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Pain is a major and common symptom reported as a top priority in patients with rheumatoid arthritis (RA). Intuitively, RA-related pain is often considered to be a natural consequence of peripheral inflammation, so treatment of RA is expected to manage pain concurrently as part of inflammation control. However, pain in patients with RA can be poorly correlated with objective measures of inflammation, for example, in patients who are otherwise in remission. Joint damage appears to account for only a fraction of this residual pain. Emerging evidence suggests that alteration of peripheral and central pain processing contributes to RA-related pain; this is parallel to, but somewhat independent of, joint inflammation. Interleukin (IL)-6 is a proinflammatory cytokine that contributes to the pathogenesis of RA. It exerts systemic effects via signaling through soluble forms of the IL-6 receptor ("trans-signaling"). Evidence from preclinical studies demonstrates that intra-articular IL-6 can produce long-lasting peripheral sensitization to mechanical stimulation and suggests an important role for IL-6 in central pain sensitization. This may be partly explained by its ability to activate neurons through trans-signaling, affecting nociceptive plasticity and nerve fiber regrowth. Local activity at neuron endings may culminate in altered pain processing in the central nervous system because of persistent signaling from sensitized peripheral neurons. Peripheral and central sensitization can promote the development of chronic pain, which can have a significant impact on patients' health and quality of life. A proportion of pain in RA may be more appropriately managed as an entity separate from inflammation. Both the peripheral and central nervous systems should be recognized as important potential systems targeted by RA. The substantial burden of RA-related chronic pain suggests that pain should be a key focus in RA management and should be assessed and addressed early and separately from the inflammatory component.
Learn More >Improving physical function among patients with chronic pain is critical for reducing disability and healthcare costs. However, mechanisms underlying improvement in patient-reported, performance-based, and ambulatory physical function in chronic pain remain poorly understood.
Learn More >Chronic pain is a complicated condition which causes substantial physical, emotional, and financial impacts on individuals and society. However, due to high cost, lack of efficacy and safety problems, current treatments are insufficient. There is a clear unmet medical need for safe, nonaddictive and effective therapies in the management of pain. Epoxy-fatty acids (EpFAs), which are natural signaling molecules, play key roles in mediation of both inflammatory and neuropathic pain sensation. However, their molecular mechanisms of action remain largely unknown. Soluble epoxide hydrolase (sEH) rapidly converts EpFAs into less bioactive fatty acid diols in vivo; therefore, inhibition of sEH is an emerging therapeutic target to enhance the beneficial effect of natural EpFAs. In this review, we will discuss sEH inhibition as an analgesic strategy for pain management and the underlying molecular mechanisms.
Learn More >To evaluate the prevalence of temporomandibular disorders (TMD) in patients with early rheumatoid arthritis (ERA) and individuals at-risk of RA.
Learn More >Atopic dermatitis (AD) is a common skin disease characterized by chronic inflammation and itchiness. Although skin barrier dysfunction and immune abnormalities are thought to contribute to the development of AD, the precise pathogenic mechanism remains to be elucidated. We have developed a unique, diet-induced AD mouse model based on the findings that deficiencies of certain polyunsaturated fatty acids and starches cause AD-like symptoms in hairless mice. Here, we present a protocol and tips for establishing an AD mouse model using a custom diet modified from a widely used standard diet (AIN-76A Rodent Diet). We also describe methods for evaluating skin barrier dysfunction and analyzing itch-related scratching behavior. This model can be used not only to investigate the complex pathogenic mechanism of human AD but also to study the puzzling relationship between nutrition and AD development.
Learn More >Knee osteoarthritis (KOA) is prevalent in middle-aged and elderly people. This condition negatively affects the quality of life of patients. Although non-steroidal anti-inflammatory drugs (NSAIDs) are often used to relieve symptoms associated with KOA, it is associated with many side effects. Acupuncture and moxibustion therapies have been applied in the treatment of KOA. However, the efficacy of various acupuncture and moxibustion treatments has not been compared.
Learn More >Despite the widespread clinical use of acupuncture in the treatment of pruritus caused by psoriasis, urticaria, uremic, and other diseases, insights into the mechanism of action of acupuncture are still emerging. For the above reasons, a beneficial effect of acupuncture on pruritus was not recommended or reported in recent clinical practice guidelines. Acupuncture is a kind of physical stimulation, which has the characteristics of multi-channel and multi-target effects. The biomechanical stimulation signal of acupuncture needling can be transformed into bioelectric and chemical signals; interfere with kinds of cells and nerve fibers in the skin and muscle; alter signaling pathways and transcriptional activity of cells, mediators, and receptors; and result in inhibition of peripheral and central transmission of pruritus. Available mechanistic data give insights into the biological regulation potency of acupuncture for pruritus and provide a basis for more in-depth and comprehensive mechanism research.
Learn More >A series of neuropathic pain conditions have a prevalence in older adults potentially associated with declined functioning of the peripheral and/or central nervous system. Neuropathic pain conditions demonstrate defective cortical excitability and intermissions, which raises questions of the impact of pain on cortical excitability changes and when to deliver repetitive transcranial magnetic stimulation (rTMS) to maximize the analgesic effects. Using prolonged continuous theta-burst stimulation (pcTBS), a relatively new rTMS protocol to increase excitability, this study was designed to investigate pcTBS analgesia and cortical excitability in the context of pain. With capsaicin application, twenty-nine healthy participants received pcTBS or Sham stimulation either in the phase of pain initialization (capsaicin applied) or pain ascending (20 min after capsaicin application). Pain intensity was measured with a visual-analogic scale (VAS). Cortical excitability was assessed by motor-evoked potential (MEP) and cortical silent period (CSP) which evaluates corticospinal excitability and GABAergic intracortical inhibition, respectively. Our data on pain dynamics demonstrated that pcTBS produced a consistent analgesic effect regardless of the time frame of pcTBS. More importantly, pcTBS delivered at pain initialization induced a larger pain reduction and a higher response rate compared to the stimulation during pain ascending. We further provide novel findings indicating distinct mechanisms of pcTBS analgesia dependent on the context of pain, in which pcTBS delivered at pain initialization was able to reverse depressed MEP, whereby pcTBS during pain ascending was associated with increased CSP. Overall, our data indicate pcTBS to be a potential protocol in pain management that could be delivered before the initialization of a pain episode to improve rTMS analgesia, potentially through inducing early corticospinal excitability changes that would be suppressed by nociceptive transmission.
Learn More >The trigeminovascular system (TGV) comprise of the trigeminal ganglion with neurons and satellite glial cells, with sensory unmyelinated C-fibers and myelinated Aδ-fibers picking up information from different parts of the head and sending signals to the brainstem and the central nervous system. In this review we discuss aspects of signaling at the distal parts of the sensory fibers, the extrasynaptic signaling between C-fibers and Aδ-fibers, and the contact between the trigeminal fibers at the nerve root entry zone where they transit into the CNS. We also address the possible role of the neuropeptides calcitonin gene-related peptide (CGRP), the neurokinin family and pituitary adenylyl cyclase-activating polypeptide 38 (PACAP-38), all found in the TGV system together with their respective receptors. Elucidation of the expression and localization of neuropeptides and their receptors in the TGV system may provide novel ways to understand their roles in migraine pathophysiology and suggest novel ways for treatment of migraine patients.
Learn More >Morphine and tramadol are the opioid analgesic drugs acting via activation of μ‑opioid receptors. It is important to understand which mechanism (synergistic or additive anti‑nociceptive activity) induced potent anti‑nociceptive effect by co‑administration of morphine and tramadol. Identification of new strategies that can potentiate analgesic effects of opioids will be good therapeutic approaches for pain relief. To this aim, male mice were cannulated in the left ventricle by a stereotaxic instrument. A tail‑flick test was used to record the pain threshold. The results revealed that intracerebroventricularly injection of morphine induced an anti‑nociceptive effect in non‑sensitized and morphine‑sensitized mice. We found that infusion of tramadol produced an anti‑nociceptive response in non‑sensitized mice, whereas tramadol in doses of 0.5 and 1 μg/mouse induced analgesia in morphine‑sensitized mice. Co‑injection of a non‑effective dose of tramadol or morphine (0.25 μg/mouse) with different doses of morphine or tramadol (0.25, 0.5, and 1 μg/mouse) respectively potentiated the analgesic effect of the previous drug. An isobolographic analysis of data was performed, indicating a synergistic interaction between morphine and tramadol in non‑sensitized and morphine‑sensitized mice. Our data indicated that both morphine and tramadol elicit more anti‑nociceptive response in morphine sensitized mice; there is a synergistic effect between morphine and tramadol upon induction of analgesic effect in non‑sensitized and morphine‑sensitized mice.
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