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Low back pain (LBP) is the leading cause of years lived with disability worldwide. Most people with LBP receive the diagnosis of nonspecific LBP or sciatica. Medications are commonly prescribed but have limited analgesic effects and are associated with adverse events. A novel treatment approach is to target neurotrophins such as nerve growth factor (NGF) to reduce pain intensity. NGF inhibitors have been tested in some randomized controlled trials (RCTs) in recent years, showing promise for the treatment of chronic LBP; however, their efficacy and safety need to be evaluated to guide regulatory actions.
Learn More >Mas-related G protein-coupled receptor-X2 (MRGPRX2) is known as a novel receptor to activate mast cells (MCs). MRGPRX2 plays a dual role in promoting MC-dependent host defense and immunomodulation and contributing to the pathogenesis of pseudo-allergic drug reactions, pain, itching, and inflammatory diseases. In this article, we discuss the possible signaling pathways of MCs activation mediated by MRGPRX2 and summarize and classify agonists and inhibitors of MRGPRX2 in MCs activation. MRGPRX2 is a low-affinity and low-selectivity receptor, which allows it to interact with a diverse group of ligands. Diverse MRGPRX2 ligands utilize conserved residues in its transmembrane (TM) domains and carboxyl-terminus Ser/Thr residues to undergo ligand binding and G protein coupling. The coupling likely initiates phosphorylation cascades, induces Ca mobilization, and causes degranulation and generation of cytokines and chemokines via MAPK and NF-κB pathways, resulting in MCs activation. Agonists of MRGPRX2 on MCs are divided into peptides (including antimicrobial peptides, neuropeptides, MC degranulating peptides, peptide hormones) and nonpeptides (including FDA-approved drugs). Inhibitors of MRGPRX2 include non-selective GPCR inhibitors, herbal extracts, small-molecule MRGPRX2 antagonists, and DNA aptamer drugs. Screening and classifying MRGPRX2 ligands and summarizing their signaling pathways would improve our understanding of MRGPRX2-mediated physiological and pathological effects on MCs.
Learn More >Tension-type headache (TTH) is the most prevalent primary headache disorder. We assessed the cross-sectional impact of TTH on health related quality of life (HRQoL) in a general population. We also examined the association of HRQoL scores with headache frequency, disability, medication overuse, poor self-rated health, psychiatric comorbidity, and pain sensitivity in individuals with TTH.
Learn More >Human voltage-gated sodium channel (VGSC) Na1.7 (hNa1.7) is involved in the generation and conduction of neuropathic and nociceptive pain signals. Compelling genetic and preclinical studies have validated that hNa1.7 is a therapeutic target for the treatment of pain, however there is a dearth of currently available compounds capable of targeting hNav1.7 with high potency and specificity. Hainantoxin-III (HNTX-III) is a 33-residue polypeptide from the venom of the spider Ornithoctonus hainana. It is a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels. Here, we report the engineering of improved potency and Na selectivity of hNa1.7 inhibition peptides derived from the HNTX-III scaffold. Alanine scanning mutagenesis showed key residues for HNTX-III interacting with hNa1.7. Site-directed mutagenesis analysis indicated key residues on hNa1.7 interacting with HNTX-III. Molecular docking was conducted to clarify the binding interface between HNTX-III and Nav1.7 and guide the molecular engineering process. Ultimately, we obtained H4 [K0G1-P18K-A21L-V] based on molecular docking of HNTX-III and hNa1.7 with a 30-fold improved potency (IC 0.007 ± 0.001 μM) and > 1000-fold selectivity against Na1.4 and Na1.5. H4 also showed robust analgesia in the acute and chronic inflammatory pain model and neuropathic pain model. Thus, our results provide further insight into peptide toxins that may prove useful in guiding the development of inhibitors with improved potency and selectivity for Na subtypes with robust analgesia.
Learn More >Advanced age and obesity are reported to increase the risk of opioid-induced respiratory depression (OIRD). Oliceridine, an intravenous opioid, is a G-protein-biased agonist at the µ-opioid receptor that may provide improved safety. The recent phase 3 ATHENA open-label, multicenter study evaluated postoperative use of oliceridine in patients with moderate-to-severe acute pain. This exploratory analysis of the ATHENA data examined the incidence of OIRD in older (≥ 65 years) and/or obese (BMI ≥ 30 kg/m) patients and analyzed risk factors of OIRD.
Learn More >The onset of chemotherapy-induced peripheral neurotoxicity (CIPN) is a leading cause of the dose reduction or discontinuation of cancer treatment due to sensory symptoms. Paclitaxel (PTX) can cause painful peripheral neuropathy, with a negative impact on cancer survivors' quality of life. While recent studies have shown that neuroinflammation is involved in PTX-induced peripheral neurotoxicity (PIPN), the pathophysiology of this disabling side effect remains largely unclear and no effective therapies are available. Therefore, here we investigated the effects of human intravenous immunoglobulin (IVIg) on a PIPN rat model. PTX-treated rats showed mechanical allodynia and neurophysiological alterations consistent with a severe sensory axonal polyneuropathy. In addition, morphological evaluation showed a reduction of intra-epidermal nerve fiber (IENF) density and evidenced axonopathy with macrophage infiltration, which was more prominent in the distal segment of caudal nerves. Three weeks after the last PTX injection, mechanical allodynia was still present in PTX-treated rats, while the full recovery in the group of animals co-treated with IVIg was observed. At the pathological level, this behavioral result was paralleled by prevention of the reduction in IENF density induced by PTX in IVIg co-treated rats. These results suggest that the immunomodulating effect of IVIg co-treatment can alleviate PIPN neurotoxic manifestations, probably through a partial reduction of neuroinflammation.
Learn More >Children and adults with atopic dermatitis suffer from intractable chronic itch and can also experience acute itch flare ups that significantly increase itch intensity. In this issue of Cell, Wang et al. demonstrate that a subset of basophils activates sensory neurons to drive allergen-evoked itch flare ups in atopic dermatitis.
Learn More >The present study aimed to explore associations between brain activity in the auditory cortex and clinical and psychiatric characteristics in patients with migraine without aura (MwoA) during interictal periods. Resting-state data were acquired from patients with episodic MwoA (n = 34) and healthy controls (n = 30). Independent component analysis was used to extract and calculate the resting-state auditory network. Subsequently, we analyzed the correlations between spontaneous activity in the auditory cortex and clinical and psychiatric features in interictal MwoA. Compared with healthy controls, patients with MwoA showed increased activity in the left superior temporal gyrus (STG), postcentral gyrus (PoCG) and insula. Brain activity in the left STG was positively correlated with anxiety scores, and activity in the left PoCG was negatively correlated with anxiety and depression scores. No significant differences were found in intracranial volume between the two groups. This study indicated that functional impairment and altered integration linked to the auditory cortex existed in patients with MwoA in the interictal period, suggesting that auditory-associated cortex disruption as a biomarker may be implemented for the early diagnosis and prediction of neuropsychiatric impairment in interictal MwoA patients.
Learn More >Spinal cord stimulation is frequently used for the treatment of intractable chronic pain conditions. Trialing of the spinal cord stimulator device is recommended to assess the patient's response to neurostimulation before permanent implantation. The trial response is often assessed by Numeric Rating Scale changes and patient-reported percentage pain improvement. Using number rating scale changes between prespinal and postspinal cord stimulation trial, a calculated percentage pain improvement can be obtained. The aim of this study was to assess the difference between calculated and patient-reported percentage improvement in pain scale during spinal cord stimulation trials.
Learn More >Voltage-gated sodium channels are key players in neuronal excitability and pain signaling. Functional expression of the voltage-gated sodium channel Na1.7 is under the control of SUMOylated collapsin response mediator protein 2 (CRMP2). When not SUMOylated, CRMP2 forms a complex with the endocytic proteins Numb, the epidermal growth factor receptor pathway substrate 15 (Eps15), and the E3 ubiquitin ligase Nedd4-2 to promote clathrin-mediated endocytosis of Na1.7. We recently reported that CRMP2 SUMO-null knock-in (CRMP2) female mice have reduced Na1.7 membrane localization and currents in their sensory neurons. Preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in CRMP2 female mice with neuropathic pain. Here we report that inhibiting clathrin assembly in nerve-injured male CRMP2 mice precipitated mechanical allodynia in mice otherwise resistant to developing persistent pain. Furthermore, Numb, Nedd4-2 and Eps15 expression was not modified in basal conditions in the dorsal root ganglia (DRG) of male and female CRMP2 mice. Finally, silencing these proteins in DRG neurons from female CRMP2 mice, restored the loss of sodium currents. Our study shows that the endocytic complex composed of Numb, Nedd4-2 and Eps15, is necessary for non-SUMOylated CRMP2-mediated internalization of sodium channels in vivo.
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