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Neuropathic pain is a refractory chronic disease affecting millions of people worldwide. Given that present painkillers have poor efficacy or severe side effects, developing novel analgesics is badly needed. The multiplex structure of active ingredients isolated from natural products provides a new source for phytochemical compound synthesis. Here, we identified a natural product, Narirutin, a flavonoid compound isolated from the , showing antinociceptive effects in rodent models of neuropathic pain. Using calcium imaging, whole-cell electrophysiology, western blotting, and immunofluorescence, we uncovered a molecular target for Narirutin's antinociceptive actions. We found that Narirutin (i) inhibits Veratridine-triggered nociceptor activities in L4-L6 rat dorsal root ganglion (DRG) neurons, (ii) blocks voltage-gated sodium (Na) channels subtype 1.7 in both small-diameter DRG nociceptive neurons and human embryonic kidney (HEK) 293 cell line, (iii) does not affect tetrodotoxin-resistant (TTX-R) Na channels, and (iv) blunts the upregulation of Na1.7 in calcitonin gene-related peptide (CGRP)-labeled DRG sensory neurons after spared nerve injury (SNI) surgery. Identifying Na1.7 as a molecular target of Narirutin may further clarify the analgesic mechanism of natural flavonoid compounds and provide an optimal idea to produce novel selective and efficient analgesic drugs.

(1) Background: To assess the time trend in the prevalence of chronic neck pain (CNP), chronic low back pain (CLBP), and migraine or frequent headache (MFH) among people with diabetes in Spain from 2014 to 2020, this study identified sex differences and compared the prevalence of these pain sites between people with diabetes and age-sex-matched non-diabetic subjects. (2) Methods: The study design included a cross-sectional and a case-control study. The data were obtained from the European Health Interview Surveys for Spain conducted in 2014 and 2020. The presence of diabetes, CNP, CLBP, and MFH was self-reported. Study covariates included sociodemographic characteristics, comorbidities, lifestyles, and pain-related variables. (3) Results: Among people with diabetes, the prevalence of CNP, CLBP, and MFH did not improve from 2014 to 2020. Women with diabetes had a significantly higher prevalence of all the pain sites analyzed than men with diabetes. After matching by sex and age, the prevalence of CNP (26.0% vs. 21.1%; < 0.001), CLBP (31.2% vs. 25.0%; < 0.001), and MFH (7.7% vs. 6.5%; = 0.028) was higher for people with diabetes than for those without diabetes. Self-reported mental disease was independently associated with reporting the three pain sites analyzed in people with diabetes. (4) Conclusions: The prevalence of CNP, CLBP, and MFH has remained stable over time. Remarkable sex differences were found, with a higher prevalence among women than men with diabetes. Diabetes was associated with reporting in all the pain sites analyzed. Self-reported mental disease was associated with reporting CNP, CLBP, and MFH.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating disease that induces mental stress, lower urinary symptoms, and pelvic pain, therefore resulting in a decline in quality of life. The present diagnoses and treatments still lead to unsatisfactory outcomes, and novel diagnostic and therapeutic modalities are needed. Although our understanding of the etiology and pathophysiology of IC/BPS is growing, the altered permeability of the impaired urothelium, the sensitized nerves on the bladder wall, and the chronic or intermittent sensory pain with inaccurate location, as well as pathologic angiogenesis, fibrosis, and Hunner lesions, all act as barriers to better diagnoses and treatments. This study aimed to summarize the comprehensive information on IC/BPS research, thereby promoting the progress of IC/BPS in the aspects of diagnosis, treatment, and prognosis. According to diverse international guidelines, the etiology of IC/BPS is associated with multiple factors, while the presence of Hunner lesions could largely distinguish the pathology, diagnosis, and treatment of non-Hunner lesions in IC/BPS patients. On the basis of the diagnosis of exclusion, the diverse present diagnostic and therapeutic procedures are undergoing a transition from a single approach to multimodal strategies targeting different potential phenotypes recommended by different guidelines. Investigations into the mechanisms involved in urinary symptoms, pain sensation, and bladder fibrosis indicate the pathophysiology of IC/BPS for further potential strategies, both in diagnosis and treatment. An overview of IC/BPS in terms of epidemiology, etiology, pathology, diagnosis, treatment, and fundamental research is provided with the latest evidence. On the basis of shared decision-making, a multimodal strategy of diagnosis and treatment targeting potential phenotypes for individual patients with IC/BPS would be of great benefit for the entire process of management. The complexity and emerging evidence on IC/BPS elicit more relevant studies and research and could optimize the management of IC/BPS patients.

(1) Background: The management of postoperative pain after knee replacement is an important clinical problem. The best results in the treatment of postoperative pain are obtained using multimodal therapy principles. Intrathecal morphine (ITM) and single-shot femoral nerve block (SSFNB) are practiced in the treatment of postoperative pain after knee replacement, with the most optimal methods still under debate. The aim of this study was to compare the analgesic efficacy with special consideration of selected side effects of both methods. (2) Materials and methods: Fifty-two consecutive patients undergoing knee arthroplasty surgery at the Department of Orthopedics and Traumatology of the Medical University of Warsaw were included in the study. Patients were randomly allocated to one of two groups. In the ITM group, 100 micrograms of intrathecal morphine were used, and in the SSFNB group, a femoral nerve block in the distal femoral triangle was used as postoperative analgesia. The other elements of anesthesia and surgery did not differ between the groups. (3) Results: The total dose of morphine administered in the postoperative period and the effectiveness of pain management did not differ significantly between the groups (cumulative median morphine dose in 24 h in the ITM group 31 mg vs. SSFNB group 29 mg). The incidence of nausea and pruritus in the postoperative period differed significantly in favor of patients treated with a femoral nerve block. (4) Conclusions: Although intrathecal administration of morphine is similarly effective in the treatment of pain after knee replacement surgery as a single femoral triangle nerve block, it is associated with a higher incidence of cumbersome side effects, primarily nausea and pruritus.

As a widely prescribed anti-diabetic drug, metformin has been receiving novel attention for its analgesic potential. In the study of the complex etiology of neuropathic pain (NeP), male and female individuals exhibit quite different responses characterized by higher pain sensitivity and greater NeP incidence in women. This "gender gap" in our knowledge of sex differences in pain processing strongly limits the sex-oriented treatment of patients suffering from NeP. Besides, the current investigation of the analgesic potential of metformin has not addressed the "gender gap" problem. Hence, this study focuses on metformin and sex-dependent analgesia in a murine model of NeP induced by chronic constriction injury of the sciatic nerve. We investigated sexual dimorphism in signaling pathways involved by 7 days of metformin administration, such as changes in AMP-activated protein kinase and the positive regulation of autophagy machinery, discovering that metformin affected in a sexually dimorphic manner the immunological and inflammatory response to nerve lesion. These effects were complemented by morphological and adaptive changes occurring after peripheral nerve injury. Altogether these data can contribute to explaining a number of potential mechanisms responsible for the complete recovery from NeP found in male mice, as opposed to the failure of long-lasting recovery in female animals.

Osteonecrosis is a terrible condition that can cause advanced arthritis in a number of joints, including the knee. The three types of osteonecrosis that can affect the knee are secondary, post-arthroscopic, and spontaneous osteonecrosis of the knee (SPONK). Regardless of osteonecrosis classification, treatment for this condition seeks to prevent further development or postpone the onset of knee end-stage arthritis. Joint arthroplasty is the best course of action whenever there is significant joint surface collapse or there are signs of degenerative arthritis. The non-operative options for treatment at the moment include observation, nonsteroidal anti-inflammatory medications (NSAIDs), protective weight bearing, and analgesia if needed. Depending on the severity and type of the condition, operational procedures may include unilateral knee arthroplasty (UKA), total knee arthroplasty (TKA), or joint preservation surgery. Joint preservation techniques, such as arthroscopy, core decompression, osteochondral autograft, and bone grafting, are frequently used in precollapse and some postcollapse lesions, when the articular cartilage is typically unaffected and only the underlying subchondral bone is affected. In contrast, operations that try to save the joint following significant subchondral collapse are rarely successful and joint replacement is required to ease discomfort. This article's goal is to summarise the most recent research on evaluations, clinical examinations, imaging and various therapeutic strategies for osteonecrosis of the knee, including lesion surveillance, medicines, joint preservation methods, and total joint arthroplasty.

This study aims to explore the quality of life (QOL) and pain after revision surgery for periprosthetic joint infection (PJI) based on patients' reported outcomes. A cross-sectional questionnaire survey was conducted and 137 valid responses were included (response rate 64.0%). A total of 42 patients underwent debridement with implant retention (DAIR), 31 underwent one-stage revision, and 64 underwent two-stage revision. The average overall SF-36 score was 70.3. The DAIR group had significantly higher SF-36 than the two-stage revision group ( = 0.01). There was no significant difference between the one-stage revision group and the other two groups. A total of 74.5% of patients reported pain with an average McGill Pain Questionnaire (MPQ) score of 8.6. There was no significant difference in the MPQ scores among the three groups. Simple linear regression analyses demonstrated that higher preoperative PMN%, VAS, and shorter hospital stay were associated with pain (adjusted R = 4%, = 0.020; adjusted R = 2.1%, = 0.048; adjusted R = 2.1%, = 0.049; respectively). We concluded that the overall QOL of patients after revision surgery for PJI is generally satisfactory. Persistent pain is prevalent, but the severity was mostly mild. Preoperative PMN%, VAS, and hospital stay were associated with postoperative pain.

As artificial intelligence technology advances, it is necessary to imitate various biological functions to complete more complex tasks. Among them, studies have been reported on the nociceptor, a critical receptor of sensory neurons that can detect harmful stimuli. Although a complex CMOS circuit is required to electrically realize a nociceptor, a memristor with threshold switching characteristics can implement the nociceptor as a single device. Here, we suggest a memristor with a Pt/HfO/TaO/TaN bilayer structure. This device can mimic the characteristics of a nociceptor including the threshold, relaxation, allodynia, and hyperalgesia. Additionally, we contrast different electrical properties according to the thickness of the HfO layer. Moreover, Pt/HfO/TaO/TaN with a 3 nm thick HfO layer has a stable endurance of 1000 cycles and controllable threshold switching characteristics. Finally, this study emphasizes the importance of the material selection and fabrication method in the memristor by comparing Pt/HfO/TaO/TaN with Pt/TaO/TaN, which has insufficient performance to be used as a nociceptor.

Opioids are the most effective drugs used for the management of moderate to severe pain; however, their chronic use is often associated with numerous adverse effects. Some results indicate the involvement of oxidative stress as well as of proteasome function in the development of some opioid-related side effects including analgesic tolerance, opioid-induced hyperalgesia (OIH) and dependence. Based on the evidence, this study investigated the impact of morphine, buprenorphine or tapentadol on intracellular reactive oxygen species levels (ROS), superoxide dismutase activity/gene expression, as well as β2 and β5 subunit proteasome activity/biosynthesis in SH-SY5Y cells. Results showed that tested opioids differently altered ROS production and SOD activity/biosynthesis. Indeed, the increase in ROS production and the reduction in SOD function elicited by morphine were not shared by the other opioids. Moreover, tested drugs produced distinct changes in β2(trypsin-like) and β5(chymotrypsin-like) proteasome activity and biosynthesis. In fact, while prolonged morphine exposure significantly increased the proteolytic activity of both subunits and β5 mRNA levels, buprenorphine and tapentadol either reduced or did not alter these parameters. These results, showing different actions of the selected opioid drugs on the investigated parameters, suggest that a low µ receptor intrinsic efficacy could be related to a smaller oxidative stress and proteasome activation and could be useful to shed more light on the role of the investigated cellular processes in the occurrence of these opioid drug side effects.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a serious side effect that impairs the quality of life of patients treated with the chemotherapeutic agent, oxaliplatin. The underlying pathophysiology of OIPN remains unclear, and there are no effective therapeutics. This study aimed to investigate the causal relationship between spinal microglial activation and OIPN and explore the analgesic effects of syringaresinol, a phytochemical from the bark of Cinnamomum cassia, on OIPN symptoms. The causality between microglial activation and OIPN was investigated by assessing cold and mechanical allodynia in mice after intrathecal injection of the serum supernatant from a BV-2 microglial cell line treated with oxaliplatin. The microglial inflammatory response was measured based on inducible nitric oxide synthase (iNOS), phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated nuclear factor-kappa B (p-NF-κB) expression in the spinal dorsal horn. The effects of syringaresinol were tested using behavioral and immunohistochemical assays. We found that oxaliplatin treatment activated the microglia to increase inflammatory responses, leading to the induction of pain. Syringaresinol treatment significantly ameliorated oxaliplatin-induced pain and suppressed microglial expression of inflammatory signaling molecules. Thus, we concluded that the analgesic effects of syringaresinol on OIPN were achieved via the modulation of spinal microglial inflammatory responses.