Effects of cyclic stretching exercise on long-lasting hyperalgesia, joint contracture, and muscle injury following cast immobilization in rats.

The effects of exercise on mechanical hyperalgesia, joint contracture, and muscle injury resulting from immobilization are not completely understood. This study aimed to investigate the effects of cyclic stretching on these parameters in a rat model of chronic post-cast pain (CPCP). Seventeen 8-week-old Wistar rats were randomly assigned to (1) control group, (2) immobilization (CPCP) group, or (3) immobilization and stretching exercise (CPCP+STR) group. In the CPCP and CPCP+STR groups, both hindlimbs of each rat were immobilized in full plantar flexion with a plaster cast for a 4-week period. In the CPCP+STR group, cyclic stretching exercise was performed 6 days/week for 2 weeks, beginning immediately after cast removal prior to reloading. Although mechanical hyperalgesia in the plantar skin and calf muscle, ankle joint contracture, and gastrocnemius muscle injury were observed in both immobilized groups, these changes were significantly less severe in the CPCP+STR group than in the CPCP group. These results clearly demonstrate the beneficial effect of cyclic stretching exercises on widespread mechanical hyperalgesia, joint contracture, and muscle injury in a rat model of CPCP.

Enhancing treatment of osteoarthritis knee pain by boosting expectancy: A functional neuroimaging study.

Objectives: Expectation can significantly modulate pain and treatment effects. This study aims to investigate if boosting patients' expectancy can enhance the treatment of knee osteoarthritis (KOA), and its underlying brain mechanism. Methods: Seventy-four KOA patients were recruited and randomized to three groups: boosted acupuncture (with a manipulation to enhance expectation), standard acupuncture, or treatment as usual (TAU). Each patient underwent six treatments before being debriefed, and four additional treatments after being debriefed. The fMRI scans were applied during the first and sixth treatment sessions. Results: We found significantly decreased knee pain in the boosted acupuncture group compared to the standard acupuncture or TAU groups after both six and ten treatments. Resting state functional connectivity (rsFC) analyses using the nucleus accumbens (NAc) as the seed showed rsFC increases between the NAc and the medial prefrontal cortex (MPFC)/rostral anterior cingulate cortex (rACC) and dorsolateral prefrontal cortex in the boosted group as compared to the standard acupuncture group after multiple treatments. Expectancy scores after the first treatment were significantly associated with increased NAc-rACC/MPFC rsFC and decreased knee pain following treatment. Conclusions: Our study provides a novel method and mechanism for boosting the treatment of pain in patients with KOA. Our findings may shed light on enhancing outcomes of pharmacological and integrative medicines in clinical settings.

Management of long-term complex regional pain syndrome with allodynia: A case report.

STUDY DESIGN: Case report. INTRODUCTION: Conventional rehabilitation alone may not be effective in reducing symptoms in some patients with complex regional pain syndrome. PURPOSE OF THE STUDY: This case report portrays the benefits of a new tailored rehabilitation program for a 39-year-old patient suffering from upper limb complex regional pain syndrome with severe touch-evoked pain (static mechanical allodynia). METHODS: This patient had previously received conventional rehabilitation for a year and a half including physical and nonsurgical medical interventions that did not improve symptoms or function. In the search for an alternative, this patient was referred to occupational therapy to try a tailored rehabilitation program, drawing on multiple strategies used sequentially according to the patient's tolerance and symptom evolution. During this 22-month program, the following methods were added (listed chronologically): somatosensory rehabilitation of pain method, graded motor imagery, pain management modalities, active mobilizations, strengthening exercises, and task simulation. The patient successively showed resolution of mechanical allodynia, decreased pain, reduction of tactile hypesthesia and improvement in active range of motion, strength, and function. These improvements allowed him to return to work. DISCUSSION: This suggests that a tailored rehabilitation program combining somatosensory rehabilitation of pain method, graded motor imagery and more conventional approaches could improve symptoms and functional status in patients with upper limb complex regional pain syndrome, even with persistent refractory symptoms. CONCLUSION: The addition of the somatosensory rehabilitation of pain method and the graded motor imagery approach to conventional therapy could be considered in cases of complex regional pain syndrome that do not respond to conventional rehabilitation alone.

Neural Mobilization Attenuates Mechanical Allodynia and Decreases Proinflammatory Cytokine Concentrations in Rats With Painful Diabetic Neuropathy.

Background: Painful diabetic neuropathy (PDN) is a common complication in patients with diabetes. It is related to ischemic nerve damage and the increase in the levels of proinflammatory mediators, such as tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß). Neural mobilization may have the potential to alleviate PDN, but it has not yet been tested. Also, the physiological mechanism of neural mobilization is unclear. Objective: The objective of this study was to investigate treatment effect and physiological mechanism of neural mobilization. Design: This was an experimental study using rats with streptozocin (or streptozotocin)-induced type 1 diabetes. Methods: Three groups were used in the study, the control group (vehicle), the diabetes group (PDN group), and the neural mobilization treatment group (PDN-NM group) (n = 6). Rats in the vehicle group were healthy rats. Rats in the PDN and PDN-NM groups were rats with diabetes. Rats in the PDN-NM group received treatment in the right sciatic nerve, whereas rats in the PDN group did not. Mechanical pain sensitivity and the levels of IL-1ß and TNF-α in the sciatic nerve branches and trunk, the L4 to L6 dorsal horn ganglion, and the spinal cord dorsal horn were measured. Results: Techanical allodynia was alleviated after treatment, but the effect was limited to the treatment side. The concentrations of proinflammatory cytokines were decreased in the nerves that received treatment compared with those on the other side, indicating that neural mobilization may reduce mechanical sensitivity by decreasing the concentrations of local sensitizing agents. Limitations: A limitation of this study was that no direct measurement of nerve blood flow was done. Conclusions: The results of this study showed that neural mobilization effectively alleviated mechanical allodynia in rats with PDN. The side that received treatment had lower concentrations of TNF-α and IL-1ß in the sciatic nerve branches and sciatic nerve trunk; this result may have been related to the alleviation of mechanical allodynia.

Somatosensory rehabilitation for allodynia in complex regional pain syndrome of the upper limb: A retrospective cohort study.

STUDY DESIGN: Retrospective cohort study. INTRODUCTION: Somatosensory rehabilitation is a standardized method of evaluation and conservative treatment of painful disorders of vibrotactile sensation, including the mechanical allodynia and burning pain of complex regional pain syndrome (CRPS). PURPOSE OF THE STUDY: The purpose of this study was to examine the effectiveness of somatosensory rehabilitation for reducing allodynia in persons with CRPS of 1 upper limb in a retrospective consecutive cohort of patients. METHODS: An independent chart review of all client records (May 2004-August 2015) in the Somatosensory Rehabilitation Centre (Fribourg, Switzerland) identified 48 persons meeting the Budapest criteria for CRPS of 1 limb who had undergone assessment and treatment. Outcomes of interest were the French version of the McGill Pain Questionnaire (Questionnaire de la Douleur St-Antoine [QDSA]), total area of allodynia as recorded by mapping the area of skin where a 15-g monofilament was perceived as painful, and the allodynia threshold (minimum pressure required to elicit pain within the allodynic territory). RESULTS: This cohort was primarily women (70%), with a mean age of 45 years (range: 18-74). Mean duration of burning pain was 31 months (range: 1 week-27.5 years), and baseline QDSA core was 48. The average primary area of allodynia was 66 cm2 (range: 2.6-320), and the most common allodynia threshold was 4.0 g. The average duration of treatment was 81 days. At cessation of treatment, the average QDSA score was 20 (effect size Cohen's d = 1.64). Allodynia completely resolved in 27 persons (56% of the total sample where only 58% completed treatment). DISCUSSION: This uncontrolled retrospective study suggests that somatosensory rehabilitation may be an effective treatment with a large effect size for reducing the allodynia and painful sensations associated with CRPS of the upper limb. More work is in progress to provide estimates of reliability and validity for the measurement tools for allodynia employed by this method. LEVEL OF EVIDENCE: 2c.

Modulation of diet-induced mechanical allodynia by metabolic parameters and inflammation.

Dietary-associated diseases have increased tremendously in our current population, yet key molecular changes associated with high-fat diets that cause clinical pre-diabetes, obesity, hyperglycemia, and peripheral neuropathy remain unclear. This study examines molecular and metabolic aspects altered by voluntary exercise and a high-fat diet in the mouse dorsal root ganglion. Mice were examined for changes in mRNA and proteins encoding anti-inflammatory mediators, metabolic-associated molecules, and pain-associated ion channels. Proteins involved in the synaptosomal complex and pain-associated TRP ion channels decrease in the dorsal root ganglion of high-fat exercise animals relative to their sedentary controls. Exercise reversed high-fat diet induced mechanical allodynia without affecting weight gain, elevated blood glucose, and utilization of fat as a fuel source. Independent of weight or fat mass changes, high-fat exercised mice display reduced inflammation-associated mRNAs. The benefits of exercise on abnormal peripheral nerve function appear to occur independent of systemic metabolic changes, suggesting that the utilization of fats and inflammation in the peripheral nervous system may be key for diet-induced peripheral nerve dysfunction and the response to exercise.

Involvement of mesolimbic dopaminergic network in neuropathic pain relief by treadmill exercise: A study for specific neural control with Gi-DREADD in mice.

BACKGROUND: Exercise alleviates pain and it is a central component of treatment strategy for chronic pain in clinical setting. However, little is known about mechanism of this exercise-induced hypoalgesia. The mesolimbic dopaminergic network plays a role in positive emotions to rewards including motivation and pleasure. Pain negatively modulates these emotions, but appropriate exercise is considered to activate the dopaminergic network. We investigated possible involvement of this network as a mechanism of exercise-induced hypoalgesia. METHODS: In the present study, we developed a protocol of treadmill exercise, which was able to recover pain threshold under partial sciatic nerve ligation in mice, and investigated involvement of the dopaminergic reward network in exercise-induced hypoalgesia. To temporally suppress a neural activation during exercise, a genetically modified inhibitory G-protein-coupled receptor, hM4Di, was specifically expressed on dopaminergic pathway from the ventral tegmental area to the nucleus accumbens. RESULTS: The chemogenetic-specific neural suppression by Gi-DREADD system dramatically offset the effect of exercise-induced hypoalgesia in transgenic mice with hM4Di expressed on the ventral tegmental area dopamine neurons. Additionally, anti-exercise-induced hypoalgesia effect was significantly observed under the suppression of neurons projecting out of the ventral tegmental area to the nucleus accumbens as well. CONCLUSION: Our findings suggest that the dopaminergic pathway from the ventral tegmental area to the nucleus accumbens is involved in the anti-nociception under low-intensity exercise under a neuropathic pain-like state.

Hormonal and molecular effects of restraint stress on formalin-induced pain-like behavior in male and female mice.

The evolutionary advantages to the suppression of pain during a stressful event (stress-induced analgesia (SIA)) are obvious, yet the reasoning behind sex-differences in the expression of this pain reduction are not. The different ways in which males and females integrate physiological stress responses and descending pain inhibition are unclear. A potential supraspinal modulator of stress-induced analgesia is the central nucleus of the amygdala (CeA). This limbic brain region is involved in both the processing of stress and pain; the CeA is anatomically and molecularly linked to regions of the hypothalamic pituitary adrenal (HPA) axis and descending pain network. The CeA exhibits sex-based differences in response to stress and pain that may differentially induce SIA in males and females. Here, sex-based differences in behavioral and molecular indices of SIA were examined following noxious stimulation. Acute restraint stress in male and female mice was performed prior to intraplantar injections of formalin, a noxious inflammatory agent. Spontaneous pain-like behaviors were measured for 60min following formalin injection and mechanical hypersensitivity was evaluated 120 and 180min post-injection. Restraint stress altered formalin-induced spontaneous behaviors in male and female mice and formalin-induced mechanical hypersensitivity in male mice. To assess molecular indices of SIA, tissue samples from the CeA and blood samples were collected at the 180min time point. Restraint stress prevented formalin-induced increases in extracellular signal regulated kinase 2 (ERK2) phosphorylation in the male CeA, but no changes associated with pERK2 were seen with formalin or restraint in females. Sex differences were also seen in plasma corticosterone concentrations 180min post injection. These results demonstrate sex-based differences in behavioral, molecular, and hormonal indices of acute stress in mice that extend for 180min after stress and noxious stimulation.

Prior voluntary wheel running attenuates neuropathic pain.

Exercise is known to exert a systemic anti-inflammatory influence, but whether its effects are sufficient to protect against subsequent neuropathic pain is underinvestigated. We report that 6 weeks of voluntary wheel running terminating before chronic constriction injury (CCI) prevented the full development of allodynia for the ∼3-month duration of the injury. Neuroimmune signaling was assessed at 3 and 14 days after CCI. Prior exercise normalized ipsilateral dorsal spinal cord expression of neuroexcitatory interleukin (IL)-1ß production and the attendant glutamate transporter GLT-1 decrease, as well as expression of the disinhibitory P2X4R-BDNF axis. The expression of the macrophage marker Iba1 and the chemokine CCL2 (MCP-1), and a neuronal injury marker (activating transcription factor 3), was attenuated by prior running in the ipsilateral lumbar dorsal root ganglia. Prior exercise suppressed macrophage infiltration and/or injury site proliferation, given decreased presence of macrophage markers Iba1, iNOS (M1), and Arg-1 (M2; expression was time dependent). Chronic constriction injury-driven increases in serum proinflammatory chemokines were suppressed by prior running, whereas IL-10 was increased. Peripheral blood mononuclear cells were also stimulated with lipopolysaccharide ex vivo, wherein CCI-induced increases in IL-1ß, nitrite, and IL-10 were suppressed by prior exercise. Last, unrestricted voluntary wheel running, beginning either the day of, or 2 weeks after, CCI, progressively reversed neuropathic pain. This study is the first to investigate the behavioral and neuroimmune consequences of regular exercise terminating before nerve injury. This study suggests that chronic pain should be considered a component of "the diseasome of physical inactivity," and that an active lifestyle may prevent neuropathic pain.

Effects of Virtual Walking Treatment on Spinal Cord Injury-Related Neuropathic Pain: Pilot Results and Trends Related to Location of Pain and at-level Neuronal Hypersensitivity.

Previous studies have shown that virtual walking to treat spinal cord injury-related neuropathic pain (SCI-NP) can be beneficial, although the type of SCI-NP that may benefit the most is unclear. This study's aims were to (1) determine the effect of location of SCI-NP on pain outcomes after virtual walking treatment and (2) examine the potential relationship between neuronal hyperexcitability, as measured by quantitative sensory testing, and pain reduction after virtual walking treatment. Participants were recruited from a larger ongoing trial examining the benefits of virtual walking in SCI-NP. Neuropathic pain was classified according to location of pain (at- or below-level). In addition, quantitative sensory testing was performed on a subset of individuals at a nonpainful area corresponding to the level of their injury before virtual walking treatment and was used to characterize treatment response. These pilot results suggest that when considered as a group, SCI-NP was responsive to treatment irrespective of the location of pain (F1, 44 = 4.82, P = 0.03), with a trend for the greatest reduction occurring in at-level SCI-NP (F1, 44 = 3.18, P = 0.08). These pilot results also potentially implicate cold, innocuous cool, and pressure hypersensitivity at the level of injury in attenuating the benefits of virtual walking to below-level pain, suggesting certain SCI-NP sensory profiles may be less responsive to virtual walking.

Somatosensory Rehabilitation for Neuropathic Pain in Burn Survivors: A Case Series.

Neuropathic pain is an enormous rehabilitation challenge that has a substantial negative effect on patient function and quality of life. Somatosensory rehabilitation is a novel, nonpharmacological intervention described by Spicher based on the neuroplasticity of the somatosensory system. The rationale for somatosensory rehabilitation is that treating hypoesthesia will decrease neuropathic pain. Particularly for those with established neuropathic pain, the hypoesthesia may be masked by mechanical allodynia, which must be treated before treating the underlying hyposensitive zone. This case series describes the outcome of 17 burn survivors treated with somatosensory rehabilitation for their neuropathic pain. Before initiating treatment a modified version of the McGill Pain Questionnaire-short form (Questionnaire de la douleur St. Antoine, QDSA) was completed with the patients. The total score (×/64) was converted to percentage. The mechanical allodynia was assessed with the Rainbow Pain Scale that uses touch with the 15-g Semmes Weinstein Monofilaments (SWMs) and that was rated as painful on the visual analog scale (3/10 or resting pain + 1/10), as the criteria for mechanical allodynia. The severity level was assessed using seven predetermined SWMs to identify the smallest that elicited pain. The treatment consisted of avoiding all touch in the allodynic zone while concurrently providing proximal sensory and vibratory counter stimulation. Once the mechanical allodynia was eliminated, the underlying hypoesthesia was treated. Hypoesthesia was evaluated with the SWMs, and the percent improvement from baseline was calculated. The sensory reeducation treatment for hypoesthesia consisted of touch discrimination, texture perception, and vibratory stimulation. Seventeen patients (71/29% male/female, 21 ± 25% TBSA burned, 486 ± 596 days postburn) were evaluated and treated. Of these 15 initially presented with mechanical allodynia. The SWM scores had improved by 27 ± 21% (n = 14) and 29 ± 26% (n = 12) at 2 and 3 months posttreatment, respectively. The QDSA scores had improved by 9 ± 14% (n = 8) and 23 ± 23% (n = 6) at 2 and 3 months posttreatment, respectively. There were two patients who initially presented with hypoesthesia and six who had their zone of hypoesthesia treated after the mechanical allodynia had resolved. For these eight patients, their ability to perceive light touch improved by 27 ± 17% (n = 8) and 35 ± 25% (n = 6) at 2 and 3 months postsensory reeducation treatment initiation, respectively. The QDSA improved by 9 and 50% for the two patients who initially presented with hypoesthesia. In this case series, the majority of patients (13/17 or 76%) showed substantial improvements after somatosensory rehabilitation suggesting this is a treatment approach that should be considered with burn survivors experiencing neuropathic pain. There is a need, however, for future controlled studies to further investigate this approach and to determine if there is a subpopulation of burn survivors that are more likely than others to benefit from this approach.

Early-onset treadmill training reduces mechanical allodynia and modulates calcitonin gene-related peptide fiber density in lamina III/IV in a mouse model of spinal cord contusion injury.

Below-level central neuropathic pain (CNP) affects a large proportion of spinal cord injured individuals. To better define the dynamic changes of the spinal cord neural network contributing to the development of CNP after spinal cord injury (SCI), we characterized the morphological and behavioral correlates of CNP in female C57BL/6 mice after a moderate T11 contusion SCI (50 kdyn) and the influence of moderate physical activity. Compared with sham-operated animals, injured mice developed mechanical allodynia 2 weeks post injury when tested with small-diameter von Frey hair filaments (0.16 g and 0.4 g filament), but presented hyporesponsiveness to noxious mechanical stimuli (1.4 g filament). The mechano-sensory alterations lasted up to 35 days post injury, the longest time point examined. The response latency to heat stimuli already decreased significantly 10 days post injury reaching a plateau 2 weeks later. In contrast, injured mice developed remarkable hyposensitivity to cold stimuli. Animals that underwent moderate treadmill training (2 × 15 minutes; 5 d/wk) showed a significant reduction in the response rate to light mechanical stimuli as early as 6 days after training. Calcitonin gene-related peptide (CGRP) labeling in lamina III-IV of the dorsal horn revealed significant increases in CGRP-labeling density in injured animals compared with sham control animals. Importantly, treadmill training reduced CGRP-labeling density by about 50% (P < 0.01), partially reducing the injury-induced increases. Analysis of IB4-labeled nonpeptidergic sensory fibers revealed no differences between experimental groups. Abnormalities in temperature sensation were not influenced by physical activity. Thus, treadmill training partially resolves signs of below-level CNP after SCI and modulates the density of CGRP-labeled fibers.

Voluntary wheel running delays disease onset and reduces pain hypersensitivity in early experimental autoimmune encephalomyelitis (EAE).

Multiple sclerosis (MS) is classically defined by motor deficits, but it is also associated with the secondary symptoms of pain, depression, and anxiety. Up to this point modifying these secondary symptoms has been difficult. There is evidence that both MS and the animal model experimental autoimmune encephalomyelitis (EAE), commonly used to study the pathophysiology of the disease, can be modulated by exercise. To examine whether limited voluntary wheel running could modulate EAE disease progression and the co-morbid symptoms of pain, mice with EAE were allowed access to running wheels for 1h every day. Allowing only 1h every day of voluntary running led to a significant delay in the onset of clinical signs of the disease. The development of mechanical allodynia was assessed using Von Frey hairs and indicated that wheel running had a modest positive effect on the pain hypersensitivity associated with EAE. These behavioral changes were associated with reduced numbers of cFOS and phosphorylated NR1 positive cells in the dorsal horn of the spinal cord compared to no-run EAE controls. In addition, within the dorsal horn, voluntary wheel running reduced the number of infiltrating CD3(+) T-cells and reduced the overall levels of Iba1 immunoreactivity. Using high performance liquid chromatography (HPLC), we observed that wheel-running lead to significant changes in the spinal cord levels of the antioxidant glutathione. Oxidative stress has separately been shown to contribute to EAE disease progression and neuropathic pain. Together these results indicate that in mice with EAE, voluntary motor activity can delay the onset of clinical signs and reduce pain symptoms associated with the disease.

Central hypersensitivity in chronic musculoskeletal pain.

Clinical research has consistently detected alteration in central pain processing leading to hypersensitivity. Most methods used in humans are reliable and have face validity to detect widespread central hypersensitivity. However, construct validity is difficult to investigate due to lack of gold standards. Reference values in the pain-free population have been generated, but need replication. Research on pain biomarkers that reflect specific central hypersensitivity processes is warranted. Few studies have analyzed the prognostic value of central hypersensitivity. Most medications acting at central level and some non-pharmacological approaches, including psychological interventions, are likely to attenuate central hypersensitivity.

Examination of contraction-induced muscle pain as a behavioral correlate of physical activity in women with and without fibromyalgia.

PURPOSE: This study aimed to compare muscle pain intensity during a sustained isometric contraction in women with and without fibromyalgia (FM), and examine the association between muscle pain and self-reported levels of physical activity. METHODS: Fourteen women with FM and 14 healthy women completed the study, where muscle pain ratings (MPRs) were obtained every 30 s during a 3 min isometric handgrip task at 25% maximal strength, and self-reported physical activity was quantified using the Baecke Physical Activity Questionnaire. RESULTS: Women with FM were less physically active than healthy controls. During the isometric contraction, MPR progressively increased in both groups at a comparable rate, but women with FM generally reported a greater intensity of muscle pain than healthy controls. Among all women, average MPR scores were inversely associated with self-reported physical activity levels. CONCLUSIONS: Women with FM exhibit augmented muscle pain during isometric contractions and reduced physical activity than healthy controls. Furthermore, contraction-induced muscle pain is inversely associated with physical activity levels. These observations suggest that augmented muscle pain may serve as a behavioral correlate of reduced physical activity in women with FM. Implications for Rehabilitation Women with fibromyalgia experience a greater intensity of localized muscle pain in a contracting muscle compared to healthy women. The intensity of pain during muscle contraction is inversely associated with the amount of physical activity in women with and without fibromyalgia. Future studies should determine whether exercise adherence can be improved by considering the relationship between contraction-induced muscle pain and participation in routine physical activity.

BDNF Induced by Treadmill Training Contributes to the Suppression of Spasticity and Allodynia After Spinal Cord Injury via Upregulation of KCC2.

BACKGROUND: Spasticity and allodynia are major sequelae that affect the quality of life and daily activities of spinal cord injury (SCI) patients. Although rehabilitation ameliorates spasticity and allodynia, the molecular mechanisms involved in these processes remain elusive. OBJECTIVE: To investigate the molecular mechanisms by which rehabilitation ameliorates spasticity and allodynia after SCI in rats. METHODS: The expression levels of brain-derived neurotrophic factor (BDNF) and potassium-chloride cotransporter-2 (KCC2), as well as the localization of KCC2, were examined in the lumbar enlargements of untrained and treadmill-trained thoracic SCI model rats. Spasticity and allodynia were determined via behavioral and electrophysiological analyses. The effects of BDNF on spasticity, allodynia, and KCC2 activation were determined by inhibition of BDNF signaling via intrathecal administration of TrkB-IgG. The effects of SCI and training on the expression levels of functional phospholipase C-γ in the lumbar enlargement were also examined. RESULTS: Treadmill training after SCI upregulated endogenous BDNF expression and posttranslational modification of KCC2 in the lumbar enlargement significantly. There were also significant correlations between increased KCC2 expression and ameliorated spasticity and allodynia. Administration of TrkB-IgG abrogated the training-induced upregulation of KCC2 and beneficial effects on spasticity and allodynia. The expression level of functional phospholipase C-γ was reduced significantly after SCI, which may have contributed to the change in the function of BDNF, whereby it did not trigger short-term downregulation or induce long-term upregulation of KCC2 expression secondary to training. CONCLUSIONS: BDNF-mediated restoration of KCC2 expression underlies the suppression of spasticity and allodynia caused by rehabilitation.

Radial nerve mobilisation had bilateral sensory effects in people with thumb carpometacarpal osteoarthritis: a randomised trial.

QUESTION: In people with thumb carpometacarpal osteoarthritis, does radial nerve mobilisation to the affected hand reduce pressure pain sensitivity in the contralateral hand? DESIGN: Secondary analysis of data from a randomised trial with concealed allocation, assessor blinding, and intention-to-treat analysis. PARTICIPANTS: Sixty people with thumb CMC osteoarthritis in the dominant hand aged 70-90 years. INTERVENTIONS: The experimental group received sliding mobilisation of the radial nerve and the control group received a non-therapeutic dose of intermittent ultrasound, on the affected side for six sessions over four weeks. OUTCOME MEASURES: On the contralateral side, pressure pain thresholds at the lateral epicondyle, thumb CMC joint, tubercle of the scaphoid bone, and hamate bone were assessed before and after the intervention with follow-up at 1 and 2 months. RESULTS: No important baseline differences were noted between groups. At the end of the intervention period, the experimental group had significantly a higher (ie, better) pressure pain threshold than the control group at the lateral epicondyle by 1.5kg/cm(2) (95% CI 0.2 to 2.2), CMC joint by 1.2kg/cm(2) (95% CI 0.5 to 2.0), scaphoid bone by 1.0kg/cm(2) (95% CI 0.2 to 1.8) and hamate bone by 1.9kg/cm(2) (95% CI 1.0 to 2.7). Although mean values in the experimental group remained better than the control group at all sites at both follow-up assessments, these differences were not statistically significant. CONCLUSION: Radial nerve gliding applied to the symptomatic hand induced hypoalgesic effects on the contralateral hand in people with CMC osteoarthritis, suggesting bilateral hypoalgesic effects of the intervention.

Treadmill running and static stretching improve long-lasting hyperalgesia, joint limitation, and muscle atrophy induced by cast immobilization in rats.

The effects of exercise on chronic pain induced by immobilization are incompletely understood. The purpose of this study was to investigate whether 30min of treadmill running (TR; active exercise) and 10min of static stretching (SS; passive exercise) of the immobilized hindlimb reduce widespread chronic pain, joint limitation, and hindlimb muscle atrophy induced by cast immobilization in rats. One hindlimb of Sprague Dawley (SD) rats was immobilized for 2 weeks with a cast, and remobilization was conducted for 7 weeks. MRI study showed that cast immobilization had induced inflammatory changes in the immobilized hindlimb, beginning as early as 2h after cast removal; these changes continued for 2-3 days. Mechanical hyperalgesia in the calf and hindpaw developed as early as 2h after cast removal and continued for 7 weeks. TR and SS were initiated 3 days after cast removal and were continued 3 times per week for 2 weeks. Both forms of exercise significantly inhibited mechanical hyperalgesia in the calf and hindpaw in immobilized rats. Range-of-motion limitations in the knee and ankle joints and calf muscle atrophy after cast removal were also decreased by both TR and SS. This study is the first to demonstrate the beneficial effect of TR and SS on widespread chronic pain, joint limitation, and muscle atrophy in a cast-immobilized rat model.

Effectiveness of water physical therapy on pain, pressure pain sensitivity, and myofascial trigger points in breast cancer survivors: a randomized, controlled clinical trial.

OBJECTIVE: To evaluate the effects of an 8-week water physical therapy program on cervical and shoulder pain, pressure sensitivity, and the presence of trigger points (TrPs) in breast cancer survivors. DESIGN: Randomized, controlled trial. SETTING: To date, no study has investigated effects of water therapy in breast cancer. PATIENTS: Sixty-six breast cancer survivors were randomly assigned into two groups: WATER group, who received a water exercise program or CONTROL group who received the usual care treatment for breast cancer. INTERVENTIONS: The WATER therapy program consisted of 24 sessions (3 times/week over 8 weeks) of low-intensity exercises in a warm pool (32°C). Each session included 10-minute warm-up period; 35 minutes of aerobic, low-intensity endurance, and core stability training; and a 15-minute cool-down period (stretching and relaxation). OUTCOMES: Neck and shoulder pain (visual analog scale, 0-100 mm), pressure pain thresholds (PPTs) over C5-C6 zygapophyseal joints, deltoid muscles, second metacarpal, and tibialis anterior muscles, and the presence of TrPs in cervical-shoulder muscles were assessed at baseline and after the 8-week program by an assessor blinded to treatment allocation. RESULTS: The WATER group demonstrated a between-group improvement for neck pain of -31 mm (95% confidence interval [CI]-49 to -22, P < 0.001; effect size 1.1, 0.81-1.75) and for shoulder-axillary of -19 mm (-40 to -04, P = 0.046; effect size 0.70, 0.14-1.40). Improvements were also noted for PPT levels over C5-C6 joints (between-group differences, affected side: 27.7 kPa, 95% CI 3.9-50.4; unaffected: 18.1 kPa, 95% CI 6.1-52.2). No between-group differences for PPT over the remaining points were observed (P > 0.05). Finally, patients in the WATER program showed a greater reduction of active TrPs as compared with the CONTROL group (P < 0.05). CONCLUSIONS: An 8-week water therapy program was effective for improving neck and shoulder/axillary pain, and reducing the presence of TrPs in breast cancer survivors as compared with usual care; however, no significant changes in widespread pressure pain hyperalgesia were found.

Ankle joint mobilization decreases hypersensitivity by activation of peripheral opioid receptors in a mouse model of postoperative pain.

OBJECTIVE: Investigate whether ankle joint mobilization (AJM) decreases hypersensitivity in the mouse plantar incision (PI) model of postoperative pain as well as to analyze the possible mechanisms involved in this effect. DESIGN: Experiment 1: PI male Swiss mice (25-35 g, N = eight animals per group) were subjected to five sessions of AJM, each lasting either 9 or 3 minutes. AJM movement was applied at a grade III as defined by Maitland. Paw withdrawal frequency to mechanical stimuli was assessed before realization of PI and before and after daily AJM sessions. Mechanical hypersensitivity was also assessed following systemic (intraperitoneal [i.p.]) and local (intraplantar) injection of naloxone (a nonselective opioid receptor antagonist; 1 mg/kg, i.p.; 5 µg/paw, respectively, experiment 2); and systemic injection of fucoidin (100 µg/mouse, i.p., an inhibitor of leukocyte rolling, experiment 3) in different groups of mice. RESULTS: Nine but not 3 minutes of AJM reduced mechanical hypersensitivity caused by PI, an effect that was prevented by systemic and local administrations of naloxone but not by fucoidin. CONCLUSIONS: Our results indicate that joint mobilization reduces postoperative pain by activation of the peripheral opioid pathway. However, antihypersensitivity induced by AJM is apparently not limited by the number of opioid-containing leukocytes but by opioid receptors availability in sensory neurons. A better understanding of the peripheral mechanisms of AJM could stimulate therapists to integrate joint mobilization with strategies also known to influence endogenous pain control, such as exercise, acupuncture, and transcutaneous electrical nerve stimulation to potentiate endogenous analgesia.