Peripheral neuritis and increased spinal cord neurochemicals are induced in a model of repetitive motion injury with low force and repetition exposure

Abstract

Performance of high repetition tasks with or without force is associated with peripheral tissue inflammation, decreased nerve function and motor dysfunction. Here, we examined whether a low repetition task with negligible force (LRNF) produces fewer tissue and behavioral pathologies than previously observed with high repetition tasks using our rat model of repetitive motion injury (RMI). Thirty-seven rats were randomized into control or LRNF groups, the latter reaching and grasping a 45 mg food pellet at a rate of 3 reaches/min. This task was performed in 4, 0.5 5 h sessions with 1.5 5 h rest periods for 3 days/week for up to 12 weeks. Examination of distal median nerve, forelimb flexor tendons and bones for ED1-positive cells (macrophages and osteoclasts) revealed increases in nerve and bone in week 12. The nerve also contained increased TNF-α expressing cells in week 12. Examination of spinal cord dorsal horns revealed increased immunoexpression of Substance P in week 8 and neurokinin-1 in weeks 8 and 12 in the superficial lamina. Motor behavioral analyses showed no changes in reach rate across weeks, slightly reduced task duration (a measurement of voluntary task participation) in week 12, but significantly increased extra arm movement reversals during reaching in week 8. These extra movement reversals were corrections for missed food pellets during a reach. Thus, performance of even a low repetition, negligible force upper extremity task for 3 months can induce mild peripheral tissue inflammation, neurochemical increases in spinal cord dorsal horns, and declines in fine motor control.

Introduction

Performance of repetitive, forceful, or awkward movements over time may lead to repetitive motion injuries (RMIs), also known as overuse injuries and work-related musculoskeletal disorders. These disorders include sprains and strains, back pain, carpel tunnel syndrome, and diseases/disorders of the musculoskeletal, neural or connective tissues that develop in response to bending, reaching, overexertion or repetitive movements (Bureau of Labor Statistics, 2005). More than 5 h a week of productive time are lost in workers due to common pain conditions such as back pain, arthritis, and musculoskeletal pain, costing an estimated $61.2 billion annually (Stewart et al., 2003). Epidemiological evidence confirms the close relationship between exposures to repetitive and/or forceful motion and the prevalence and incidence of these disorders (Bernard, 1997, National Research Council and Institute of Medicine, 2001). Several researchers have attempted to establish criteria for maximum acceptable forces and movements for work tasks based on psychosocial outcomes (see Barr et al., 2002 for review). Silverstein et al. (1986) performed job analyses of industrial workers and defined high repetition rate as less than 30 s/cycle and low repetition rate as greater than 30 s/cycle. Using these criteria, several animal models have been developed to simulate RMI (Soslowsky et al., 1996, Nakama et al., 2005, Williems and Stauber, 1999, Sommerich et al., 2007).

Our laboratory has developed a rat model of RMI that leads to exposure-dependent pathophysiological and behavioral changes similar to chronic median nerve compression or carpel tunnel syndrome after performance of a voluntary, highly repetitive upper extremity task with negligible or high force (Clark et al., 2003, Clark et al., 2004). Nerve fibrosis and motor dysfunction resulting from performing high repetition, high force tasks were clearly greater than responses to a high repetition task with negligible force (Clark et al., 2004). In addition, our model induces inflammatory responses in forearm nerve and musculoskeletal tissues (Barbe et al., 2003, Barr et al., 2004, Clark et al., 2003, Clark et al., 2004, Al-Shatti et al., 2005, Barbe et al., in press). For example, performance of a high repetition, negligible force task (HRNF) resulted in increased ED1 positive macrophages and cells immunopositive for pro-inflammatory cytokines (IL1-α, IL1-β, TNF-α, and IL6) in the median nerve (Clark et al., 2003, Al-Shatti et al., 2005). We have yet to study the effects of performing a low repetition, negligible force (LRNF) task on peripheral nerves using our model. A number of other investigations have found histopathological changes following repetitive motion tasks, including necrotic muscle fibers with inflammatory cell infiltrates and tendinopathy (Baker et al., 2007, Geronilla et al., 2003, Nakama et al., 2005, Perry et al., 2005, Stauber and Willems, 2002). For example, using a 16-week overuse injury model, Soslowsky and colleagues showed temporal fluctuations of inflammatory markers in tendon (Perry et al., 2005). At 8 weeks of intensive treadmill running by rats, there was a significant but transient increase in tendon cyclooxygenase-2 (Perry et al., 2005). However, there are no studies of RMIs examining whether these peripheral tissue injury and inflammatory changes are associated with altered neurochemical changes in the spinal cord.

Numerous studies have found that Substance P (SP) and its receptor, neurokinin-1 (NK-1), are significantly elevated in the spinal cord dorsal horns after peripheral nerve injuries, such as nerve ligation and chronic compression, and in models of peripheral inflammatory pain (Delander et al., 1997, Rothman et al., 2005, Honore et al., 1999, Honore et al., 2000, McCarson, 1999, Abbadie et al., 1996, Allen et al., 1999.). Since the neurochemical response of the spinal cord to peripheral neuroinflammation has not been studied in a model of RMI, we have begun our investigation using a low repetition task with negligible force (LRNF) performed for 3 months. We hypothesize that this low demand task will produce low grade, but significant, inflammatory changes in peripheral tissues towards the end of this time period, changes that will correlate with increases in spinal cord neurochemical production. Furthermore, we hypothesize that these peripheral and central changes will be associated with a small decline in motor function. To explore these hypotheses, we examined the effects of performing the LRNF task on macrophage infiltration of forearm nerve, tendon and bone, and immunoexpression of SP and NK-1 in the dorsal horns of the cervical spinal cord. We also examined three variables of motor performance: reach rate (ability or willingness to maintain task pace), task duration (ability or willingness to participate), and number of extra forearm movement reversals during a reach in order to successfully retrieve a food pellet (examines accuracy of fine motor skills).