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Using EEG recordings of patients with endometriosis-related chronic pelvic pain, we have examined the effective connectivity within the cortical pain-related network during rest and during pain-related imagery. During rest, an altered connectivity was hypothesized between cortical somatosensory pain areas and regions involved in emotional and cognitive modulation of pain. During pain-related imagery, alterations in prefrontal-temporal connectivity were expected. The effective connectivity was estimated using the Directed Transfer Function method. Differences between endometriosis patients and controls were found in the beta band (14-25Hz). During rest, endometriosis was associated with an increased connectivity from the left dorsolateral prefrontal cortex to the left somatosensory cortex and also from the left somatosensory cortex to the orbitofrontal cortex and the right temporal cortex. These results might be related to sustained activation of the somatosensory pain system caused by the ongoing pain. During pain-related imagery, endometriosis patients showed an increased connectivity from the left dorsolateral prefrontal cortex to the right temporal cortex. This finding might point to impaired emotional regulation when processing pain-related stimuli, or it might be related to altered memorization of pain experiences. Results of this study open up new directions in chronic pain research aimed at exploring the beta band connectivity alterations. PERSPECTIVE: This study examined the pain system's dynamics in endometriosis patients with chronic pelvic pain during resting-state and pain-related mental imagery. The results could contribute to the development of new therapies using guided mental imagery.
Learn More >Patients with irritable bowel syndrome (IBS) show pain hypersensitivity and smooth muscle hypercontractility in response to colorectal distension (CRD). Synaptic plasticity, a key process of memory formation, in the enteric nervous system may be a novel explanation. This study aimed to explore the regulatory role of ephrinB2/ephB2 in enteric synaptic plasticity and colonic hyperreactive motility in IBS. Postinfectious (PI)-IBS was induced by infection in rats. Isometric contractions of colonic circular muscle strips, particularly neural-mediated contractions, were recorded . Meanwhile, ephrinB2/ephB2-mediated enteric structural and functional synaptic plasticity were assessed in the colonic muscularis, indicating that ephrinB2 and ephB2 were located on enteric nerves and up-regulated in the colonic muscularis of PI-IBS rats. Colonic hypersensitivity to CRD and neural-mediated colonic hypercontractility were present in PI-IBS rats, which were correlated with increased levels of cellular homologous fos protein () and activity-regulated cystoskeleton-associated protein (arc), the synaptic plasticity-related immediate early genes, and were ameliorated by ephB2Fc (an ephB2 receptor blocker) or MK801 (an NMDA receptor inhibitor) exposure. EphrinB2/ephB2 facilitated synaptic sprouting and NMDA receptor-mediated synaptic potentiation in the colonic muscularis of PI-IBS rats and in the longitudinal muscle-myenteric plexus cultures, involving the Erk-MAPK and PI3K-protein kinase B pathways. In conclusion, ephrinB2/ephB2 promoted the synaptic sprouting and potentiation of myenteric nerves involved in persistent muscle hypercontractility and pain in PI-IBS. Hence, ephrinB2/ephB2 may be an emerging target for the treatment of IBS.-Zhang, L., Wang, R., Bai, T., Xiang, X., Qian, W., Song, J., Hou, X. EphrinB2/ephB2-mediated myenteric synaptic plasticity: mechanisms underlying the persistent muscle hypercontractility and pain in postinfectious IBS.
Learn More >: Calcitonin Gene-Related Peptide (CGRP) plays a crucial role in migraine pathophysiology. A novel specific treatment strategy for the prevention of migraine incorporates monoclonal antibodies (mAbs) against CGRP and its canonical receptor. Eptinezumab, fremanezumab and galcanezumab block CGRP mediated effects by binding to the peptide, while erenumab blocks the CGRP receptor. : Following a brief overview of pharmacological characteristics, we will review phase III trials for the use of CGRP mAbs in the prevention of episodic and chronic migraine. : All four CGRP mAbs demonstrated an excellent safety, tolerability and efficacy profile in migraine patients. Across all trials mAbs showed superior efficacy for the reduction of monthly migraine days compared to placebo with a net benefit of 2.8 days. Neither cardiovascular nor immunological safety concerns have emerged from clinical trials. Fremanezumab, galcanezumab, and erenumab are approved in the USA and Europe. Based on trial data there is no reason why these mAbs should not become first line therapies in future. For now, we advocate for the use of mAbs in migraine prevention for patients who failed a minimum of two standard oral treatments based on the novelty and costs of this approach. mAbs are also effective in patients with medication overuse and with comorbid depression or anxiety disorders. Taken together, mAbs are likely to usher in a new era in migraine prevention and provide significant value to patients.
Learn More >Inflammatory response triggered by nerve injury plays important roles in the development of neurological disorders, such as neuropathic pain. The signaling events leading to inflammation in the nervous system remain poorly understood. Here, by deleting Dlk in sensory neurons driven by Wnt1a-Cre, we show that dual leucine zipper kinase (DLK) is required for the neuronal intrinsic immune response to induce cytokines and chemokines such as Ccl2, Ccl7, and Ccl12 upon nerve injury. The DLK-controlled injury response in sensory neurons could regulate CD11b immune cell infiltration in the dorsal root ganglia, as well as microgliosis and astrogliosis in the spinal dorsal horn but not the ventral horn. Deficiency of Dlk drastically alleviates the neuropathic pain elicited by chronic constriction injury of the sciatic nerve. Thus, DLK is an essential component that mediates the neuronal intrinsic immune response to nerve injury in sensory neurons and regulates inflammation in the spinal cord.
Learn More >There are a growing number of cancer survivors in the United States who are at risk for chronic pain due to cancer disease and treatments. The prevalence of chronic pain among cancer survivors has not been comprehensively reported.
Learn More >Educating medical trainees across the continuum is essential to a multifaceted strategy for addressing the opioid epidemic.
Learn More >Artemin is a neurotrophic factor that plays a crucial role in the regulation of neural development and regeneration and has also been implicated in the pathogenesis of inflammatory pain. The receptor for artemin, GFRα3, is expressed by sympathetic and nociceptive sensory neurons, including some that innervate the bone marrow, but it is unclear if it is also expressed in other cell types in the bone marrow. Our goal in the present study was to characterise the expression of GFRα3 in nonneuronal cells in the bone marrow. Immunohistochemical studies revealed that GFRα3-expressing cells in the bone marrow are spatially associated with blood vessels and are in intimate contact with nerve fibres. We used various combinations of markers to distinguish different cell types and found that the GFRα3-expressing cells expressed markers of nonmyelinating Schwann cells (e.g. GFAP, p75NTR, nestin). Analysis of bone marrow sections of Wnt1-reporter mice also demonstrated that they originate from the neural crest. Further characterisation using flow cytometry revealed that GFRα3 is expressed in a population of CD51Sca1PDGFRα cells, reinforcing the notion that they are neural crest-derived, nonmyelinating Schwann cells. In conclusion, there is a close association between peripheral nerve terminals and a population of nonneuronal cells that express GFRα3 in the bone marrow. The nonneuronal cells have characteristics consistent with a neural crest-derived, nonmyelinating Schwann cell phenotype. Our findings provide a better understanding of the expression pattern of GFRα3 in the bone marrow microenvironment.
Learn More >Although much is known about the correlates of heroin overdose, less is known about pharmaceutical opioid (PO) overdose. This study aimed to examine correlates of opioid overdose deaths by opioid and compare correlates between opioids.
Learn More >Chronic musculoskeletal pain in adolescence is a significant public health concern with 3-5% of adolescents suffering from significant pain-related disability. Pain-related fear and avoidance of activities has been found to have a significant influence on pain outcomes in children and adolescents and is a risk factor for less favorable response to treatment. To address this need, we developed graded exposure treatment for youth with chronic pain (GET Living). We describe the rationale, design, and implementation of a two-group randomized controlled trial (RCT) enhanced with single-case experimental design (SCED) methodology with a sample of 74 adolescents with chronic musculosketal pain and their parent caregivers. GET Living includes education, behavioral exposures, and parent intervention jointly delivered by pain psychology and physical therapy providers. The multidisciplinary pain management control group includes pain psychology delivered education and pain self-management skills training (e.g., relaxation, cognitive skills) and separate physical therapy. Assessments include brief daily diaries (baseline to discharge, 7-days at 3-month and 6-month follow-up), comprehensive in-person evaluations at baseline and discharge, and questionnaire across all time points (baseline, discharge, 3-month and 6-month follow-up). Primary outcome is pain-related fear avoidance. Secondary outcome is functional disability. We also outline all additional outcomes, exploratory outcomes, covariates, and implementation measures. The objective is to offer a mechanism-based, targeted intervention to youth with musculoskeletal pain to enhance likelihood of return to function.
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