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, 158 (2), 922-31

High Force Reaching Task Induces Widespread Inflammation, Increased Spinal Cord Neurochemicals and Neuropathic Pain

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High Force Reaching Task Induces Widespread Inflammation, Increased Spinal Cord Neurochemicals and Neuropathic Pain

M B Elliott et al. Neuroscience.

Abstract

Repetitive strain injuries (RSI), which include several musculoskeletal disorders and nerve compression injuries, are associated with performance of repetitive and forceful tasks. In this study, we examined in young, adult Sprague-Dawley rats, the effects of performing a voluntary, moderate repetition, high force (MRHF; nine reaches/min; 60% maximum pulling force) task for 12 weeks on motor behavior and nerve function, inflammatory responses in forearm musculoskeletal and nerve tissues and serum, and neurochemical immunoexpression in cervical spinal cord dorsal horns. We observed no change in reach rate, but reduced voluntary participation and grip strength in week 12, and increased cutaneous sensitivity in weeks 6 and 12, the latter indicative of mechanical allodynia. Nerve conduction velocity (NCV) decreased 15% in the median nerve in week 12, indicative of low-grade nerve compression. ED-1 cells increased in distal radius and ulna in week 12, and in the median nerve and forearm muscles and tendons in weeks 6 and 12. Cytokines IL-1alpha, IL-1beta, TNF-alpha, and IL-10 increased in distal forearm bones in week 12, while IL-6 increased in tendon in week 12. However, serum analysis revealed only increased TNF-alpha in week 6 and macrophage inflammatory protein 3a (MIP3a) in weeks 6 and 12. Lastly, Substance P and neurokinin-1 were both increased in weeks 6 and 12 in the dorsal horns of cervical spinal cord segments. These results show that a high force, but moderate repetition task, induced declines in motor and nerve function as well as peripheral and systemic inflammatory responses (albeit the latter was mild). The peripheral inflammatory responses were associated with signs of central sensitization (mechanical allodynia and increased neurochemicals in spinal cord dorsal horns).

Figures

Figure 1
Figure 1
Means (+ SEM) for behavioral parameters over weeks of task performance. A) Task duration and B) Reach rate after 1 (baseline), 6 and 12 weeks of MRHF task performance. C) Cutaneous sensitivity (withdrawal threshold) and D) grip strength are shown for controls (C) and after 6 and 12 weeks of task performance. Significant declines from week 1 or control levels are denoted by symbols (*p<0.01, **p<0.001). The number of animals quantified per group: controls (n=39), week 1 (n=11), week 6 (n=17) and week 12 (n=13).
Figure 2
Figure 2
Mean (+ SEM) for nerve conduction velocity (NCV) after 12 weeks of MRHF task performance compared to normal controls (C). The significant difference from controls are denoted by a symbol (**p<0.001). The number of animals quantified per group: controls (n=20) and week 12 (n=8).
Figure 3
Figure 3
Mean (+ SEM) ED1-positive cells (a marker of macrophages, osteoclasts (OC) or their progenitors (Prog)) was examined in distal radius and ulna bones, median nerves, forelimb flexor muscles or forelimb flexor tendons. Normal controls (C, n=4) and rats that had performed the MRHF task for 6 weeks (n=4) or 12 weeks (n=4) were evaluated. Significant increases from control levels are denoted by symbols (*p<0.01 and **p<0.001 compared to controls; # p<0.001 compared to bone osteoclasts, muscle or tendon).
Figure 4
Figure 4
Mean (+ SEM) for cytokine levels in forelimb flexor muscles, forelimb flexor tendons, and distal bone (which included distal radius and ulna, and first row of carpal bones). Controls (white bars; n=6, which included 3 normal controls and 3 trained controls) and rats that had performed the MRHF for 6 weeks (n=4) or 12 weeks (n=4) were tested using ELISA. IL-6 was not tested in distal bone (N/A). Significant increases from control levels are denoted by symbols (**p<0.001).
Figure 5
Figure 5
Mean (+ SEM) level of TNF-alpha or MIP3a in serum. Normal and trained controls (C, n=21, 11 of which were normal controls) and rats that had performed the MRHF task for 6 weeks (n=4) or 12 weeks (n=4) were evaluated. Significant increases from control levels are denoted by symbols (*p<0.01 and **p<0.001 compared to controls).
Figure 6
Figure 6
Substance P and NK-1 immunostaining in the superficial lamina of dorsal horns in cervical spinal cord segments. (A) Dorsal horns of week 6 MRHF rats have punctuate substance P immunofluorescence (green) staining that is distributed across the entire zone, medial to lateral, of the superficial lamina with increased expression more laterally. Medial (med) and lateral (lat) regions of the superficial lamina are indicated. Inset in panel (A) shows a C7 spinal cord cross-section at low power. (B) Dorsal horns of control rats have low levels of substance P immunofluorescence staining in the superficial lamina. (C) Dorsal horns of week 6 MRHF rats have NK-1 immunofluorescence (red) staining on plasma membranes and dendrites with some endosome swellings that spans the entire zone of the superficial lamina in which increased expression is observed more medially. (D) Dorsal horns of control rats have low levels of NK-1 immunofluorescence staining in the dorsal horn superficial lamina. Bar = 10 μm. D and E) Mean (+ SEM) percent immunofluorescent staining for substance P and neurokinin1 in the spinal cord dorsal horn superficial lamina. Normal and trained controls (C, n=4 each group for a total of 8 control rats) and rats that had performed the MRHF task for 6 weeks (n=4) or 12 weeks (n=4) were quantified. Significant increases from control levels are denoted by symbols (*p<0.01 and **p<0.001 compared to controls).

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