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Factors contributing to development of Complex Regional Pain Syndrome (CRPS) are not fully understood. This study examined possible epigenetic mechanisms that may contribute to CRPS following traumatic injury. DNA methylation profiles were compared between individuals developing CRPS (n=9) and those developing non-CRPS neuropathic pain (n=38) after undergoing amputation following military trauma. Linear Models for Microarray (LIMMA) analyses revealed 48 differentially methylated cytosine-phosphate-guanine dinucleotide (CpG) sites between groups (unadjusted p's<.005), with the top gene COL11A1 meeting Bonferroni-adjusted p<0.05. The second largest differential methylation was observed for the HLA-DRB6 gene, an immune-related gene linked previously to CRPS in a small gene expression study. For all but seven of the significant CpG sites, the CRPS group was hypomethylated. Numerous functional Gene Ontology-Biological Process categories were significantly enriched [FDR (q value)<.15], including multiple immune-related categories (e.g., activation of immune response, immune system development, regulation of immune system processes, antigen processing and presentation). Differentially methylated genes were more highly connected in human protein-protein networks than expected by chance (p<.05), supporting the biological relevance of the findings. Results were validated in an independent sample linking a DNA biobank with electronic health records (n=126 CRPS phenotype, n=19,768 non-CRPS chronic pain phenotype). Analyses using PrediXcan methodology indicated differences in the genetically-determined component of gene expression in 7 of 48 genes identified in methylation analyses (p's<.02). Results suggest immune- and inflammatory-related factors might confer risk for developing CRPS following traumatic injury. Validation findings demonstrate the potential of using electronic health records linked to DNA for genomic studies of CRPS.
Learn More >Recently, a relationship was found between periodontitis and chronic migraine. Calcitonin gene-related peptide (CGRP) is a key element in migraine pathophysiology. However, no information exists of the potential association between periodontal inflammation and CGRP in chronic migraine. The aim of the study was, therefore, to investigate whether there is a link between periodontitis and peripheral levels of CGRP in a cohort of patients with chronic migraine.
Learn More >Fibroblast growth factor-inducible-14 (Fn14), a receptor for tumor necrosis-like weak inducer of apoptosis, is expressed in the neurons of dorsal root ganglion (DRG). Its mRNA is increased in the injured DRG following peripheral nerve injury. Whether this increase contributes to neuropathic pain is unknown. We reported here that peripheral nerve injury caused by spinal nerve ligation (SNL) increased the expression of Fn14 at both protein and mRNA levels in the injured DRG. Blocking this increase attenuated the development of SNL-induced mechanical, thermal, and cold pain hypersensitivities. Conversely, mimicking this increase produced the increases in the levels of phosphorylated extracellular signal-regulated kinase ½ and glial fibrillary acidic protein in ipsilateral dorsal horn and the enhanced responses to mechanical, thermal, and cold stimuli in the absence of SNL. Mechanistically, the increased Fn14 activated the NF-κB pathway through promoting the translocation of p65 into the nucleus of the injured DRG neurons. Our findings suggest that Fn14 may be a potential target for the therapeutic treatment of peripheral neuropathic pain.
Learn More >Prescribed opioids for chronic pain management contribute significantly to the opioid crisis. There is a need to understand the real-world benefits that, despite risks, lead chronic pain patients to persist in opioid use. Negative reinforcement models of addiction posit that individuals use substances to reduce aversive states but have seldom been applied to prescribed opioids. Using ecological momentary assessment, we examined reciprocal associations between opioid use and physical pain, for which opioids are prescribed, and negative affect (NA), for which they are not.
Learn More >Irritable bowel syndrome patients frequently complain of pain in body regions somatotopically distinct from the gut, suggesting the involvement of an exaggerated signaling process in both visceral and somatic sensory pathways. Increasing evidence has shown that sprouting of tyrosine hydroxylase immunoreactive (TH-IR) fibers toward sensory neurons in dorsal root ganglia maintains and exacerbates the neuropathic and inflammatory pain, as well as colonic inflammation. The aim of the present study was to determine whether electroacupuncture could alleviate the visceral and secondary somatic hyperalgesia in colitis rats by suppressing the TH-IR expression in related dorsal root ganglia. After trinitrobenzene sulfonic acid irritation, rats developed inflammatory tissue damage in the distal colon, which was accompanied by visceral hypersensitivity and secondary hind paw hyperalgesia, as indicated by enhanced visceromotor response to colorectal distension and decreased mechanical and thermal withdrawal latency of the hind paw. Additionally, excessive TH-IR fibers sprouted toward calcitonin gene-related peptide immunoreactive sensory neurons, and TH-IR neurons also increased in the sixth lumbar dorsal root ganglia of colitis rats. Both electroacupuncture and guanethidine attenuated visceral and referred hind paw hyperalgesia by inhibiting the over-expression of TH-IR neurons and fibers in the sixth lumbar dorsal root ganglia. Moreover local inflammatory damage in the distal colon was restored after 7 days of electroacupuncture intervention. These results suggest that electroacupuncture relieved visceral and referred hind paw hypersensitivity in colitis rats by inhibiting TH expression in the sixth lumbar dorsal root ganglia.
Learn More >One in 2 Canadians is expected to acquire cancer in their lifetime. Many cancers, including breast, ovarian, and lung cancer, are treated using taxane chemotherapy with curative intent. A major adverse effect with the use of taxane chemotherapeutic agents is taxane-induced peripheral neuropathy (TIPN). Both positive (spontaneous pain, heightened sensitivity with light touch, tingling, itching, burning) and negative (loss of touch, loss of hot/cold sensations, and loss of pain) sensory symptoms can be experienced in the hands and feet and worsen with increasing dose and treatment duration. The pathophysiology of TIPN is still unknown but likely involves multiple mechanisms, including microtubule impairment, neuroimmune and inflammatory changes, ion channel remodeling, impaired mitochondrial function, and genetic predisposition. This review highlights current theories on the pathophysiology for TIPN, the cellular responses thought to maintain neuropathic pain, and the growing support for exercise in the treatment and prevention of peripheral neuropathy and neuropathic pain in both animal and human models.
Learn More >Endometriosis is a common incurable inflammatory disorder that is associated with debilitating pelvic pain in women. Macrophages are central to the pathophysiology of endometriosis: they dictate the growth and vascularization of endometriosis lesions and more recently have been shown to promote lesion innervation. The aim of this study was to determine the mechanistic role of macrophages in producing pain associated with endometriosis. Herein, we show that macrophage depletion in a mouse model of endometriosis can reverse abnormal changes in pain behavior. We identified that disease-modified macrophages exhibit increased expression of IGF-1 in an model of endometriosis-associated macrophages and confirmed expression by lesion-resident macrophages in mice and women. Concentrations of IGF-1 were elevated in peritoneal fluid from women with endometriosis and positively correlate with their pain scores. Mechanistically, we demonstrate that macrophage-derived IGF-1 promotes sprouting neurogenesis and nerve sensitization . Finally, we show that the Igf-1 receptor inhibitor linsitinib reverses the pain behavior observed in mice with endometriosis. Our data support a role for macrophage-derived IGF-1 as a key neurotrophic and sensitizing factor in endometriosis, and we propose that therapies that modify macrophage phenotype may be attractive therapeutic options for the treatment of women with endometriosis-associated pain.-Forster, R., Sarginson, A., Velichkova, A., Hogg, C., Dorning, A., Horne, A. W., Saunders, P. T. K., Greaves, E. Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis.
Learn More >Calcitonin gene-related peptide (CGRP) released from trigeminal nerve fibres indicates trigeminal activation and has a key role in migraine pathophysiology. The trigeminal nerve directly innervates the eye. Therefore, in this study, we compared Calcitonin gene-related peptide in tear fluid of migraine patients and healthy controls.
Learn More >The aetiological role of work-related psychological stress in the development of musculoskeletal pain disorders (MDs) has been systematically investigated. Less clear however, is the role of perceived stress and life stressors. This review aimed to assess the evidence for an aetiological role of perceived stress and life stressors in the development of chronic MDs. Database searches were conducted to identify prospective longitudinal studies that assessed perceived stress and life stressors in individuals without, or in the first 6 weeks of musculoskeletal pain. The primary outcome was the development of a chronic MD. Methodological quality was investigated using an adapted version of the Quality Assessment Tool for Observational Cohort studies and Cross-Sectional studies, and the strength of evidence using the GRADE approach. Seven studies were included representing data from six independent cohorts. There was some evidence to support the aetiological role of perceived stress and life stressors in the development of arthritis (low quality) and chronic spinal pain (low quality). The limited number of studies, the poor quality of the evidence and heterogeneity of stress measures used across studies suggest that further high quality prospective studies are required to clarify the role of perceived stress and life stressors in the development of chronic MDs. PROSPERO: CRD42017059949 Perspective: This review summarizes and critically appraises the evidence for the aetiological role of perceived stress and life stressors in the development of chronic MDs. The limited number of studies, the low quality of the evidence and heterogeneity across studies suggest that further research is needed on perceived stress and life stressors in MDs.
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