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Our tibial fracture orthopaedic injury model in mice recapitulates the major manifestations of complex trauma including nociceptive sensitization, bone fracture, muscle fibrosis and muscle fibre loss. Delayed exercise after complex orthopaedic trauma results in decreased muscle fibrosis and improved pain Losartan, an angiotensin-receptor blocker with antifibrotic abilities, recapitulates the effect of exercise on post-injury recovery and may provide an enhanced recovery option for those who are unable to exercise after injury ABSTRACT: Chronic pain and disability after limb injury are major public health problems. Early mobilization after injury improves functional outcomes for patients but when and how to implement rehabilitation strategies remains a clinical challenge. Additionally, whether the beneficial effects of exercise can be reproduced using pharmacological tools remains unknown and may benefit patients who are unable to exercise due to immobilization. We developed a murine model of orthopaedic trauma combining tibia fracture and pin fixation with muscle damage. Behavioral measures included mechanical nociceptive thresholds and distances run on exercise wheels. Bone healing was quantified using microCT scanning, and muscle fibre size distribution and fibrosis were followed using immunohistochemistry. We found that the model provided robust mechanical allodynia, fibrosis and a shift to smaller average muscle fibre size lasting up to 5 weeks from injury. We also observed that allowing "late" (weeks 1-2) rather than "early" (weeks 0-1) exercise after injury resulted in greater overall running activity and greater reversal of allodynia. In parallel, the late running paradigm was associated with reduced muscle fibrosis, earlier increase in muscle fibre diameter and a short-term benefit in reducing callus volume. Providing the anti-fibrotic angiotensin receptor blocker losartan to mice in drinking water reduced both allodynia and muscle fibrosis. Combining losartan and late exercise provided no additional benefit. We conclude that early healing after orthopaedic trauma must be allowed prior to the initiation of exercise to achieve optimal pain, functional and physiological outcomes and that losartan is a viable candidate for translational studies. This article is protected by copyright. All rights reserved.
Learn More >The pathogenesis of cancer induced bone pain (CIBP) is extremely complex, and glutamate receptor dysfunction plays an important role in the formation of CIBP. Synapse-associated protein 102 (SAP102) anchors glutamate receptors in the postsynaptic membrane. However, its effect on hyperalgesia formation in CIBP has not been clarified. This study investigated the role of SAP102 in the formation of hyperalgesia in rats with CIBP SAP102 is present in spinal dorsal horn neurons, but not in astrocytes or microglia. NMDAR-NR2B is localized with neurons. In addition, SAP102 and NMDAR-NR2B expression levels in spinal dorsal horn tissues were detected by Western blot and co-immunoprecipitation. Intrathecal injection of lentiviral vector of RNAi to knockdown SAP102 expression in the spinal dorsal horn significantly attenuated abnormal mechanic pain when compared to non-coding lentiviral vector. These findings indicate that SAP102 can anchor NMDA receptors to affect hyperalgesia formation in bone cancer pain.
Learn More >The findings of resting-state functional MRI studies have suggested that abnormal functional integration between interconnected cortical networks characterises the brain of patients with migraine. The aim of this study was to investigate the functional connectivity between the hypothalamus, brainstem, considered as the migraine generator, and the following areas/networks that are reportedly involved in the pathophysiology of migraine: default mode network (DMN), executive control network, dorsal attention system, and primary and dorsoventral visual networks.
Learn More >For patients with nonspecific chronic low back pain CLBP, exercise therapy is stated to be the most effective intervention strategy but it is unclear which kind of exercise therapy is most beneficial.
Learn More >Glutamate, as well as nerve growth factor (NGF), is involved in nociception from peripheral tissues, such as muscles. However, the potential interaction between glutamate and NGF still remains unclear. This study investigated the interaction between glutamate-induced masseter muscle pain and NGF-induced allodynia on pain perception and jaw function in healthy individuals, and any possible sex differences in the response. Thirty pain-free adult participants (15 men and 15 women, mean age ± : 24 ± 4 years) participated in this study consisting of three sessions (Day 0, Day 3, and Day 4). NGF (5 μg/mL, 1.0 mL) was injected into the masseter muscle on Day 0 to induce muscle allodynia. On Day 3, glutamate (1M, 0.2 mL) was injected into the same masseter muscle. Before and after injections on Day 0 and 3, and post-injection (Day 4), spontaneous pain, temporal summation pain, as well as functional pain and fatigue in response to chewing were assessed with validated scales, and the pressure pain threshold (PPT) was recorded. Spontaneous pain intensity was significantly higher after glutamate than NGF ( < 0.001). PPTs, temporal summation pain and functional measures were all reduced 3 days after NGF injection ('s < 0.001). Injection of glutamate on Day 3 did not further affect PPTs or temporal summation pain and there were no sex differences in the effects ( > 0.189). Chewing pain ( = 0.022) and fatigue increased after glutamate injection to a higher degree in the women than men ( = 0.037). Taken together, while glutamate injected into the NGF-sensitized muscle was painful, it did not alter muscle tenderness in women vs. men. However, pain and fatigue evoked by jaw function were higher in women after glutamate injection. This suggest that sex differences reported for masseter myalgia, mimicked by glutamate and NGF mediated pain in this study, may be greater for measures of perceived jaw function, which should be considered in a clinical evaluation.
Learn More >Cortical thickness (CTh) via surface-based morphometry analysis is a popular method to characterize brain morphometry. Many studies have been performed to investigate CTh abnormalities in migraine. However, the results from these studies were not consistent and even conflicting. These divergent results hinder us to obtain a clear picture of brain morphometry regarding CTh alterations in migraine. Coordinate-based meta-analysis (CBMA) is a promising technique to quantitatively pool individual neuroimaging studies to identify consistent brain areas involved. Electronic databases (PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, WanFang, and SinoMed) and other sources (bioRxiv and reference lists of relevant articles and reviews) were systematically searched for studies that compared regional CTh differences between patients with migraine and healthy controls (HCs) up to May 15, 2020. A CBMA was performed using the Seed-based d Mapping with Permutation of Subject Images approach. In total, we identified 16 studies with 17 datasets reported that were eligible for the CBMA. The 17 datasets included 872 patients with migraine (average sample size 51.3, mean age 39.6 years, 721 females) and 949 HCs (average sample size 59.3, mean age 44.2 years, 680 females). The CBMA detected no statistically significant consistency of CTh alterations in patients with migraine relative to HCs. Sensitivity analysis and subgroup analysis verified this result to be robust. Metaregression analyses revealed that this CBMA result was not confounded by age, gender, aura, attack frequency per month, and illness duration. Our CBMA adds to the evidence of the replication crisis in neuroimaging research that is increasingly recognized. Many potential confounders, such as underpowered sample size, heterogeneous patient selection criteria, and differences in imaging collection and methodology, may contribute to the inconsistencies of CTh alterations in migraine, which merit attention before planning future research on this topic.
Learn More >Endometriosis is a debilitating women's health condition and is the most common cause of chronic pelvic pain. Impaired cognitive control is common in chronic pain conditions, however, it has not yet been investigated in endometriosis. The aim of this study was to explore the neuronal correlates of cognitive control in women with endometriosis. Using a cross-sectional study design with data collected at a single time-point, event-related potentials were elicited during a cued continuous performance test from 20 women with endometriosis (mean age = 28.5 ± 5.2 years) and 20 age- and gender-matched controls (mean age = 28.5 ± 5.2 years). Event-related potential components were extracted and P3 component amplitudes were derived with temporal principal components analysis. Behavioral and ERP outcomes were compared between groups and subjective pain severity was correlated with ERP component amplitudes. No significant behavioral differences were seen in task performance between the groups (all > 0.094). Target P3b (all < 0.034) and SW (all < 0.040), and non-target early P3a (eP3a; all < 0.023) and late P3a (lP3a; all < 0.035) amplitudes were smaller for the endometriosis compared to the healthy control group. Lower non-target eP3a ( < 0.001), lP3a ( = 0.013), and SW ( = 0.019) amplitudes were correlated with higher pain severity scores. Findings suggest that endometriosis-associated chronic pelvic pain is linked to alterations in stimulus-response processing and inhibitory control networks, but not impaired behavioral performance, due to compensatory neuroplastic changes in overlapping cognitive control and pain networks.
Learn More >Ankylosing spondylitis (AS) mainly affects the axial skeleton and is an important factor leading to chronic lower back pain in young individuals. However, few studies have explored alterations of brain gray matter volume in AS patients. The purpose of the present study was to describe brain gray matter abnormalities associated with AS pain. A total of 61 AS patients and 52 healthy controls (HCs) were included in this study. Using voxel-based morphometrics, we detected abnormal gray matter volume in AS patients. Based on the voxel-wise analysis, the gray matter volume in the left putamen of the AS group was increased significantly compared with that of the HC group. In addition, we found that the gray matter volume of the left putamen was positively correlated with the duration of AS and total back pain scores, whereas it was not significantly correlated with Bath Ankylosing Spondylitis Disease Activity Index scores, C-reactive protein, or erythrocyte sedimentation rate in AS patients. Taken together, our findings improve our understanding of the neural substrates of pain in AS and provide evidence of AS-related neurological impairment. Hence, further investigation of the pathophysiology of the left putamen in AS is warranted.
Learn More >Pelvic pain is a common symptom of endometriosis. Our understanding of its etiology remains incomplete and medical management is limited by poor translation from preclinical models to clinical trials. In this review, we briefly consider the evidence, or lack thereof, that different subtypes of lesion, extra-uterine bleeding, and neuropathic pathways add to the complex and heterogeneous pain experience of women with the condition. We summarize the studies in rodent models of endometriosis that have used behavioral endpoints (evoked and non-evoked) to explore mechanisms of endometriosis-associated pain. Lesion innervation, activation of nerves by pronociceptive molecules released by immune cells, and a role for estrogen in modulating hyperalgesia are key endometriosis-associated pain mechanisms replicated in preclinical rodent models. The presence of ectopic (full thickness uterus or endometrial) tissue may be associated with changes in the spinal cord and brain, which appear to model changes reported in patients. While preclinical models using rats and mice have yielded insights that appear relevant to mechanisms responsible for the development of endometriosis-associated pain, they are limited in scope. Specifically, most studies are based on models that only resulted in the formation of superficial lesions and use induced (evoked) behavioral 'pain' tests. We suggest that translation for patient benefit will be improved by new approaches including models of ovarian and deep infiltrating disease and measurement of spontaneous pain behaviors. Future studies must also capitalize on new advances in the wider field of pain medicine to identify more effective treatments for endometriosis-associated pain.
Learn More >Alterations of the expression of microRNAs (miRNAs) in chronic pain models seem to play a crucial role in the development of neuropathic pain, with microRNA-1 (miR-1) being of particular interest. Recently, we were able to show that decreased miR-1 levels were associated with increased expression of brain-derived neurotrophic factor (BDNF) and Connexin 43 (Cx43). We hypothesized that miR-1 mimetic nucleotides could alleviate neuropathic pain caused by chronic constriction injury in rats.
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