Ibuprofen as a Treatment for Work-Related Musculoskeletal Disorders: Effectiveness versus Caveats

Work-related upper limb disorders (WMSDs), also known as repetitive strain injuries, affect a large subsection of the US population. These disorders are a significant source of injury, morbidity, loss of work, and pain. We have developed a rat model of upper extremity repetitive work at high forces, and observed exposure-dependent increased inflammatory responses in all tissues involved in performing the task. A 2- to 8-week regimen of oral ibuprofen provided to rats while they continued to perform a high-repetition high-force task ameliorated these inflammatory responses as well as several motor declines. Ibuprofen treatment also attenuated task-induced tissue fibrosis, cartilage degeneration, and bone osteopenia, indicating their link to inflammatory processes. However, ibuprofen did not significantly attenuate persistent nocifensive pain behaviors (reflexive grip strength results are presented) likely because of persistent increases in inflammatory cytokines in the spinal cord, suggestive of central sensitization. Since long-term ibuprofen use can induce a number of negative side effects, such as gastritis, multi-pronged approaches should be considered with anti-inflammatory drugs included for only short time periods

Group IV Nociceptors Develop Axonal Chemical Sensitivity During Neuritis And Following Treatment Of The Sciatic Nerve With Vinblastine

We have previously shown that nerve inflammation (neuritis) and transient vinblastine application lead to axonal mechanical sensitivity in nociceptors innervating deep structures. We have also shown that these treatments reduce axonal transport, and proposed that this leads to functional accumulation of mechanically sensitive channels in the affected part of the axons. While informing the etiology of mechanically induced pain, axonal mechanical sensitivity does not address the common report of ongoing radiating pain during neuritis, which could be secondary to the provocation of axonal chemical sensitivity. We proposed that neuritis and vinblastine application would induce sensitivities to noxious chemicals, and that the number of chemo-sensitive channels would be increased at the affected site. In adult female rats, nerves were either untreated, or treated with complete Freund’s adjuvant (to induce neuritis) or vinblastine. After 3-7 days, dorsal root teased fiber recordings were taken from Group IV neurons with axons within the sciatic nerve. Sciatic nerves were injected intraneurally with a combination of noxious inflammatory chemicals. While no normal sciatic axons responded to this stimulus, 80% and 38% of axons responded in the neuritis and vinblastine groups, respectively. In separate experiments, sciatic nerves were partially ligated and treated with complete Freund’s adjuvant or vinblastine (with controls), and after 3-5 days were immunolabeled for the histamine 3 receptor. The results supported that both neuritis and vinblastine treatment reduce transport of the histamine 3 receptor. The finding that nociceptor axons can develop ectopic chemical sensitivity is consistent with ongoing radiating pain due to nerve inflammation

Acute effects of a selective cannabinoid-2 receptor agonist on neuroinflammation in a model of traumatic brain injury.

Proposed therapeutic strategies for attenuating secondary traumatic brain injury (TBI) include modulation of acute neuroimmune responses. The goal of this study was to examine the acute effects of cannabinoid-2 receptor (CB(2)R) modulation on behavioral deficits, cerebral edema, perivascular substance P, and macrophage/microglial activation in a murine model of TBI. Thirty male C57BL/6 mice underwent sham surgery, or cortical contusion impact injury (CCI). CCI mice received vehicle or the CB(2)R agonist 0-1966 at 1 and 24 h after injury. Performance on the rotarod, forelimb cylinder, and open-field tests were evaluated before and at 48 h after sham or CCI surgery. Cerebral edema was evaluated using the wet-dry weight technique. Immunohistochemical analysis was used to examine changes in substance P and macrophage/microglia-specific Iba1 protein immunoreactivity. Locomotor performance and exploratory behavior were significantly improved in mice receiving 0-1966 (CB(2)R agonist) compared to vehicle-treated mice. Significant reductions were found for cerebral edema, number of perivascular areas of substance P immunoreactivity, and number of activated macrophages/microglial cells in the injured brains of 0-1966-treated mice compared to vehicle-treated mice. The findings show that the effects of the CB(2)R agonist 0-1966 on edema, substance P immunoreactivity, and macrophage/microglial activation, were associated with recovery of acute motor and exploratory deficits. This study provides evidence of acute neuroprotective effects derived from selective CB(2)R activation that may represent an avenue for further development of novel therapeutic agents in the treatment of TBI

Performance of a repetitive task by aged rats leads to median neuropathy and spinal cord inflammation with associated sensorimotor declines

Epidemiological studies have demonstrated a relationship between advancing age and susceptibility to risk factors for median neuropathies and musculoskeletal disorders. In this study, we determined if performance of a voluntary reaching task by aged rats induced sensorimotor declines, median nerve dysfunction and increased inflammatory cytokines in peripheral nerves, muscle and spinal cord neurons. Aged (14 mon) rats were trained for 15 min/day for 4 weeks to learn a high repetition, low force (HRLF) task (19 reaches/min; 15% maximum pulling force). Aged task rats performed the task for 2 h/day, 3 days/wk, for 12 weeks (until they were 18 mon of age). No behavioral changes were detected in normal controls (NC) or food-restricted controls (FR C) as they aged. However, grip strength declined in HRLF rats in weeks 6-12 (P\u3c0.01 each) and 12-week trained-only rats (TR; P\u3c0.05), compared to NC. Mechanical hypersensitivity was present in weeks 9 and 12 HRLF reach limb forepaws (P\u3c0.01 and P\u3c0.05, respectively), and 12-week HRLF support limb forepaws (P\u3c0.01) and hindpaws (P=0.03), compared to NC. By week 12, median nerve conduction velocity declined 23%, bilaterally, in HRLF (P\u3c0.001 each), and 13% in TR (P\u3c0.05), compared to NC. Tumor necrosis factor alpha (TNFα) increased in 12-week HRLF muscle (P=0.005), median nerve (P\u3c0.01), and neurons in superficial lamina of HRLF cervical spinal cords (P\u3c0.01), compared to NC. interleukin 1 beta (IL1β) also increased in superficial lamina neurons (P\u3c0.01). Loss of grip strength was correlated with median nerve conduction slowing (r=0.70) as well as increased nerve and muscle TNFα (r=-0.38 and r=-0.41, respectively); decrease in forepaw withdrawal thresholds was correlated with median nerve conduction slowing (r=0.81), increased nerve TNFα (r=-0.59), and increased TNFα and IL1β in neurons in spinal cord dorsal horns (r=-0.52 and r=-0.47, respectively). Thus, aged rats performing a repetitive task exhibited sensorimotor declines that were associated with decreased median nerve conduction, and increased pro-inflammatory cytokines in the median nerve and cervical spinal cord neurons

Systemic inflammatory profiles and their relationships with demographic, behavioural and clinical features in acute low back pain

Systemic inflammation is linked with development and persistence of many pathological pain states. Although chronic phase inflammatory responses are well reported, the acute phase has received limited attention. Here we investigated circulating pro-inflammatory cytokines and C-reactive protein (CRP), and explored their relationships with symptom severity and other factors in acute low back pain (LBP). Ninety-nine individuals within two weeks of onset of acute LBP and 55 pain-free controls completed questionnaires related to their pain (visual analogue scale, VAS) and disability, behaviour, sleep quality and psychological status. CRP, interleukin-6 (IL-6), tumor necrosis factor (TNF) and interleukin-1β (IL-1β) were measured from serum samples. Biomarkers were compared between LBP and control participants, and in a separate analysis, for those with “high-pain” (VAS ⩾4) and “low-pain” (VA

Aberrant neuronal activity in a model of work-related upper limb pain and dysfunction

Work-related musculoskeletal disorders associated with intense repetitive tasks are highly prevalent. Painful symptoms associated with such disorders can be attributed to neuropathy. In this study, we characterized the neuronal discharge from the median nerve in rats trained to perform an operant repetitive task. After 3-weeks of the task, rats developed pain behaviors and a decline in grip strength. Ongoing activity developed in 17.7% of slowly conducting neurons at 3-weeks, similar to neuritis. At 12-weeks, an irregular high frequency neuronal discharge was prevalent in >88.4% of slow and fast conducting neurons. At this time point, 8.3% of slow and 21.2% of fast conducting neurons developed a bursting discharge, which, combined with a reduction in fast-conducting neurons with receptive fields (38.4%), is consistent with marked neuropathology. Taken together, we have shown that an operant repetitive task leads to an active and progressive neuropathy that is characterized by marked neuropathology following 12-weeks task that mainly affects fast conducting neurons. Such aberrant neuronal activity may underlie painful symptoms in patients with work-related musculoskeletal disorders

Performance of Repetitive Tasks Induces Decreased Grip Strength and Increased Fibrogenic Proteins in Skeletal Muscle: Role of Force and Inflammation

Background This study elucidates exposure-response relationships between performance of repetitive tasks, grip strength declines, and fibrogenic-related protein changes in muscles, and their link to inflammation. Specifically, we examined forearm flexor digitorum muscles for changes in connective tissue growth factor (CTGF; a matrix protein associated with fibrosis), collagen type I (Col1; a matrix component), and transforming growth factor beta 1 (TGFB1; an upstream modulator of CTGF and collagen), in rats performing one of two repetitive tasks, with or without anti-inflammatory drugs. Methodology/Results To examine the roles of force versus repetition, rats performed either a high repetition negligible force food retrieval task (HRNF), or a high repetition high force handle-pulling task (HRHF), for up to 9 weeks, with results compared to trained only (TR-NF or TR-HF) and normal control rats. Grip strength declined with both tasks, with the greatest declines in 9-week HRHF rats. Quantitative PCR (qPCR) analyses of HRNF muscles showed increased expression of Col1 in weeks 3–9, and CTGF in weeks 6 and 9. Immunohistochemistry confirmed PCR results, and also showed greater increases of CTGF and collagen matrix in 9-week HRHF rats than 9-week HRNF rats. ELISA, and immunohistochemistry revealed greater increases of TGFB1 in TR-HF and 6-week HRHF, compared to 6-week HRNF rats. To examine the role of inflammation, results from 6-week HRHF rats were compared to rats receiving ibuprofen or anti-TNF-α treatment in HRHF weeks 4–6. Both treatments attenuated HRHF-induced increases in CTGF and fibrosis by 6 weeks of task performance. Ibuprofen attenuated TGFB1 increases and grip strength declines, matching our prior results with anti-TNFα. Conclusions/Significance Performance of highly repetitive tasks was associated with force-dependent declines in grip strength and increased fibrogenic-related proteins in flexor digitorum muscles. These changes were attenuated, at least short-term, by anti-inflammatory treatments

Plasticity of Adult Sensorimotor System

International audienc

Individual variation in pain sensitivity and conditioned pain modulation in acute low back pain: impact of stimulus type, sleep, psychological and lifestyle factors

Generalised hyperalgesia and impaired pain modulation are reported in chronic low back pain (LBP). Few studies have tested whether these features are present in the acute-phase. This study aimed to test for differences in pain presentation in early-acute LBP and evaluate the potential contribution of other factors to variation in sensitivity. Individuals within two weeks of onset of acute LBP (N=126) and pain-free controls (N=74) completed questionnaires related to their pain, disability, behaviour and psychological status before undergoing conditioned pain modulation (CPM) and pain threshold (heat, cold and pressure) testing at the back and forearm/thumb. LBP participants were more sensitive to heat and cold at both sites and pressure at the back than controls, without differences in CPM. Only those with high-pain (numerical rating scale, NRS≥4) were more sensitive to heat at the forearm and pressure at the back. Four subgroups with distinct features were identified: "high sensitivity", "low CPM efficacy", "high sensitivity/low CM efficacy", and "low sensitivity/high CPM efficacy". Various factors such as sleep and alcohol were associated with each pain measure. Results provide evidence for generalised hyperalgesia in many, but not all, individuals during acute LBP, with variation accounted for by several factors. Specific pain phenotypes provide candidate features to test in longitudinal studies of LBP outcome