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The dissemination of cancer to bone can cause significant cancer-induced bone pain (CIBP), severely impairing the patient's quality of life. Several rodent models have been developed to explore the nociceptive mechanisms of CIBP, including intratibial inoculation of breast carcinoma cells in syngeneic Sprague Dawley rats. Using this model, we investigated whether resident spinal microglial cells are involved in the transmission and modulation of CIBP, a long-debated disease feature. Immunohistochemical staining of ionizing calcium-binding adaptor molecule 1 (Iba-1) and phosphorylated p38-mitogen-activated protein kinase (P-p38 MAPK) showed no spinal microglial reaction in cancer-bearing rats, independently of disease stage, sex, or carcinoma cell line. As a positive control, significant upregulation of both Iba-1 and P-p38 was observed in a rat model of neuropathic pain. Additionally, intrathecal administration of the microglial inhibitor minocycline did not ameliorate pain-like behaviors in cancer-bearing rats, in contrast to spinal morphine administration. Our results indicate that microglial reaction is not a main player in CIBP, adding to the debate that even within the same models of CIBP, significant variations are seen in disease features considered potential drug targets. We suggest that this heterogeneity may reflect the clinical landscape, underscoring the need for understanding the translational value of CIBP models.
Learn More >Chronic pain is more common among veterans than among the general population. Expert guidelines recommend multimodal chronic pain care. However, there is substantial variation in the availability and utilization of treatment modalities in the Veterans Health Administration. We explored health care providers' and administrators' perspectives on the barriers to and facilitators of multimodal chronic pain care in the Veterans Health Administration to understand variation in the use of multimodal pain treatment modalities.
Learn More >The adult K/BxN transgenic mouse develops spontaneous autoimmune arthritis with joint remodeling and profound bone loss. We report that both males and females display a severe sustained tactile allodynia which is reduced by gabapentin but not the potent cyclooxygenase inhibitor ketorolac. In dorsal horn, males and females show increased GFAP astrocytic cells; however, only males demonstrate an increase in Iba1 microglia. In dorsal root ganglia (DRG), there is an increase in CGRP, TH, and Iba1 (macrophage) labeling, but no increase in ATF3 cells. At the ankle there is increased CGRP, TH, and GAP-43 fiber synovial innervation. Thus, based on the changes in dorsal horn, DRG and peripheral innervation, we suggest that the adult K/BxN transgenic arthritic mice display a neuropathic phenotype, an assertion consistent with the analgesic pharmacology seen in this animal. These results indicate the relevance of this model to our understanding of the nociceptive processing which underlies the chronic pain state that evolves secondary to persistent joint inflammation.
Learn More >Children aged ≥6 to <12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16-week, randomized, placebo-controlled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)-4/IL-13 signaling, significantly improved signs and symptoms with acceptable safety; longer-term safety and efficacy data are lacking.
Learn More >Objectives Chronic pain patients often suffer in multiple locations. In health care, examinations of bodily pain usually do not include questions about temporomandibular disorders (TMD); hence TMD symptoms and potential comorbidities are not regularly assessed. Therefore, the primary aim was to evaluate the prevalence of TMD in patients referred to a pain rehabilitation clinic, and the secondary aim was to evaluate possible factors associated with TMD symptoms. Methods Consecutive chronic pain patients referred to the Pain Rehabilitation Clinic at the Umeå University Hospital in Sweden were included. TMD symptoms were assessed using three valid screening questions – 3Q/TMD. Pain sites, emotional distress, kinesiophobia, and demographics were obtained from the Swedish Quality Registry for Pain Rehabilitation. Results In total, 188 (144 women) chronic pain patients (mean age 41.8 years) were included. Of these, 123 (96 women) answered affirmatively to at least one of the 3Q/TMD. The relative risk of TMD symptoms among the patients with chronic pain, in comparison to the general population, was 7.1 (95% CI 5.9-8.4). Age was the only independent variable associated with TMD among the patients (p = 0.018). Conclusions The prevalence of TMD symptoms was higher in a chronic pain population compared to the general population. The 3Q/TMD questionnaire could be a suitable screening tool at pain rehabilitation clinics to identify patients for further examination of involvement of pain in the trigeminal region. Our results reinforce the clinical importance of paying attention to concurrent widespread pain and local TMD symptoms.
Learn More >Almost a half century of research has elaborated the discoveries of the central mechanisms governing the analgesic responses of opiates, including their receptors, endogenous peptides, genes and their putative spinal and supraspinal sites of action. One of the central tenets of "gate-control theories of pain" was the activation of descending supraspinal sites by opiate drugs and opioid peptides thereby controlling further noxious input. This review in the Special Issue dedicated to the research of Dr. Gavril Pasternak indicates his contributions to the understanding of supraspinal mediation of opioid analgesic action within the context of the large body of work over this period. This review will examine (a) the relevant supraspinal sites mediating opioid analgesia, (b) the opioid receptor subtypes and opioid peptides involved, (c) supraspinal site analgesic interactions and their underlying neurophysiology, (d) molecular (particularly AS) tools identifying opioid receptor actions, and (e) relevant physiological variables affecting site-specific opioid analgesia. This review will build on classic initial studies, specify the contributions that Gavril Pasternak and his colleagues did in this specific area, and follow through with studies up to the present.
Learn More >Mutations within the SCN11A gene which encodes the voltage-gated sodium channel Na1.9 mainly expressed in small fiber sensory neurons have been associated with neuropathic disorders; however, suitable medications have not been fully investigated. To develop drug therapies against Na1.9-related neuropathic pain, we aimed to establish a novel model using mice carrying the Scn11a p.R222S mutation initially identified in patients with familial episodic limb pain that is characterized by paroxysmal pain induced by fatigue or bad weather conditions. We investigated the influence of cold exposure (4 °C, overnight) on the behavioral and biochemical phenotypes of Scn11a p.R222S mutant (R222S) and wild type C57BL/6N (WT) mice. We also tested the effects of acetaminophen (125, 250 mg/kg, perorally, p.o.) and traditional Japanese medicine, goshajinkigan (0.5 or 1.0 g/kg, p.o.), which are analgesic drugs prescribed to patients with neuropathic pain, in this model of cold-induced mechanical allodynia in R222S mice.Cold-exposed R222S mice exhibited enhanced mechanical allodynia and thermal hypersensitivity compared with WT mice. The decrease of the mechanical withdrawal threshold in R222S mice was reversible 24 h after housing at room temperature. There was no significant change in the levels of interleukin-1β, interleukin-6, tumor necrosis factor-α, or interferon-γ in the plasma or spinal cords of WT and R222S mice after cold exposure. Both acetaminophen (250 mg/kg) and goshajinkigan (1.0 g/kg) significantly attenuated mechanical allodynia in R222S mice. The model of cold-induced mechanical allodynia in mice with the Scn11a p.R222S mutation is novel and useful for evaluating analgesic drugs for intractable neuropathies related to Na1.9.
Learn More >Guidelines for acute postoperative pain management recommend administering analgesics in multimodal combination to facilitate synergistic benefit, reduce opioid requirements and decrease side-effects. However, limited observational research has examined the extent to which multimodal analgesics are prescribed and administered postoperatively following joint replacement.
Learn More >Migraine is the most common neurological disorder worldwide and it has been shown to have complex polygenic origins with a heritability of estimated 40-70%. Both common and rare genetic variants are believed to underlie the pathophysiology of the prevalent types of migraine, migraine with typical aura and migraine without aura. However, only common variants have been identified so far. Here we identify for the first time a gene module with rare mutations through a systems genetics approach integrating RNA sequencing data from brain and vascular tissues likely to be involved in migraine pathology in combination with whole genome sequencing of 117 migraine families. We found a gene module in the visual cortex, based on single nuclei RNA sequencing data, that had increased rare mutations in the migraine families and replicated this in a second independent cohort of 1930 patients. This module was mainly expressed by interneurons, pyramidal CA1, and pyramidal SS cells, and pathway analysis showed association with hormonal signalling (thyrotropin-releasing hormone receptor and oxytocin receptor signalling pathways), Alzheimer's disease pathway, serotonin receptor pathway and general heterotrimeric G-protein signalling pathways. Our results demonstrate that rare functional gene variants are strongly implicated in the pathophysiology of migraine. Furthermore, we anticipate that the results can be used to explain the critical mechanisms behind migraine and potentially improving the treatment regime for migraine patients.
Learn More >More than 50 million adults in America suffer from chronic pain. Opioids are commonly prescribed for their effectiveness in relieving many types of pain. However, excessive prescribing of opioids can lead to abuse, addiction, and death. Non-steroidal anti-inflammatory drugs (NSAIDs), another major class of analgesic, also have many problematic side effects including headache, dizziness, vomiting, diarrhea, nausea, constipation, reduced appetite, and drowsiness. There is an urgent need for the understanding of molecular mechanisms that underlie drug abuse and addiction to aid in the design of new preventive or therapeutic agents for pain management. To facilitate pain related small-molecule signaling pathway studies and the prediction of potential therapeutic target(s) for the treatment of pain, we have constructed a comprehensive platform of pain domain-specific chemogenomics knowledgebase (Pain-CKB) with integrated data mining computing tools. Our new computing platform describes the chemical molecules, genes, proteins, and signaling pathways involved in pain regulation. Pain-CKB is implemented with a friendly user-interface for the prediction of the relevant protein targets and analysis and visualization of the outputs, including HTDocking, TargetHunter, BBB predictor, and Spider Plot. Combining with other novel tools, we performed three case studies to systematically demonstrate how further studies can be conducted based on the data generated from Pain-CKB and its algorithms/tools. First, systems pharmacology target mapping was carried out for four FDA approved analgesics in order to identify the known target and predict off-targets. Subsequently, the target mapping outcomes were applied to build physiologically based pharmacokinetic (PBPK) models for acetaminophen and fentanyl to explore the drug-drug interaction (DDI) between this pair of drugs. Finally, pharmaco-analytics was conducted to explore the detailed interaction pattern of acetaminophen reactive metabolite and its hepatotoxicity target thioredoxin reductase.
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