Abstract
BackgroundSystemic inflammation is known to induce sickness behaviors, including decreased social interaction and pain. We have reported increased serum inflammatory cytokines in a rat model of repetitive strain injury (rats perform an upper extremity reaching task for prolonged periods). Here, we sought to determine if sickness behaviors are induced in this model and the effectiveness of conservative treatments.MethodsExperimental rats underwent initial training to learn a high force reaching task (10 min/day, 5 days/week for 6 weeks), with or without ibuprofen treatment (TRHF vs. TRHF + IBU rats). Subsets of trained animals went on to perform a high repetition high force (HRHF) task for 6 or 12 weeks (2 h/day, 3 days/week) without treatment, or received two secondary interventions: ibuprofen (HRHF + IBU) or a move to a lower demand low repetition low force task (HRHF-to-LRLF), beginning in task week 5. Mixed-effects models with repeated measures assays were used to assay duration of social interaction, aggression, forepaw withdrawal thresholds and reach performance abilities. One-way and two-way ANOVAs were used to assay tissue responses. Corrections for multiple comparisons were made.ResultsTRHF + IBU rats did not develop behavioral declines or systemic increases in IL-1beta and IL-6, observed in untreated TRHF rats. Untreated HRHF rats showed social interaction declines, difficulties performing the operant task and forepaw mechanical allodynia. Untreated HRHF rats also had increased serum levels of several inflammatory cytokines and chemokines, neuroinflammatory responses (e.g., increased TNFalpha) in the brain, median nerve and spinal cord, and Substance P and neurokinin 1 immunoexpression in the spinal cord. HRHF + IBU and HRHF-to-LRLF rats showed improved social interaction and reduced inflammatory serum, nerve and brain changes. However, neither secondary treatment rescued HRHF-task induced forepaw allodynia, or completely attenuated task performance declines or spinal cord responses.ConclusionsThese results suggest that inflammatory mechanisms induced by prolonged performance of high physical demand tasks mediate the development of social interaction declines and aggression. However, persistent spinal cord sensitization was associated with persistent behavioral indices of discomfort, despite use of conservative secondary interventions indicating the need for prevention or more effective interventions.
Highlights
Systemic inflammation is known to induce sickness behaviors, including decreased social interaction and pain
Social interaction declines occurring in rats trained to high force task levels (TRHF) and high repetition high force (HRHF) rats are ameliorated with ibuprofen or move to a low demand task The duration of social interaction with a novel juvenile rat declined precipitously with training to high force levels (TRHF rats and 0-week HRHF time point) and remained decreased in HRHF rats through week 12, compared to age-matched food-restricted control rats (FRC) rats (Fig. 1a). This response was ameliorated in TRHF + TRHF rats treated with ibuprofen (IBU) rats, TRHF + Rest rats, 6-week HRHF + IBU and HRHF-to-low repetition low force (LRLF) rats, and 12-week HRHF + IBU rats, compared to age-matched untreated TRHF or HRHF rats (Fig. 1a)
Duration of social interaction was near control levels in 12-week HRHF-to-LRLF rats, not significantly improved from 12-week HRHF levels
Summary
Systemic inflammation is known to induce sickness behaviors, including decreased social interaction and pain. Increased pro-inflammatory cytokines provoke central nervous system (CNS) neuroinflammation via several mechanisms: diffusion from the circulatory system into the brain through blood brain barrier deficient areas; active transport by endothelial cells; activation of blood brain barrier or endothelial cells that activate neurons and glia; and retrograde transport of afferent nerve signals centrally [48, 54, 73] This is relevant to human subjects with upper extremity WMSDs show increased serum levels of TNFalpha, IL-1beta and soluble receptors, IL-6 or macrophage inflammatory proteins [12, 36, 56, 63]. The role of inflammation and its negative effects on the CNS is an under-investigated topic in the clinical management of workers with increased sickness absences, depression or persistent pain
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