercise increases plasma corticosterone levels in models of traumatic brain injury
      • Griesbach G.S.
      • Tio D.L.
      • Vincelli J.
      • McArthur D.L.
      • Taylor A.N.
      Differential effects of voluntary and forced exercise on stress responses after traumatic brain injury.
      and brain ischemia,
      • Ke Z.
      • Yip S.P.
      • Li L.
      • Zheng X.X.
      • Tong K.Y.
      The effects of voluntary, involuntary, and forced exercises on brain-derived neurotrophic factor and motor function recovery: A rat brain ischemia model.
      whereas voluntary exercise prevents corticosterone increases in these models as well as preventing stress-induced increases in plasma corticosterone
      • Greenwood B.N.
      • Loughridge A.B.
      • Sadaoui N.
      • Christianson J.P.
      • Fleshner M.
      The protective effects of voluntary exercise against the behavioral consequences of uncontrollable stress persist despite an increase in anxiety following forced cessation of exercise.
      and other stress hormones.
      • Melo S.F.
      • Lunz W.
      • Fontes E.P.
      • Dias C.M.
      • Carneiro Jr., M.A.
      • Moura A.G.
      • Del Carlo R.J.
      • Natali A.J.
      Different levels of Hsp72 in female rat myocardium in response to voluntary exercise and forced exercise.
      As such, our results support a beneficial role for voluntary exercise-related stress and cardiac health benefits in persistent pain states.

      Peripheral Inflammation

      Although some groups have reported that aerobic exercise can decrease swelling around the arthritic joint
      • Minor M.A.
      • Hewett J.E.
      • Webel R.R.
      • Anderson S.K.
      • Kay D.R.
      Efficacy of physical conditioning exercise in patients with rheumatoid arthritis and osteoarthritis.
      and that reduced body weight can attenuate osteoarthritic joint pain in humans,
      • Gudbergsen H.
      • Boesen M.
      • Lohmander L.S.
      • Christensen R.
      • Henriksen M.
      • Bartels E.M.
      • Christensen P.
      • Rindel L.
      • Aaboe J.
      • Danneskiold-Samsoe B.
      • Riecke B.F.
      • Bliddal H.
      Weight loss is effective for symptomatic relief in obese subjects with knee osteoarthritis independently of joint damage severity assessed by high-field MRI and radiography.
      • Powell A.
      • Teichtahl A.J.
      • Wluka A.E.
      • Cicuttini F.M.
      Obesity: A preventable risk factor for large joint osteoarthritis which may act through biomechanical factors.
      our findings show that a relatively moderate voluntary exercise paradigm altered neither body weight gain nor ankle swelling compared with the sedentary inflamed group. Of course, although ankle swelling does not reflect the full complement of peripheral inflammatory processes, it underscores the potential independence of pain and swelling in peripheral inflammatory pain states. Indeed, although swelling as well as hypersensitivity can be dose-dependently reduced with nonsteroidal anti-inflammatory drugs,
      • Gris G.
      • Merlos M.
      • Vela J.M.
      • Zamanillo D.
      • Portillo-Salido E.
      S1RA, a selective sigma-1 receptor antagonist, inhibits inflammatory pain in the carrageenan and complete Freund’s adjuvant models in mice.
      • Mirshafiey A.
      • Cuzzocrea S.
      • Rehm B.
      • Mazzon E.
      • Saadat F.
      • Sotoude M.
      Treatment of experimental arthritis with M2000, a novel designed non-steroidal anti-inflammatory drug.
      hypersensitivity can also be attenuated independently from swelling.
      • Brittain J.M.
      • Duarte D.B.
      • Wilson S.M.
      • Zhu W.
      • Ballard C.
      • Johnson P.L.
      • Liu N.
      • Xiong W.
      • Ripsch M.S.
      • Wang Y.
      • Fehrenbacher J.C.
      • Fitz S.D.
      • Khanna M.
      • Park C.K.
      • Schmutzler B.S.
      • Cheon B.M.
      • Due M.R.
      • Brustovetsky T.
      • Ashpole N.M.
      • Hudmon A.
      • Meroueh S.O.
      • Hingtgen C.M.
      • Brustovetsky N.
      • Ji R.R.
      • Hurley J.H.
      • Jin X.
      • Shekhar A.
      • Xu X.M.
      • Oxford G.S.
      • Vasko M.R.
      • White F.A.
      • Khanna R.
      Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca(2)(+) channel complex.
      • Doak G.J.
      • Sawynok J.
      Formalin-induced nociceptive behavior and edema: Involvement of multiple peripheral 5-hydroxytryptamine receptor subtypes.
      • Walker K.
      • Bowes M.
      • Panesar M.
      • Davis A.
      • Gentry C.
      • Kesingland A.
      • Gasparini F.
      • Spooren W.
      • Stoehr N.
      • Pagano A.
      • Flor P.J.
      • Vranesic I.
      • Lingenhoehl K.
      • Johnson E.C.
      • Varney M.
      • Urban L.
      • Kuhn R.
      Metabotropic glutamate receptor subtype 5 (mGlu5) and nociceptive function. I. Selective blockade of mGlu5 receptors in models of acute, persistent and chronic pain.
      Therefore, although ankle swelling alone should not be considered to be a definitive measure of the state of peripheral inflammation, it suggests that the processes underlying ongoing swelling may be unaffected by voluntary exercise, in contrast to pain- and stress-related behaviors. Clearly, studies addressing specific peripheral inflammatory processes are required.

      Variability in Running Behavior

      Some rats are more inclined to engage in high-level running whereas others remain relatively low-level runners.
      • Afonso V.M.
      • Eikelboom R.
      Relationship between wheel running, feeding, drinking, and body weight in male rats.
      • D’Anci K.E.
      • Gerstein A.V.
      • Kanarek R.B.
      Long-term voluntary access to running wheels decreases kappa-opioid antinociception.
      • Tarr B.A.
      • Kellaway L.A.
      • St Clair Gibson A.
      • Russell V.A.
      Voluntary running distance is negatively correlated with striatal dopamine release in untrained rats.
      We, too, observed substantial variability in voluntary running behavior in our rats. Many groups have exploited these interindividual differences, creating breeding lines of high and low runners that were reported to have different dopaminergic
      • Mathes W.F.
      • Nehrenberg D.L.
      • Gordon R.
      • Hua K.
      • Garland Jr., T.
      • Pomp D.
      Dopaminergic dysregulation in mice selectively bred for excessive exercise or obesity.
      • Waters R.P.
      • Renner K.J.
      • Pringle R.B.
      • Summers C.H.
      • Britton S.L.
      • Koch L.G.
      • Swallow J.G.
      Selection for aerobic capacity affects corticosterone, monoamines and wheel-running activity.
      and opioidergic tone,
      • Li G.
      • Rhodes J.S.
      • Girard I.
      • Gammie S.C.
      • Garland Jr., T.
      Opioid-mediated pain sensitivity in mice bred for high voluntary wheel running.
      as well as plasma corticosterone responses to running.
      • Waters R.P.
      • Renner K.J.
      • Pringle R.B.
      • Summers C.H.
      • Britton S.L.
      • Koch L.G.
      • Swallow J.G.
      Selection for aerobic capacity affects corticosterone, monoamines and wheel-running activity.
      Considering that high-intensity aerobic exercise increases endogenous opioid-induced euphoria
      • Boecker H.
      • Sprenger T.
      • Spilker M.E.
      • Henriksen G.
      • Koppenhoefer M.
      • Wagner K.J.
      • Valet M.
      • Berthele A.
      • Tolle T.R.
      The runner’s high: Opioidergic mechanisms in the human brain.
      and analgesia,
      • Koltyn K.F.
      Analgesia following exercise: A review.
      we expected that high-running inflamed rats would experience greater benefit in stress- and pain-related outcomes. Instead, with 1 exception, our data indicate that the level of running is unrelated to weight-bearing, plasma corticosterone, and HRV in a persistent inflammatory pain state. First, in terms of the significant positive correlation that we observed between average velocity and the change in plasma corticosterone, this finding is neither surprising nor contradictory to our suggestion that voluntary exercise benefits stress in persistent pain states. Specifically, although we found an association between changes in plasma corticosterone and running velocity, overall corticosterone levels were significantly lower in the CFA-RUN group compared with the CFA-SED group. Moreover, vigorous exercise can acutely increase cortisol levels in humans
      • Hill E.E.
      • Zack E.
      • Battaglini C.
      • Viru M.
      • Viru A.
      • Hackney A.C.
      Exercise and circulating cortisol levels: The intensity threshold effect.
      as well as promote longer-term cortisol increases in endurance athletes.
      • Skoluda N.
      • Dettenborn L.
      • Stalder T.
      • Kirschbaum C.
      Elevated hair cortisol concentrations in endurance athletes.
      Importantly, despite higher cortisol levels, regular exercise and high cardiorespiratory fitness are nonetheless associated with reduced risk for cardiovascular diseases.
      • Carnethon M.R.
      • Gidding S.S.
      • Nehgme R.
      • Sidney S.
      • Jacobs Jr., D.R.
      • Liu K.
      Cardiorespiratory fitness in young adulthood and the development of cardiovascular disease risk factors.
      As such, although some of the faster running rats exhibited increased levels of plasma corticosterone, corticosterone decreased for most of the group. In terms of the overall lack of association between running behavior and other outcomes, it is possible that interindividual differences in factors such as stress susceptibility and/or sensitivity to reward play a role. Indeed, reward sensitivity is not the same for everyone; response to reward and/or predictive cues varies among individuals
      • Beaver J.D.
      • Lawrence A.D.
      • van Ditzhuijzen J.
      • Davis M.H.
      • Woods A.
      • Calder A.J.
      Individual differences in reward drive predict neural responses to images of food.
      • Cohen M.X.
      • Young J.
      • Baek J.M.
      • Kessler C.
      • Ranganath C.
      Individual differences in extraversion and dopamine genetics predict neural reward responses.
      • Shoaib M.
      • Spanagel R.
      • Stohr T.
      • Shippenberg T.S.
      Strain differences in the rewarding and dopamine-releasing effects of morphine in rats.
      in a dopamine-dependent manner.
      • Yacubian J.
      • Sommer T.
      • Schroeder K.
      • Glascher J.
      • Kalisch R.
      • Leuenberger B.
      • Braus D.F.
      • Buchel C.
      Gene-gene interaction associated with neural reward sensitivity.
      In fact, although the level of voluntary wheel-running correlates with gray matter volume in the rat motor cortex
      • Sumiyoshi A.
      • Taki Y.
      • Nonaka H.
      • Takeuchi H.
      • Kawashima R.
      Regional gray matter volume increases following 7days of voluntary wheel running exercise: A longitudinal VBM study in rats.
      as well as with hippocampal neurogenesis and spatial learning in mice,
      • Rhodes J.S.
      • van Praag H.
      • Jeffrey S.
      • Girard I.
      • Mitchell G.S.
      • Garland Jr., T.
      • Gage F.H.
      Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running.
      the amount of running does not correlate with nucleus accumbens ΔFosB/FosB labeling,
      • Greenwood B.N.
      • Foley T.E.
      • Le T.V.
      • Strong P.V.
      • Loughridge A.B.
      • Day H.E.
      • Fleshner M.
      Long-term voluntary wheel running is rewarding and produces plasticity in the mesolimbic reward pathway.
      conditioned place preference for the exercise chamber,
      • Belke T.W.
      • Wagner J.P.
      The reinforcing property and the rewarding aftereffect of wheel running in rats: A combination of two paradigms.
      stress resistance,
      • Greenwood B.N.
      • Foley T.E.
      • Day H.E.
      • Campisi J.
      • Hammack S.H.
      • Campeau S.
      • Maier S.F.
      • Fleshner M.
      Freewheel running prevents learned helplessness/behavioral depression: Role of dorsal raphe serotonergic neurons.
      or opioid sensitivity.
      • Kanarek R.B.
      • Gerstein A.V.
      • Wildman R.P.
      • Mathes W.F.
      • D’Anci K.E.
      Chronic running-wheel activity decreases sensitivity to morphine-induced analgesia in male and female rats.
      • Smith M.A.
      • Lyle M.A.
      Chronic exercise decreases sensitivity to mu opioids in female rats: Correlation with exercise output.
      • Smith M.A.
      • Yancey D.L.
      Sensitivity to the effects of opioids in rats with free access to exercise wheels: Mu-opioid tolerance and physical dependence.
      Therefore, it appears that although certain brain functions (ie, spatial and/or motor learning) are clearly related to the amount of exercise, the relationship between reward/stress processing and exercise is more complex.

      Limitations

      It must be noted that a few limitations influence our interpretation of the observed results. First, although we did not observe exercise-induced changes in ankle swelling, it cannot be said that ankle swelling reflects all inflammatory processes occurring in the periphery. Because we did not measure specific inflammatory mediators in the hind paw, we cannot conclude that our effects were independent of peripheral inflammatory effects. In addition, it is possible that exercise-induced changes in ankle swelling required more time to become apparent. Another important note involves the lack of association between running intensity and pain- or stress-related outcomes—a finding that appears to contrast human studies showing running intensity-related beneficial effects.
      • Koltyn K.F.
      Exercise-induced hypoalgesia and intensity of exercise.
      Although it is difficult to compare rodent running with human running behavior, it must be noted that the average self-regulated running velocity in our rodents was relatively low compared with running velocity seen in other rodent studies.
      • Koch L.G.
      • Britton S.L.
      Artificial selection for intrinsic aerobic endurance running capacity in rats.
      • Moraska A.
      • Deak T.
      • Spencer R.L.
      • Roth D.
      • Fleshner M.
      Treadmill running produces both positive and negative physiological adaptations in Sprague-Dawley rats.
      As such, it is possible that the intensity-related benefits seen in human studies are related to running intensities well above those seen in our rats. Alternatively, although higher intensity running may be beneficial for acute pain thresholds, it may have little or no effect in persistent pain states. Additional experiments are required to address these issues. Last, we are unable to address potential sex-related effects of voluntary exercise because of our exclusive use of male rats.

      Conclusions

      In this study, we addressed the question of whether or not voluntary exercise can be analgesic in the absence of stressors such as forced running. We showed that indeed, voluntary exercise improves pain-related behavior independently of running intensity. Although we did not identify a specific mechanism underlying these outcomes, the observed improvement in stress-related measures clearly shows that the analgesia was not due to increased stress, such as the stress that may be produced in forced running paradigms. As such, our study provides valuable evidence supporting not only an analgesic but also a stress-reducing role for voluntary exercise in chronic pain states that cannot necessarily be said of studies using forced exercise paradigms. Although further work is required to define the mechanisms contributing to voluntary exercise-induced analgesia, our findings suggest that consistent, self-regulated levels of exercise may be more relevant to health improvement in persistent pain states than standardized activity goals.

      Acknowledgments

      The authors thank Latoya Hyson, Scott Thompson, Graham Pitcher, and the National Institutes of Health Section on Instrumentation for their valuable advice and technical support.

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        The Journal of PainVol. 18Issue 8
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          Pitcher MH, Tarum F, Rauf IZ, Low LA, and Bushnell MC. Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation. J Pain 18:687-701.
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