Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy

Grace, Peter M.; Loram, Lisa C.; Christianson, John P.; Strand, Keith A.; Flyer-Adams, Johanna G.; Penzkover, Kathryn R.; Forsayeth, John; Dam, Anne Marie Van; Mahoney, Melissa J.; Maier, Steven F.; Chavez, Raymond A.; Watkins, Linda R.

doi:10.1016/j.bbi.2016.05.012

Cited by 52 publications

(35 citation statements)

References 39 publications

(57 reference statements)

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“…In contrast to studies using exercise as a therapeutic tool, a number of studies have used voluntary running behavior as a diagnostic tool in persistent pain states [25; 43; 60; 61; 115; 127]. In studies using CFA-induced inflammation, wheel running in rodents pre-trained with running wheels is reduced for approximately 3 days post-injury [25; 60; 61].…”

Section: Discussionmentioning

confidence: 99%

Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation

Pitcher

Tarum

Rauf

et al. 2017

The Journal of Pain

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Aerobic exercise improves outcomes in a variety of chronic health conditions, yet the support for exercise-induced effects on chronic pain in humans is mixed. While many rodent studies have examined the effects of exercise on persistent hypersensitivity, the vast majority employed forced exercise paradigms that are known to be highly stressful. Since stress can also produce analgesic effects, we studied how voluntary exercise, known to reduce stress in healthy subjects, alters hypersensitivity, stress and swelling in a rat model of persistent hind paw inflammation. Our data indicate that voluntary exercise rapidly and effectively reduces both hypersensitivity and stress-related outcomes without altering swelling. Moreover, the level of exercise is unrelated to the analgesic and stress-reducing effects, suggesting that even modest amounts of exercise may impart significant benefit in persistent inflammatory pain states.

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Section: Discussionmentioning

confidence: 99%

Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation

Pitcher

Tarum

Rauf

et al. 2017

The Journal of Pain

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“…However, a more recent report demonstrated in rats with experimental autoimmune encephalomyelitis (EAE), which is a rodent model of multiple sclerosis, robust allodynia and a profound reduction of wheel running activity that occurred prior to the onset of EAE-induced motor weakness. Allodynia and decreased wheel activity levels coincided with decreased social exploration [43] , a test of anxiety in rodents [44, 45] . Notably, hindpaws are not directly affected in EAE and in this report, rats were allowed voluntary unrestricted access to in-cage running wheels.…”

Section: Discussionmentioning

confidence: 99%

Chronic Sciatic Neuropathy in Rat Reduces Voluntary Wheel-Running Activity With Concurrent Chronic Mechanical Allodynia

Whitehead

Lam

Sun

et al. 2017

Anesthesia &Amp; Analgesia

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BACKGROUND Animal models of peripheral neuropathy produced by a number of manipulations are assessed for the presence of pathological pain states such as allodynia. While stimulus-induced behavioral assays are frequently used and important to examine allodynia (i.e. sensitivity to light mechanical touch; von Frey fiber test) other measures of behavior that reflect overall function are not only complementary to stimulus-induced responsive measures, but are also critical to gain a complete understanding of the effects of the pain model on quality of life, a clinically relevant aspect of pain on general function. Voluntary wheel running activity in rodent models of inflammatory and muscle pain is emerging as a reliable index of general function that extends beyond stimulus-induced behavioral assays. Clinically, reports of increased pain intensity occur at night, a period typically characterized with reduced activity during the diurnal cycle. We therefore examined in rats whether alterations in wheel running activity were more robust during the inactive phase compared to the active phase of their diurnal cycle in a widely used rodent model of chronic peripheral neuropathic pain, the sciatic nerve chronic constriction injury (CCI) model. METHODS In adult male Sprague Dawley rats, baseline (BL) hindpaw threshold responses to light mechanical touch were assessed using the von Frey test prior to measuring BL activity levels using freely accessible running wheels (1 hr/day for 7 sequential days) to quantify distance traveled. Running wheel activity BL values are expressed as total distance traveled (m). The overall experimental design was: following BL measures, rats underwent either sham or CCI surgery followed by repeated behavioral re-assessment of hindpaw thresholds and wheel running activity levels for up to 18 days after surgery. Specifically, separate groups of rats were assessed for wheel running activity levels (1 hr total/trial) during the onset (within first 2 hrs) of either the (1) inactive (n=8/gp) or (2) active (n = 8/gp) phase of the diurnal cycle. An additional group of CCI-treated rats (n = 8/gp) were exposed to a locked running wheel to control for the potential effects of wheel running exercise on allodynia. The 1-hr running wheel trial period was further examined at discrete 20-min intervals to identify possible pattern differences in activity during the first, middle and last portion of the 1-hr trial. The effect of neuropathy on activity levels were assessed by measuring the change from their respective BLs to distance traveled in the running wheels. RESULTS While wheel running distances between groups were not different at BL from rats examined during either the inactive phase of the diurnal cycle or active phase of the diurnal cycle, sciatic nerve CCI reduced running wheel activity levels compared to sham-operated controls during the inactive phase. Additionally, compared to sham controls, bilateral low threshold mechanical allodynia was observed at all time-points after surgical induction of...

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“…Treg cells exert their suppressive function by multiple mechanisms including cytolysis of effector cells, metabolic disruption of T-cell proliferation, modulation of antigen-presenting cell function, and the release of anti-inflammatory cytokines transforming growth factor-beta (TGF-␤), interleukin-10 (IL-10), and IL-35 (Collison et al, 2007;Duffy et al, 2018a). Unlike IL-10, which has been demonstrated to significantly attenuate mechanical allodynia in EAE (Sloane et al, 2009;Grace et al, 2017), little is known about the effects of IL-35 in pain associated with EAE. IL-35, the most recently discovered IL-12 family member, is a heterodimeric cytokine composed of p35 and EBI3 and its action appears to be purely immunosuppressive (Collison and Vignali, 2008).…”

Section: Significance Statementmentioning

confidence: 99%

Regulatory T Cells and Their Derived Cytokine, Interleukin-35, Reduce Pain in Experimental Autoimmune Encephalomyelitis

et al. 2019

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Sensory problems such as neuropathic pain are common and debilitating symptoms in multiple sclerosis (MS), an autoimmune inflammatory disorder of the CNS. Regulatory T (Treg) cells are critical for maintaining immune homeostasis, but their role in MS-associated pain remains unknown. Here, we demonstrate that Treg cell ablation is sufficient to trigger experimental autoimmune encephalomyelitis (EAE) and facial allodynia in immunized female mice. In EAE-induced female mice, adoptive transfer of Treg cells and spinal delivery of the Treg cell cytokine interleukin-35 (IL-35) significantly reduced facial stimulus-evoked pain and spontaneous pain independent of disease severity and increased myelination of the facial nociceptive pathway. The effects of intrathecal IL-35 therapy were Treg-cell dependent and associated with upregulated IL-10 expression in CNS-infiltrating lymphocytes and reduced monocyte infiltration in the trigeminal afferent pathway. We present evidence for a beneficial role of Treg cells and IL-35 in attenuating pain associated with EAE independently of motor symptoms by decreasing neuroinflammation and increasing myelination.

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Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy

Cited by 52 publications

References 39 publications

Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation

Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation

Chronic Sciatic Neuropathy in Rat Reduces Voluntary Wheel-Running Activity With Concurrent Chronic Mechanical Allodynia

Regulatory T Cells and Their Derived Cytokine, Interleukin-35, Reduce Pain in Experimental Autoimmune Encephalomyelitis

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