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Mast cells, eosinophils, and basophils are central effector immune cells in allergic skin inflammation including atopic dermatitis (AD). Recent studies revealed that the bidirectional interaction between these three immune cell types (mast cells, eosinophils, and basophils) and the nervous system is involved in the pathogenesis of neurogenic inflammation, pain, and pruritus. Emerging evidence shows that these cells are the main source of pruritogens such as histamine, neuropeptides, cytokines, which are potential new therapeutic targets for drug development in chronic pruritus. For instance, many Th2 cytokines including interleukin (IL)-4, 13, and 31 have been recognized as some of the most promising targets for the treatment of chronic pruritus in AD. In this review, we highlight the link between these three immune cell subsets and peripheral nerves, with emphasis on the development of chronic pruritus such as AD. We present cytokines and receptors of these three immune cells and peripheral nerves, and discuss the therapeutic potential of targeting these neuro-immunological processes. This article is protected by copyright. All rights reserved.
Learn More >Migraine with brainstem aura is a rare subtype of migraine with aura. Although this entity has been known for many years, its diagnosis and even its existence are still a matter of debate. Previous studies demonstrated that current diagnostic criteria for migraine with brainstem aura are too open and brainstem symptoms may originate within the cortex and not in the brainstem. The aims of the present study were to analyse whether aura from the brainstem exists, how prevalent such a core syndrome is, to analyse if current diagnostic criteria define such a core syndrome and, if necessary, to develop new diagnostic criteria that define only the core syndrome. We analysed all migraine with brainstem aura cases described in detail in the literature, clinical cases from the Danish Headache Center (DHC) and our large sample of telephone interviewed cases with migraine with aura. We selected the 20 most convincing cases from the literature and convincing cases from the DHC. Of 79 migraine with brainstem aura cases described in detail in the literature, 44 fulfilled the diagnostic criteria for migraine with brainstem aura of the International Classification of Headache Disorders, 3rd edition (ICHD-3). In the DHC after face-to-face interview, neurological examination and imaging, four migraine with brainstem aura of 293 cases with migraine with aura (1.37%) were found, corresponding to 0.04% of the general population. The 20 most convincing cases had symptoms that likely originated in the brainstem. Our telephone-interviewed cohort included 1781 subjects with a diagnosis of migraine with aura or probable migraine with aura. Of these, 228 fulfilled the diagnostic criteria for migraine with brainstem aura of the ICHD-3. Thus, using telephone interview diagnosis according to current diagnostic criteria results in too many cases of migraine with brainstem aura being diagnosed. Therefore, we developed stricter diagnostic criteria in an attempt to include only those rare cases that definitely have aura originating from the brainstem. Migraine with brainstem aura does exist, but it is very rare. Existing diagnostic criteria are too unspecific, but it was possible to develop tighter criteria that define a core syndrome probably caused by brainstem dysfunction.
Learn More >Many people with HIV (PWH) experience chronic pain that limits daily function and quality of life. PWH with chronic pain have commonly been prescribed opioids, sometimes for many years, and it is unclear if and how the management of these legacy patients should change in light of the current US opioid epidemic. Guidelines, such as the Centers for Disease Control and Prevention Guideline for Prescribing Opioids for Chronic Pain (CDCG), provide recommendations for the management of such patients but have yet to be translated into easily implementable interventions; there is also a lack of strong evidence that adhering to these recommendations improves patient outcomes such as amount of opioid use and pain levels. Herein we describe the development and preliminary testing of a theory-based intervention, called TOWER (ard Saf Opioid Prescribing), designed to support HIV primary care providers in CDCG-adherent opioid prescribing practices with PWH who are already prescribed opioids for chronic pain. TOWER incorporates the content of the CDCG into the theoretical and operational framework of the Information Motivation and Behavioral Skills (IMB) model of health-related behavior. The development process included elicitation research and incorporation of feedback from providers and PWH; testing is being conducted via an adaptive feasibility clinical trial. The results of this process will form the basis of a large, well-powered clinical trial to test the effectiveness of TOWER in promoting CDCG-adherent opioid prescribing practices and improving outcomes for PWH with chronic pain.
Learn More >To evaluate previous results from a questionnaire-based study, we studied objective neuropathy measures to determine sex differences in the prevalence of neuropathy and neuropathic pain in longstanding type 1 diabetes. Despite better neuropathy measures in females compared to males, we confirmed a trend towards higher neuropathic pain in females.
Learn More >Trigeminal neuropathic pain is seen as a huge clinical challenge. Although numerous drugs have been developed to treat the condition, some patients have shown intolerance to the drugs and thus continue to suffer. In the present study, a rat model of trigeminal neuropathic pain was established using incorrectly positioned dental implants, which had various manifestations that were similar to human trigeminal neuropathic pain. Using this model, we investigated the differential regulation of JAK2 and PTEN. Firstly, we examined the expression of JAK2 and PTEN in the medullary dorsal horn. After inhibiting JAK2/PTEN, we evaluated nociception-related behavioral alterations. The rat models were established by replacing the left lower second molar with a mini dental implant. Immunoblot assay and immunofluorescence experiments indicated high expression of JAK2 and PTEN in medullary dorsal horn after the nerve injury, which attained plateau levels on post-operative day (POD) 5-10 and 10-20. Administration of adenovirus-shRNA-JAK2 on POD 1 reduced mechanical allodynia and downstream STAT activation. Meanwhile, the administration of adenovirus-shRNA-PTEN on POD 1 attenuated mechanical allodynia while upregulating AKT. In addition to postoperative JAK2 and PTEN activation, dexmedetomidine treatment (10 mg/kg) also modulated the downstream sensors of these signaling molecules. These data suggest that JAK2 and PTEN are pivotal to the development of trigeminal neuropathic pain, and that JAK2 and PTEN suppression alleviates the neuropathic pain.
Learn More >In well-controlled rheumatoid arthritis (RA) without significant joint damage, a substantial proportion of patients complain of persistent pain. Previous studies have identified different pain phenotypes in RA, in which non-nociceptive pain phenotypes are associated with higher concurrent disease activity scores. In this longitudinal study, we explored associations between pain phenotypes and long-term disease activity outcome in RA patients. Secondly, we explored whether pain phenotype is associated with comorbid conditions.
Learn More >Neuropathic pain is a common, debilitating clinical issue. Here, the weighted gene co-expression network analysis (WGCNA) was used to identify the specific modules and hub genes that are related to neuropathic pain. The microarray data set of a neuropathic rat model induced by tibial nerve transection (TNT), including dorsal root ganglion (DRG) tissues from TNT model (n = 7) and sham (n = 8) rats, was downloaded from the ArrayExpress database (E-MTAB-2260). The co-expression network modules were identified by the WGCNA package. The protein-protein interaction (PPI) network was constructed, and the node with highest level of connectivity in the network were identified as the hub gene. A total of 1,739 genes and seven modules were identified. The most significant module was the brown module, which contained 215 genes that were primarily associated with the biological process of the defense response and molecular function of calcium ion binding. Furthermore, Ccl2, Fos and Timp1 which were identified as the hub genes in the PPI network and two subnetworks separately. The in vivo studies validated that mRNA and protein levels of Ccl2, Fos and Timp1 were upregulated in DRG and spinal cord tissues after TNT. This study offers novel insights into the molecular mechanisms of neuropathic pain in the context of peripheral nerve injury.
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