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Although electroacupuncture is widely used in chronic pain management, it is quite controversial due to its unclear mechanism. We hypothesised that EA alleviates pain by inhibiting degradation of the ecto-nucleotidase prostatic acid phosphatase (PAP) and facilitating ATP dephosphorylation in dorsal root ganglions (DRGs).
Learn More >This review was designated to evaluate the efficacy of parenteral ketorolac in treating acute migraine headache.
Learn More >Post-traumatic headache is a common sequela of injury to the head and/or neck. Here, we review the current approach to pharmacologic management of post-traumatic headache and explore the therapeutic promise of targeting calcitonin gene-related peptide signaling to address unmet treatment needs.
Learn More >High-frequency (10-kHz) spinal cord stimulation (SCS) continues to be an emerging therapy in chronic pain management. The same complications that plagued earlier SCS systems may affect newer stimulation technologies, although there is limited data on the type of complications and surgical management of these complications.
Learn More >Meniere disease (MD) is a rare set of conditions associated with the accumulation of endolymph in the cochlear duct and the vestibular labyrinth with a decrease of endocochlear potential. It is considered a chronic inflammatory disorder of the inner ear with a multifactorial origin. The clinical syndrome includes several groups of patients with a core phenotype: sensorineural hearing loss, episodes of vertigo, and tinnitus with a non-predictable course. Genetic factors and the innate immune response seem to play a central role in the pathophysiology of the condition. Autoimmune MD should be diagnosed if a patient fulfills the diagnostic criteria for MD and one of the following autoimmune disorders: autoimmune thyroid disease, psoriasis, autoimmune arthritis, ankylosing spondylitis, or systemic lupus erythematosus. We summarize the evidence to support autoimmune MD as an endophenotype in bilateral MD associated with the allelic variant rs4947296 and nuclear factor-kappa B (NF-κB)-mediated inflammation, the role of cytokines (particularly interleukin-1β and tumor necrosis factor-α) in defining a subset of patients with autoinflammation, and the potential role of cytokines as biomarkers to distinguish between patients with MD and vestibular migraine. Finally, we also introduce a list of potential drugs that could regulate the immune response in MD with potential for repurposing in clinical trials.
Learn More >G protein-coupled receptors (GPCRs) regulate many pathophysiological processes and are major therapeutic targets. The impact of disease on the subcellular distribution and function of GPCRs is poorly understood. We investigated trafficking and signaling of protease-activated receptor 2 (PAR) in colitis. To localize PAR and assess redistribution during disease, we generated knockin mice expressing PAR fused to monomeric ultrastable green fluorescent protein (muGFP). PAR-muGFP signaled and trafficked normally. PAR messenger RNA was detected at similar levels in and wild-type mice. Immunostaining with a GFP antibody and RNAScope in situ hybridization using (PAR) and probes revealed that PAR-muGFP was expressed in epithelial cells of the small and large intestine and in subsets of enteric and dorsal root ganglia neurons. In healthy mice, PAR-muGFP was prominently localized to the basolateral membrane of colonocytes. In mice with colitis, PAR-muGFP was depleted from the plasma membrane of colonocytes and redistributed to early endosomes, consistent with generation of proinflammatory proteases that activate PAR PAR agonists stimulated endocytosis of PAR and recruitment of Gα, Gα, and β-arrestin to early endosomes of T84 colon carcinoma cells. PAR agonists increased paracellular permeability of colonic epithelial cells, induced colonic inflammation and hyperalgesia in mice, and stimulated proinflammatory cytokine release from segments of human colon. Knockdown of dynamin-2 (), the major colonocyte isoform, and Dnm inhibition attenuated PAR endocytosis, signaling complex assembly and colonic inflammation and hyperalgesia. Thus, PAR endocytosis sustains protease-evoked inflammation and nociception and PAR in endosomes is a potential therapeutic target for colitis.
Learn More >Painful peripheral neuropathy is a common dose-limiting side effect of chemotherapeutic paclitaxel (PTX) treatment. The American Society of Clinical Oncology (ASCO) recommends duloxetine (DUL) as a promising treatment alternative for chemotherapy-induced peripheral neuropathic pain. However, this recommendation lacks a robust theoretical basis and supporting data. To elucidate the involvement of transient receptor potential vanilloid 1 (TRPV1) in the analgesic effect of DUL for PTX-induced neuropathic pain, TRPV1 expression in the lumbar dorsal root ganglion (DRG) and spinal cord was evaluated following intraperitoneal administration of PTX (2mg/kg/day) for four alternate days in rats. Western blot and immunohistochemistry suggested that a cumulative dosage of PTX (8 mg/kg) upregulated TRPV1 expression in the lumbar DRG and spinal dorsal horn (SDH) at day 14 post treatment. TRPV1 upregulation in the DRG was mainly expressed in calcitonin gene-related peptide (CGRP) and IB-4 positive small-size sensory neurons. Additionally, PTX increased CGRP and substance P (SP) expression in the DRG and SDH, induced SDH microglia and astrocyte activation, and upregulated spinal tumor necrosis factor-α (TNF-α) but not IL-1β or IL-10 expression. Behavioral detection showed that PTX-related mechanical and thermal hyperalgesia was significantly inhibited by consecutive administration of DUL 20 mg/kg/day greater than 10 mg/kg/day for 5 days starting at day 10 post PTX injection. Furthermore, DUL (20 mg/kg/day) for 5 days markedly ameliorated PTX-induced TRPV1, CGRP, and SP upregulation in the DRG and SDH, and mitigated PTX-induced spinal cord glia activation and TNF-α expression. Moreover, the pharmacological blockade of TRPV1 resulted in an analgesic effect on PTX-induced hyperalgesia. Collectively, these results suggest that DUL alleviates PTX-induced peripheral neuropathic pain by suppressing TRPV1 upregulation in the lumbar DRG and SDH, which is followed by a reduction in CGRP and SP release, as well as spinal glia activation and TNF-α expression.
Learn More >Bee Venom (BV) has been used to treat rheumatoid arthritis (RA) for many centuries. However, its clinical use is limited by pain and fear of bee stings/injection. Nanoemulsions (NEs) are nanocarriers that are able to help their content(s) penetrate through the skin. They also act as drug reservoirs on the skin to provide an efficient, sustained-release vehicle.
Learn More >Inflammatory pain serves as a protective defense mechanism which becomes pathological when it turns into chronic inflammatory pain. This transition is mediated by a variety of peripheral mediators that sensitize nociceptors and increase pain perception in sensory neurons. Besides cytokines, chemokines and growth factors, accumulating evidence shows that oxidized lipids, such as eicosanoids and oxidized linoleic acid metabolites, contribute to this sensitization process. Most notably, the oxidized linoleic acid metabolite and partial TRPV1 agonist 9-HODE (hydroxyoctadecadienoic acid) was shown to be involved in this sensitization process. However, it is still unknown how some of the oxidized linoleic acid metabolites are synthesized in the inflammatory environment and in which phase of inflammation they become relevant. Here we show that the concentrations of oxidized linoleic acid metabolites, especially 9-HODE and 13-HODE, are significantly increased in inflamed paw tissue and the corresponding dorsal root ganglia in the sub-chronic phase of inflammation. Surprisingly, classical inflammatory lipid markers, such as prostaglandins were at basal levels in this phase of inflammation. Moreover, we revealed the cell type specific synthesis pathways of oxidized linoleic acid metabolites in primary macrophages, primary neutrophils and dorsal root ganglia. Finally, we show that blocking the most elevated metabolites 9-HODE and 13-HODE at the site of inflammation in the sub-chronic phase of inflammation, leads to a significant relief of mechanical and thermal hypersensitivity in vivo. In summary, these data offer an approach to specifically target oxidized linoleic acid metabolites in the transition of acute inflammatory pain to chronic inflammatory pain.
Learn More >The purpose of this study was to investigate if vessel-wall magnetic resonance imaging (VW-MRI) could differentiate among primary headaches disorders, such as migraine and cluster headache (CH), and detect the presence of neurogenic inflammation.
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