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We aimed to examine the risk of cardiovascular adverse events by tricyclic antidepressant (TCA) dosage among patients with chronic pain.
Learn More >Globally, there is a paucity of multimorbidity and comorbidity data, especially for minority ethnic groups and younger people. We estimated the frequency of common disease combinations and identified non-random disease associations for all ages in a multiethnic population.
Learn More >Advances have been made in the search for new multi-target modulators to control pain and inflammation. Therefore, compound 3,5-di-tert-butyl-4-hydroxyphenyl)(4-methylpiperazin-1-yl)methanone (LQFM202) was synthesised and evaluated. First, in vitro assays were performed for COX-1, COX-2, and 5-LOX enzymes. Subsequently, adult female Swiss albino mice treated orally with LQFM202 at doses of 25-200 mg/kg were subjected to acetic acid-induced writhing, formalin-induced pain, carrageenan-induced hyperalgesia, carrageenan- or zymosan-induced paw oedema, or pleurisy. LQFM202 inhibited COX-1, COX-2, and LOX-5 (IC = 3499 µM, 1565 µM, and 1343 µM, respectively). In acute animal models, LQFM202 (50, 100, or 200 mg/kg) decreased the amount of abdominal writhing (29%, 52% and 48%, respectively). Pain in the second phase of the formalin test was reduced by 46% with intermediate dose. LQFM202 (100 mg/kg) reduced the difference in nociceptive threshold in all 4 h evaluated (46%, 37%, 30%, and 26%, respectively). LQFM202 (50 mg/kg) decreased the carrageenan-oedema from the second hour (27%, 31% and 25%, respectively); however, LQFM202 (100 mg/kg) decreased the carrageenan-oedema in all hours evaluated (35%, 42%, 48% and 50%, respectively). When using zymosan, LQFM202 (50 mg/kg) decreased the oedema in all hours evaluated (33%, 32%, 31% and 20%, respectively). In the carrageenan-pleurisy test, LQFM202 (50 mg/kg) reduced significantly the number of polymorphonuclear cells (34%), the myeloperoxidase activity (53%), TNF-α levels (47%), and IL-1β levels (58.8%). When using zymosan, LQFM202 (50 mg/kg) reduced the number of polymorphonuclear and mononuclear cells (54% and 79%, respectively); and the myeloperoxidase activity (46%). These results suggest antinociceptive and anti-inflammatory effects of LQFM202.
Learn More >Pain sensitization is a phenomenon that occurs to protect tissues from damage and recent studies have shown how a variety of non-noxious stimuli included in our everyday lives can lead to pain sensitization Consumption of large amounts of alcohol over a long period of time invokes alcohol use disorder (AUD), a complex pathological state that has many manifestations, including alcohol peripheral neuropathy (neuropathic pain). We asked if 'non-pathological' alcohol consumption can cause pain sensitization in the absence of other pathology? Studies have pointed to glia and other immune cells and their role in pain sensitization that results in cell and sex-specific responses (Wang et al., 2010; Obad et al., 2018). Using a low-dose and short-term ethanol exposure model, we investigated whether this exposure would sensitize mice to a subthreshold dose of an inflammatory mediator that normally does not induce pain, or cause hypersensitivity. We observed female mice exhibited specific mechanical and higher thermal sensitivity than males. We also observed an increase in CD68 macrophages in the ipsilateral dorsal root ganglia (DRG) and Iba1 microglia in the ipsilateral spinal dorsal horn of animals that were exposed to ethanol and injected with subthreshold prostaglandin E2. Our findings suggest that short-term ethanol exposure stimulates peripheral and central, immune, and glial activation, respectively to induce pain sensitization. This work begins to reveal a possible mechanism behind the development of alcoholic peripheral neuropathy.
Learn More >The role(s) of anticipatory postural adjustments (APAs) in changes in subsequent motor and postural controls in response to movement perturbations are unclear in individuals with chronic low back pain (CLBP). This study aimed to clarify the relationships among kinesiophobia, APAs, lumbar kinematic output, and postural control associated with lumbar movement in individuals with CLBP.
Learn More >As a global health problem, chronic pain is one of the leading causes of disability, and it imposes a huge economic and public health burden on families and society. Opioids represent the cornerstone of analgesic drugs. However, opioid tolerance caused by long-term application of opioids is a major factor leading to drug withdrawal, serious side effects caused by dose increases, and even the death of patients, placing an increasing burden on individuals, medicine, and society. Despite efforts to develop methods to prevent and treat opioid tolerance, no effective treatment has yet been found. Therefore, understanding the mechanism underlying opioid tolerance is crucial for finding new prevention and treatment strategies. Noncoding RNAs (ncRNAs) are important parts of mammalian gene transcriptomes, and there are thousands of unique noncoding RNA sequences in cells. With the rapid development of high-throughput genome technology, research on ncRNAs has become a hot topic in biomedical research. In recent years, studies have shown that ncRNAs mediate physiological and pathological processes, including chromatin remodeling, transcription, posttranscriptional modification and signal transduction, which are key regulators of physiological processes in developmental and disease environments and have become biomarkers and potential therapeutic targets for various diseases. An increasing number of studies have found that ncRNAs are closely related to the development of opioid tolerance. In this review, we have summarized the evidence that ncRNAs play an important role in opioid tolerance and that ncRNAs may be novel targets for opioid tolerance.
Learn More >Optical control of G protein-coupled receptor (GPCR) signaling is a highly valuable approach for comprehensive understanding of GPCR-based physiologies and controlling them precisely. However, optogenetics for GPCR signaling is still developing and requires effective and versatile tools with performance evaluation from their molecular properties. Here, we systematically investigated performance of two bistable opsins that activate Gi/Go-type G protein (mosquito Opn3 (MosOpn3) and lamprey parapinopsin (LamPP)) in optical control in vivo using . Transgenic worms expressing MosOpn3, which binds 13- retinal to form photopigments, in nociceptor neurons showed light-induced avoidance responses in the presence of all- retinal, a retinal isomer ubiquitously present in every tissue, like microbial rhodopsins and unlike canonical vertebrate opsins. Remarkably, transgenic worms expressing MosOpn3 were ~7,000 times more sensitive to light than transgenic worms expressing ChR2 in this light-induced behavior, demonstrating the advantage of MosOpn3 as a light switch. LamPP is a UV-sensitive bistable opsin having complete photoregenerative ability by green light. Accordingly, transgenic worms expressing LamPP in cholinergic motor neurons stopped moving upon violet light illumination and restored coordinate movement upon green light illumination, demonstrating color-dependent control of behavior using LamPP. Furthermore, we applied molecular engineering to produce MosOpn3-based tools enabling light-dependent upregulation of cAMP or Ca levels and LamPP-based tool enabling clamping cAMP levels color dependently and context independently, extending their usability. These findings define the capacity of two bistable opsins with similar retinal requirement as ChR2, providing numerous strategies for optical control of various GPCR-based physiologies as well as GPCR signaling itself.
Learn More >The biogenic amine serotonin modulates pain perception by activating several types of serotonergic receptors, including the 5-HT 7 type. These receptors are widely expressed along the pain axis, both peripherally, on primary nociceptors, and centrally, in the spinal cord and the brain. The role of 5-HT 7 receptors in modulating pain has been explored in vivo in different models of inflammatory and neuropathic pain. While most studies have reported an antinociceptive effect of 5- HT 7 receptor activation, some authors have suggested a pronociceptive action. Differences in pain models, animal species and gender, receptor types, agonists, and route of administration could explain these discrepancies. In this mini-review, some of the main findings concerning the function of 5-HT 7 receptors in the pain system have been presented. The expression patterns of the receptors at the different levels of the pain axis, along with the cellular mechanisms involved in their activity, have been described. Alterations in receptor expression and/or function in different pain models and the role of 5-HT 7 receptors in controlling pain transmission have also been discussed. Finally, some of the future perspectives in this field have been outlined.
Learn More >There is a common symptom pattern with most chronic low back pain (CLBP), suggesting that there is a common underlying etiology, belying the term "nonspecific." Many studies of CLBP and its treatment have been conducted with the assumption of nonspecificity, and as a result, treatment has not been focused, thus there has not been a significant change in CLBP prevalence over the past several decades. It is the thesis of this study to show that there is an underlying, specific cause of CLBP and that the presumption that CLBP is nonspecific is misdirected. The lumbosacropelvic (LSP) region, including the sacroiliac joint (SIJ), is part of a neuromusculoskeletal (NMSK) feedback system, and it is proposed here that CLBP is the result of a change in the feedback (afferent) aspect in that system.
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