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. Author manuscript; available in PMC: 2011 Apr 1.
Published in final edited form as: J Pain. 2009 Dec 3;11(4):369–377. doi: 10.1016/j.jpain.2009.08.007

Mechanisms Mediating Vibration-induced Chronic Musculoskeletal Pain Analyzed in the Rat

Olayinka A Dina 1, Elizabeth K Joseph 1, Jon D Levine 1,2,*, Paul G Green 1
PMCID: PMC2847637  NIHMSID: NIHMS162862  PMID: 19962353

Abstract

While occupational exposure to vibration is a common cause of acute and chronic musculoskeletal pain, eliminating exposure produces limited symptomatic improvement, and re-exposure precipitates rapid recurrence or exacerbation. To evaluate mechanisms underlying these pain syndromes, we have developed a model in the rat, in which exposure to vibration (60–80 Hz) induces, in skeletal muscle, both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to a pro-inflammatory cytokine or re-exposure to vibration. Exposure of a hind limb to vibration produced mechanical hyperalgesia measured in the gastrocnemius muscle of the exposed hind limb, which persisted for ~2 weeks. When nociceptive thresholds had returned to baseline, exposure to a pro-inflammatory cytokine or re-exposure to vibration produced markedly prolonged hyperalgesia. The chronic prolongation of vibration- and cytokine-hyperalgesia induced by vibration was prevented by spinal intrathecal injection of oligodeoxynucleotide (ODN) antisense to protein kinase Cε, a second messenger in nociceptors implicated in the induction and maintenance of chronic pain. Vibration-induced hyperalgesia was inhibited by spinal intrathecal administration of ODN antisense to receptors for the type-1 tumor necrosis factor-α (TNFα) receptor. Finally, in TNFα-pretreated muscle, subsequent vibration-induced hyperalgesia was markedly prolonged.

Perspective

These studies establish a model of vibration-induced acute and chronic musculoskeletal pain, and identify the proinflammatory cytokine TNFα and the second messenger PKCε as targets against which therapies might be directed to prevent and/or treat this common and very debilitating chronic pain syndrome.

Keywords: Muscle, hyperalgesia, tumor necrosis factor alpha, protein kinase c epsilon, vibration

Introduction

Musculoskeletal pain is the most common symptom produced by occupational exposure to vibration 27. Vibration-induced acute and chronic musculoskeletal pain is a significant health problem 10, 14, 17, 28 that can worsen with prolonged or repeated exposure 10, 46, 74, although the relationship between occupational exposure and musculoskeletal disorders is still poorly understood 27. Approximately 6% of the work force in industrialized countries is exposed to occupational vibration transmitted to the hand 50 with about one-third of these individuals exposed to excessive doses of vibration 30. Hand arm vibration syndrome is a common painful musculoskeletal condition that develops in these individuals 10, 17. Stopping the use of vibrating tools does not produce much short-term symptomatic improvement 43, and in long-term follow up, while frequency of attacks decreased pain severity changed minimally 49.

While little is known about the cellular mechanisms underlying work-related muscle pain syndromes 9 it is likely due, at least in part to inflammation 7, 67, 69, which sensitizes high-threshold mechano-sensitive muscle afferents 20. Cytokine involvement in muscle inflammation and subsequent chronic pain has been inferred from studies showing that in a repetitive motion-induced muscle pain model in the rat, pro-inflammatory cytokine levels are increased in the median nerve of the exercised limb 1. Pronociceptive cytokines are increased in muscle after inflammation or injury, for example tumor necrosis factor α (TNFα) is increased in muscle from patients with active myofascial pain 62 and following eccentric exercise 29. We have recently established an experimental model for chronic primary mechanical hyperalgesia in muscle induced by intramuscular administration of the inflammogen carrageenan. Following recovery to baseline nociceptive threshold, hyperalgesia produced by subsequent administration of the inflammatory mediator, prostaglandin E2 (PGE2), is markedly prolonged 23, 24. This chronic-latent enhancement of hyperalgesia, which is qualitatively similar to a model of chronic latent inflammatory pain in cutaneous tissues 5, 35, 53, 55, appears to be dependent, at least in part, on protein kinase Cε (PKCε, a second messenger that has been implicated in playing a critical role in long-lasting plasticity in nociceptor function 5, 35, 55.

To better understand the mechanisms underlying chronic ergonomic pain we developed a model of work-related muscle pain produced by vibration which gives rise to a long-term enhancement of muscle hyperalgesia after subsequent exposure to proinflammatory cytokines or re-exposure to vibration. This model has enabled us to evaluate the contribution of the pronociceptive inflammatory cytokine, TNFα, which can be increased in painful muscles, 61, 63 to chronic muscle hyperalgesia in rats.

Methods

Animals

Adult male Sprague Dawley rats weighing 250–400 g (Charles River, Hollister, CA) were used in these experiments and were housed in the Animal Care Facility at UCSF, under environmentally controlled conditions (7 am to 7 pm lights on; 21–23°C) with food and water available ad libitum. Animal care and use conformed to the NIH guidelines for the care and use of experimental animals; the UCSF Committee on Animal Research approved all experimental protocols.

Drugs

PGE2 and TNFα were purchased from Sigma Chemical Co. (St. Louis, Mo).

Mechanical vibration

The hind limbs of rats were vibrated with a Digital Vortex Genie II laboratory vortex mixer (Fisher Scientific, Waltham MA), which has a variable-speed motor with a real-time digital read-out of the vibration speed of the head. Rats were anesthetized with 3% isoflurane in oxygen and one hind leg affixed to the platform of with Micropore® surgical tape so that the knee and ankle joint angles were both ~90°, without rotational torque on the leg. The leg was vibrated at a frequency of 60–80 Hz, with a 5-mm peak-to-peak displacement amplitude. These vibration frequencies are within the range that produced by hand-held power tools (35 – 150 Hz) 58. In previous studies in the rat, more intense hind limb vibration at 80 Hz for 5 hours daily for 2 days, did not cause muscle necrosis, 40, 48 and 43.5 Hz for 4 hours daily for 7 days produced changes in myelin sheath and damage to sciatic nerve axon microtubes and microfilaments 42. In the initial experiment, data given in Figure 1, to determine whether duration of vibration differential affect nociceptive threshold, hind limbs were vibrated for either 15 or 60 minutes. In all subsequent experiments (Figures 2–4), hind limbs were vibrated for 15 minutes.

Figure 1. Vibration induces muscle hyperalgesia.

Figure 1

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One hind limb was exposed to vibration for either 15 min (filled circles, n=6) or 60 min (filled triangles, n=6), in separate groups of rats and mechanical nociceptive thresholds of the gastrocnemius muscle in that and the contralateral control extremity measured over time. Compared to the control limbs (open symbols, both n=6) there was a significant decrease in nociceptive threshold in the vibrated limbs, which lasted at least 15 days post-vibration.

Figure 2. Vibration induces hyperalgesic priming.

Figure 2

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A. Priming to subsequent vibration Twenty days after a 15 min exposure to vibration (filled circles, n=8), at which time there was complete recovery to baseline nociceptive threshold, the vibrated hind limb was again exposed to the same vibration protocol. The duration of the decrease in nociceptive threshold in the re-vibrated hind limb was significantly longer than after the initial exposure. In non-vibrated contralateral limbs (open circles, n=8) there was no change in nociceptive threshold.

B. Enhancement of PGE2 muscle hyperalgesia by vibration is prevented by PKCε antisense treatment Twenty-one days after a 15 min exposure to vibration, following recovery of nociceptive threshold to baseline, PGE2 (1 μg) was injected into the ipsilateral gastrocnemius muscle. In non-vibrated contralateral limbs (open circles, n=6) PGE2-induced hyperalgesia had completely resolved within 4 h, while in vibrated limbs (filled circles, n=6), hyperalgesia was greatly prolonged, being undiminished 14 d after PGE2 administration. In rats that had received ODN antisense against PKCε, for 3 days before and 3 days after vibration (filled triangles, n=6), PGE2–induced hyperalgesia was no longer enhanced, returning to baseline by 4 h post PGE2.

C. PKCε antisense inhibits vibration-induced hyperalgesia Administration of ODN antisense against PKCε (intrathecally) for the 3 days before vibration (filled triangles, n=6) suppressed the acute hyperalgesia measured 2 days post vibration; however by day 7 hyperalgesia developed, and persisted, at the level seen after mismatch ODN treatment (filled squares, n=6). Administration of ODN antisense against PKCε for 3 days before and 3 days after vibration (filled circles, n=6) completely prevented the expression of hyperalgesia. No significant changes in nociceptive threshold in the contralateral non-vibrated hind limb were observed (data not shown).

Figure 4. TNFα produces priming for subseqent vibration hyperalgesia.

Figure 4

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Five days after intra-muscular injection of TNFα (filled squares, n=4), following complete recovery from acute hyperalgesia, rats were exposed to a single session of unilateral hind limb vibration (filled circles and filled squares). Mechanical nociceptive thresholds, measured daily for 4 days post-vibration were significantly lower in rats that had previously received TNFα (compared to vehicle treated; filled circles, n=6). There was no change in nociceptive threshold in limbs contralateral to the vibrated limbs (open circles and open squares, both n=4).

Measurement of hyperalgesia

Mechanical nociceptive thresholds were quantified using a Chatillon digital force transducer (model DFI2, Amtek Inc., Largo, FL). Rats were lightly restrained in an acrylic holder that allows for easy access to the hind limb, and a 6 mm diameter probe attached to the transducer applied to the gastrocnemius muscle to deliver an increasing compression force. The nociceptive threshold was defined as the force, in Newtons, at which the rat withdrew its hind leg. Baseline withdrawal threshold was defined as the mean of 2 readings taken at 5-min intervals. Each hind limb is treated as an independent measure and each experiment performed on a separate group of rats. All behavioral testing was done between 10 am and 4 pm.

Intramuscular injection of agents

Rats were briefly anesthetized with 3% isoflurane to facilitate the administration of PGE2, TNFα or vehicle (in a volume of 20 μl) into the belly of the gastrocnemius muscle; skin over the injection site was marked with a fine-tip indelible pen so that the underlying injection site in the muscle could be repeatedly tested for mechanical nociceptive threshold.

Antisense oligodeoxynucleotide administration

The method for intrathecal oligodeoxynucleotide (ODN) injection has been described previously 2–4, 22, 38, 39, 52–54. Briefly, for ODN injections, rats were briefly anesthetized with 3% isoflurane, and a 30-gauge needle inserted into the subarachnoid space on the midline between the L4 and L5 vertebrae. ODN (80 μg/10 μl) was slowly injected. This procedure was repeated so that ODN was administered on 3 or 6 consecutive days. Control animals received injections of mismatch ODN.

To attenuate the expression of TNFα type-1 receptor, the antisense oligodeoxynucleotide (ODN) sequence 5′-ACACGGTGTTCTGTTTCTCC-3′ directed against a unique sequence of rat TNFα type-1 receptor was used. The mismatch ODN sequence, 5′-ACCCGTTGTTCGGTTGCTCC-3′ is the antisense sequence, with four bases mismatched (denoted by bold face). We have previously shown that this antisense ODN against TNFα type-1 receptor (at a dose of 80 μg) decreases TNFα type-1 receptor protein in dorsal root ganglia 53.

To disrupt the expression of PKCε we used a 20-mer antisense ODN sequence, 5′-GCC AGC TCG ATC TTG CGC CC-3′, directed against a unique sequence of rat PKCε. The corresponding GenBank accession number and ODN position within the cDNA sequence are XM345631 and 226–245, respectively. The mismatch ODN sequence, 5′-GCC AGC GCG ATC TTT CGC CC-3′, corresponds to the PKCε subunit antisense sequence with 2 bases mismatched (in bold typeface). We have previously shown that this antisense ODN (at a dose of 80 μg) protocol decreases PKCε protein in dorsal root ganglia 21.

A search of EMBL and NCBI GenBank Rattus norvegicus databases to TNFα type-1 receptor and PKCε identified no homologous sequences.

Experimental groups

Twelve groups of animals were used in measuring changes in nociceptive threshold. Two groups were exposed to different durations of vibration, either 15 min (n=6) or 60 min (n=6). One group was exposed to two 15 min vibration sessions (n=8). Another group received PGE2 after prior exposure to 15 min vibration (n=6). Two groups received ODN or mismatch antisense to PKCε prior to 15 min vibration (n=6), and two groups received ODN or mismatch antisense to TNFα-receptor followed by 15 min vibration (n=6 and n=4, respectively) or by intramuscular TNFα (n=4 both groups). One group received ODN to PKCε 3 days before and 3 days after vibration, and one week later PGE2 was administered intramuscularly to test for presence of priming. The last two groups were given intramuscular injection of TNFα or vehicle and after recovery to normal nociceptive thresholds, were exposed to 15 min vibration (n=4 and n=6, respectively).

Statistics

Group data are expressed as mean ± SEM of n distinct observations. Statistical comparisons were made by a two-tailed Student’s t-test (for one or two independent populations) and by one-way ANOVA for comparing multiple treatments, using StatView statistical software. P<0.05 was considered statistically significant.

Results

Vibration-induced muscle hyperalgesia

Comparing duration of vibration, 15 vs. 60 min, there was no significant main effect of vibration duration (F1,120 = 4.90; P = 0.051), but the nociceptive threshold in the gastrocnemius muscle of the hind limbs that were vibrated were significantly decreased (two-way ANOVA demonstrating a significant vibration duration × time; F12,120 = 25.04; P < 0.0001). This indicates that vibration produces muscle hyperalgesia and that the time course for decrease in nociceptive threshold is different, depending on duration of vibration exposure. The gastrocnemius muscle in the contralateral non-vibrated leg did not demonstrate a significant effect of vibration (P > 0.05, Figure 1).

Vibration-induced hyperalgesic priming

a) Vibration-induced hyperalgesic priming on subsequent vibration

Hyperalgesic priming is a phenomenon in which following recovery from inflammatory hyperalgesia (i.e. nociceptive threshold have returned to baseline) subsequent exposure to an inflammatory agent results in markedly prolonged hyperalgesia 23, 34, 35, 53–55. We tested whether exposure to vibration would affect the duration of hyperalgesia induced by a subsequent exposure to vibration. 21 days after a 15 min hind limb vibration session, when nociceptive threshold in the gastrocnemius muscle had returned to pre-vibration baseline, the hind limb was re-exposed to this vibration protocol. Two-way ANOVA demonstrated a significant effect of vibration (F1,182 = 229.74; P < 0.0001), with Bonferroni post hoc analysis showing that after the first vibration withdrawal threshold had returned to baseline by day 14, while after the second vibration, withdrawal threshold was still significantly lower than baseline at day 27 post second vibration (P<0.001), only returning to baseline by day 35 (Figure 2A).

b) Vibration-induced priming on subsequent cytokine hyperalgesia

To test whether vibration induces hyperalgesic priming to cytokine hyperalgesia in muscle, one hind limb of each rat was vibrated for 15 min and following recovery of nociceptive threshold to baseline (21 days later), PGE2 (1 μg), the proinflammatory cytokine used to characterize hyperalgesia priming in skin, 54 was injected into the gastrocnemius muscle. In the control hind limb, PGE2 produced a rapid decrease in nociceptive threshold that returned to baseline by 3 h. In the vibrated leg, however, PGE2-induced hyperalgesia was still present after 2 weeks; two-way ANOVA indicates that vibration produced significant hyperalgesia (F1,70 = 639.93; P < 0.0001), with Bonferroni post-hoc analysis demonstrating hyperalgesia only returning to baseline by day 16 (Figure 2B). Thus, vibration, like carrageenan administration in the skin 54, produces hyperalgesic priming.

c) Effect of PKCε antisense on vibration-induced hyperalgesia and vibration-induced priming

When administered once daily for 3 days prior to a 15 min vibration exposure, intrathecal injection of antisense (n=6) ODN (80 μg/20 μl, intrathecal) against PKCε prevented the expression of acute hyperalgesia for 2 days post vibration, but by day 7 hyperalgesia developed and persisted for several days, similar to that seen after mismatch ODN treatment. However, when ODN against PKCε was injected intrathecally once daily for 3 days before and 3 days after 15 min vibration, hyperalgesia was completely prevented (Figure 2C). No significant changes in nociceptive threshold in the contralateral non-vibrated hind limb were observed (data not shown). When ODN against PKCε was injected intrathecally once daily for 3 days before and 3 days after vibration, PGE2 produced a rapid decrease in nociceptive threshold that returned to baseline by 3 h, which contrasts with PGE2-induced hyperalgesia which lasted 2 weeks in rats previously exposed to vibration without ODN treatment (cf. Figure 2B)

Effect of TNFα type-1 receptor antisense treatment on vibration-induced hyperalgesia

Since proinflammatory cytokines, such as TNFα, are elevated in work-related muscle pain syndromes 12, 13, 18, 56, 70, 72, and TNFα can produce hyperalgesic priming 53, we evaluated for its role in vibration-induced hyperalgesic priming in muscle. Injection of antisense, but not mismatch ODN (80 μg/20 μl, intrathecal) against TNFα receptor type-1 subunit significantly (P<0.01) for 3 days prior to 15 min vibration, reduced the magnitude of vibration-induced acute hyperalgesia (Figure 3A). Injection of antisense but not mismatch ODNs (80 μg/20 μl, intrathecal) against this TNFα type-1 receptor significantly (P<0.01) reduced the magnitude of TNFα acute hyperalgesia (Figure 3B).

Figure 3. TNFα receptor antisense prevents TNFα hyperalgesia.

Figure 3

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A. In rats that received ODN antisense to the TNFα receptor (n=4) for 3 days prior to vibration, hyperalgesia 1 day after vibration (filled squares, n=6) was significantly less than in vibrated limbs of rats receiving mismatch TNFα antisense (open squares, n=4). There was no change in nociceptive threshold in limbs contralateral to the vibrated limbs (circles, both n=6).

B. Intrathecal administration of antisense ODN directed against the TNFα receptor (closed circles, n=4) daily for 3 days completely prevented hyperalgesia induced by subsequent intramuscular TNFα. Administration of TNFα in rats that had received mismatch ODN (open squares, n=4) did not affect the magnitude of TNFα-induced muscle hyperalgesia. There was no change in nociceptive threshold after saline in rats pretreated with either TNFα receptor (type I) antisense ODN (filled squares, n=4) or mismatch ODN (open circles, n=4).

Effect of intramuscular TNFα on hyperalgesia induced by subsequent vibration

Five days after intra-gastrocnemius injection of TNFα (100 ng), when mechanical nociceptive threshold had returned to baseline, rats were exposed to a single session of 15 min unilateral hind limb vibration. Mechanical nociceptive thresholds were measured daily for 4 days post-vibration. Repeated measures ANOVA demonstrates a significant effect of vibration (F2,8 = 10.36; P = 0.006), and Bonferroni post hoc analysis reveals that rats that had previously received TNFα had significantly greater vibration-induced hyperalgesia over the 4-day period compared to rats that had not received TNFα (Figure 4; P<0.05).

Discussion

In the current study we show that hind limb vibration enhances subsequent vibration- or inflammatory mediator-induced primary muscle hyperalgesia, i.e. produces hyperalgesic priming. Muscle vibration produced both acute mechanical hyperalgesia and a remarkably long-lasting chronic enhancement of a subsequent episode of mechanical hyperalgesia in that muscle. PKCε antisense ODN treatment prevented chronic-latent muscle hyperalgesia produced by hind limb vibration implicating this second messenger in the development of chronic muscle hyperalgesia, as also reported for hyperalgesic priming in the skin 54. We also observed that primary muscle hyperalgesia is prevented with antisense ODN treatment to ‘knock down’ type-1 receptors for TNFα in the primary afferent nociceptor innervating that muscle and that administration of TNFα produced hyperalgesic priming, shown by enhanced vibration-induced hyperalgesia. A role for TNFα in muscle hyperalgesia is consistent with the finding that TNFα was significantly increased in a use-dependent muscle pain model in which rats were trained 3–5 weeks to perform a voluntary repetitive reaching and grasping task 1. These investigators noted that rats developed histological changes in muscles and tendons (e.g. fraying tendons) and exhibited signs of repetitive motion-induced muscle pain 6, 7, and that in this model there was also a decrease in cutaneous mechanical nociceptive threshold in the paw of the exposed extremity (i.e. secondary hyperalgesia), but primary hyperalgesia by assessing muscle nociceptive threshold was not tested 25.

Several other studies have suggested an association between pain and cytokine levels in muscle 29, 31, 37, 61, 62, 70, 73. In particular, TNFα has been strongly implicated in the pathophysiology of muscle pain 31, 60–62 a suggestion further supported by our finding that intramuscular injection of TNFα produces primary mechanical hyperalgesia. We have also provided evidence that hyperalgesic priming induced by muscle vibration is dependent on PKCε, similar to our previous findings indicating a key role for PKCε in TNFα–induced cutaneous hyperalgesic priming 54, 55 and for carrageenan-induced muscle hyperalgesia 24.

Occupational exposure to vibration, which frequently produces musculoskeletal pain, and arm, shoulder and hand disabilities 32, is a significant public health problem 11, 15, 16, 26, 33, 41, 47, 51, 71. In an attempt to determine the underlying mechanism(s), several animal models have been developed. For example, electrophysiological studies by Mense and colleagues demonstrated lowered mechanical threshold in muscle nociceptors following injection of carrageenan into the cat gastrocnemius muscle 8 and increased background activity in nociceptors from rats and cats 19, while an analgesic-sensitive decrease in fore limb grip strength was observed following injection of carrageenan into triceps of rats 36. In addition to carrageenan, other agents, such as capsaicin 65 and formalin 61 have been injected intramuscularly to produce muscle hyperalgesia. However, these hyperalgesic agents are usually administered at doses that also produce overt tissue damage and immune cell infiltration 61, therefore not reflecting the more subtle changes produced by vibration. While other models using intramuscular injection of TNFα or acidic saline have been shown to produce muscle pain without causing damage to the muscle tissue or immune cell recruitment 61, 66; these approaches have been criticized as not adequately modeling chronic musculoskeletal pain syndromes 59. In a series of studies, Sluka and colleagues have evaluated a model of muscle pain produced by injection of carrageenan into the gastrocnemius muscle of rats 57, 64, 67, 68. Of note, in this model, rats develop a bilateral hyperalgesia 1–2 weeks after injection of 3 mg carrageenan into the gastrocnemius muscle 57, which contrasts with our observation in which we see no significant change in the nociceptive threshold of the hind limb contralateral to the carrageenan injection. However, Sluka and colleagues also noted that compared with 3 mg carrageenan, hyperalgesia produced by 1 mg carrageenan into the gastrocnemius muscle was not only significantly less and shorter in duration, it remained unilateral 57. This is consistent with our previous observation in which the muscle hyperalgesia following injection of 0.1 mg carrageenan into the gastrocnemius muscle was only unilateral 24, and similar in magnitude and unilateal restriction to what we observed in the vibration model. These observations suggest that magnitude of initial hyperalgesia may determine whether the subsequent hyperalgesia remains unilateral or becomes bilateral, possibly as a result of central sensitization with more intense nociceptive stimulation.

Clinically as well as economically, one of the most important aspects of work-related musculoskeletal syndromes is chronic debilitating pain. We hypothesized that this process involves cellular mechanisms in the primary afferent nociceptor different from those of acute inflammatory pain, and that after the resolution of a transient acute inflammatory event, a long-lasting state of enhanced responsiveness to subsequent hyperalgesic stimuli can be produced. For example, we have shown that intradermal injection of TNFα 53 and intramuscular injections of carrageenan 24 produce such a chronic latent enhancement of hyperalgesia. Importantly, this chronic latent muscle hyperalgesia is markedly prolonged compared to that in cutaneous inflammatory hyperalgesia 53, suggesting that this mechanism plays an even more important role in chronic muscle pain syndromes. Of note, chronic musculoskeletal pain is seen in a number of clinical disorders 44, and it is clinically more prominent than chronic cutaneous pain 45.

We describe a novel model for chronic mechanical hyperalgesia in skeletal muscle produced by vibration exposure, and the role of PKCε and TNFα. This model is based on the induction of hyperalgesic priming, which is not defined by the presence of the initial hyperalgesia, but rather the enhancement of hyperalgesia to a subsequent noxious stimulus, at a time of normal nociceptive thresholds following the initial noxious stimulus, or in the case of the current study, also a subsequent ergonomic stimulus. Thus, we observed vibration-induced hyperalgesic priming that is prevented by pretreatment with ODN antisense to PKCε. This model has clinical relevance since it tracks the transition from acute to chronic muscle pain, and has the potential to reveal cellular processes by which acute inflammation or muscle trauma can create a state of enhanced susceptibility to inflammatory mediators or subsequent mechanical stimulation. These findings, which begin to clarify mechanisms underlying a chronic muscle pain syndrome, have the potential to provide information necessary for the development of strategies for the prevention and treatment of chronic musculoskeletal pain.

Acknowledgments

This research was supported by a grant from NIAMS AR054635.

Footnotes

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