This study investigated changes in motor skills and tissues of the upper extremity (UE) with regard to injury and inflammatory reactions resulting from performance of a voluntary forelimb repetitive reaching and grasping task in rats. Rats reached for food at a rate of 4 reachedmin, 2 h/day, and 3 dayslweek for up to 8 weeks during which reach rate, task duration and movement strategies were observed. UE tissues were collected bilaterally at weekly time points of 3-8 weeks and examined for morphological changes. Serum was tested for levels of interleukin-la (IL-1) protein. The macrophage-specific antibody, E D l , was used to identify infiltrating macrophages and the ED2 antibody was used to identify resident macrophages. Rats were unable to maintain baseline reach rate in weeks 5 and 6 of task performance. Alternative patterns of movement emerged. Fraying of tendon fibrils was observed after 6 weeks in the mid-forelimb. After 4 weeks, a general elevation of EDl-IR macrophages were seen in all tissues examined bilaterally including the contralateral, uninvolved forelimb and hindlimbs. significantly more resident macrophages were seen at 6 and 8 weeks in the reach limb. At 8 weeks, serum levels of IL-la increased significantly above week 0. Our results demonstrate that performance of repetitive tasks elicits motor decrements, signs of injury and a cellular and tissue responses associated with inflammation.

Upper extremity tendinopathies are associated with performance of forceful repetitive tasks. We used our rat model of repetitive strain injury to study changes induced in forelimb flexor digitorum tendons. Rats were trained to perform a high repetition high force (HRHF) handle-pulling task (12 reaches/min at 60 AE 5% maximum pulling force [MPF]), or a low repetition negligible force (LRNF) reaching and food retrieval task (three reaches/min at 5 AE 5% MPF), for 2 h/day in 30 min sessions, 3 days/week for 3-12 weeks. Forelimb grip strength was tested. Flexor digitorum tendons were examined at midtendon at the level of the carpal tunnel for interleukin (IL)-1b, neutrophil, and macrophage influx, Substance P, connective tissue growth factor (CTGF), and periostin-like factor (PLF) immunoexpression, and histopathological changes. In HRHF rats, grip strength progressively decreased, while IL-1b levels progressively increased in the flexor digitorum peritendon (para-and epitendon combined) and endotendon with task performance. Macrophage invasion was evident in week 6 and 12 HRHF peritendon but not endotendon. Also in HRHF rats, Substance P immunoexpression increased in week 12 peritendon as did CTGF-and PLF-immunopositive fibroblasts, the increased fibroblasts contributing greatly to peritendon thickening. Endotendon collagen disorganization was evident in week 12 HRHF tendons. LRNF tendons did not differ from controls, even at 12 weeks. Thus, we observed exposure-dependent changes in flexor digitorum tendons within the carpal tunnel, including increased inflammation, nociceptor-related neuropeptide immunoexpression, and fibrotic histopathology, changes associated with grip strength decline. Keywords: cytokines; inflammation; flexor digitorum tendon; repetitive task; PLF; CTGF; WMSD Tendinopathies of the hand and wrist tendons are associated with forceful repetition in the workplace. 1-3The incidence of flexor tenosynovitis is significantly higher in strenuous meat processing jobs: 25.3% for female packers, 16.8% for female sausage makers, and 12.5% for male meat cutters. The incidence in nonstrenuous jobs was less than 1% during a 31 month study period.4,5 Manufacturing workers performing highly repetitive and forceful jobs are 29 times more likely to develop wrist and hand tendonitis than workers performing low repetition and low force jobs. 5,6The etiology and pathophysiology of overuse-induced tendinopathies are still under investigation. Although the presence of an inflammatory component has not been identified by all investigators, 7-9 increased inflammatory molecules, for example, PGE 2 , have been found in tenosynovium of patients diagnosed with carpal tunnel syndrome (CTS), especially during the intermediate phase.10,11 However, PGE 2 was not found in tendon biopsies collected during the chronic painful tendinosis stage, although increased glutamate neurotransmitter and its receptor were evident. 8,9 The neurochemical Substance P is associated with chronic pain mediation 12 and has also been identif...

Anatomical and physiological changes were evaluated in the median nerves of rats trained to perform repetitive reaching. Motor degradation was evident after 4 weeks. ED1-immunoreactive macrophages were seen in the transcarpal region of the median nerve of both forelimbs by 5-6 weeks. Fibrosis, characterized by increased immunoexpression of collagen type I by 8 weeks and connective tissue growth factor by 12 weeks, was evident. The conduction velocity (NCV) within the carpal tunnel showed a modest but significant decline after 9-12 weeks. The lowest NCV values were found in animals that refused to participate in the task for the full time available. Thus, both anatomical and physiological signs of progressive tissue damage were present in this model. These results, together with other recent findings indicate that work-related carpal tunnel syndrome develops through mechanisms that include injury, inflammation, fibrosis and subsequent nerve compression.

We investigated inflammation in rats performing a low repetition, negligible force (LRNF) or high repetition, negligible force (HRNF) task of reaching and retrieving food pellets at target rates of two or four reaches/min for 2 h/day, for 6-8 weeks. Serum was assayed for 11 cytokines and chemokines; forelimb tissues for four cytokines. Macrophages were counted in forelimb tissues of LRNF rats to add to results from our previous studies of HRNF rats. In HRNF rats, serum IL-1a, IL-1b, TNFa, MIP2, MIP3a, and RANTES were elevated in weeks 6 and 8. In contrast, only MIP2 and MIP3a increased in serum of LRNF rats. In 8 week HRNF reach limb tissues, IL-1a, IL-1b, TNFa, and IL-10 increased in distal bones, IL-1a and -b in muscles, and TNFa in tendons. Only IL-10 increased in LRNF reach limb muscles in week 8. Serum IL-1a and MIP2 correlated with macrophages in LRNF loose connective tissues, serum MIP3a and MIP2 correlated negatively with grip strength, while serum TNFa, MIP3a, and MIP2 correlated positively with total number of reaches. Thus, several tissue and circulating cytokines/chemokines increase in an exposure dependent manner following short-term performance of repetitive reaching tasks and correlate with macrophage infiltration and decreasing grip strength. Keywords: cytokines; chemokines; macrophages; repetitive motion injury; WMSD Repetitive motion injuries (RMI) of the wrist and hand are painful, potentially disabling, and costly. Recent work suggests that RMIs induce injury in several tissue types in animal models, 1-6 as well as an early inflammatory response at the tissue level. 2,3,[7][8][9] Increases in four circulating inflammatory mediators, C-reactive protein, interleukin 1 beta (IL-1b), IL-6, and tumor necrosis factor alpha (TNFa) have also been shown to increase in patients with upper extremity overuse disorders. 10 The factors triggering underlying pathophysiological responses are still under investigation, which impedes progress toward their primary and secondary prevention.Using a rat model, we have reported that repetitive reaching causes injury and wide-spread increases in macrophage influx into musculotendinous tissues and peripheral nerves, extraneural fibrosis, decreased nerve conduction, and decreased grip strength. [2][3][4]7,9 The macrophage response is associated with increased inflammatory cytokines in the median nerve, 9 and increased serum IL-1a following HRNF task performance. 2 A variety of inflammatory mediators including cytokines and chemokines are released by injured cells and infiltrating macrophages. 9,11 Although serum cytokine and chemokine response patterns to exercise of varying intensities 12-15 and multiple organ trauma and fractures have been studied, [16][17][18] exposure to more chronic, lower levels of injury are not yet well characterized.Here, we examine several cytokines and chemokines in forelimb musculoskeletal tissues and serum to identify their response profiles, as well as potential cellular sources, after the performance of a voluntary repetitive ...

Study Design: A randomized controlled prospective experimental study with some repeated measures. Objectives: To characterize behavioral, sensory, motor, and nerve conduction decrements, and histological changes in the median nerve in rats trained to perform a high-force repetitive task. Background: Understanding of work-related carpal tunnel syndrome is hampered by the lack of experimental studies of the causes and mechanisms of nerve compression induced by repetitive motion. Most animal models of nerve compression have not employed voluntary repetitive motion as the stimulus for pathophysiological changes. Methods and Measures: Thirty Sprague-Dawley rats served as controls for 1 or more studies. Ten rats were trained to pull on a bar with 60% maximum force 4 times per minute, 2 h/d, 3 d/wk for 12 weeks. Motor behavior and limb withdrawal threshold force were characterized weekly. Grip strength and median nerve conduction velocity were measured after 12 weeks. Median nerves were examined immunohistochemically for ED1-positive macrophages, collagen, and connective tissue growth factor. Results: Reach rate and duration of task performance declined over 12 weeks. Grip strength and nerve conduction velocity were significantly lower after 12 weeks than in controls. Limb withdrawal threshold increased between weeks 6 and 12. Median nerves at the level of the wrist showed increases in macrophages, collagen, and connective-tissue growth-factor-positive cells. These effects were seen in both the reach and nonreach limbs. Conclusions: This animal model exhibits all the features of human carpal tunnel syndrome, including impaired sensation, motor weakness, and decreased median nerve conduction velocity. It establishes a causal relationship between performance of a repetitive task and development of carpal tunnel syndrome.