Molecular Pain最新文献

Background: Chronic Back Pain (CBP) may lead to a reorganization of brain function, which can be observed through the indicator of degree centrality (DC). Traditional pain research has predominantly focused on static measurements of brain function within classical frequency bands, which may not fully capture the complexities of chronic pain. This study not only employed static frequency division but also incorporated dynamic analyses to capture the evolving nature of brain activity in chronic pain conditions.

Methods: This study included a total of 31 patients with CBP and 33 age- and gender-matched healthy controls. Spontaneous brain activity was investigated by traditional DC, DC in subfrequency bands (slow-5, slow-4) and dynamic DC (dDC). Differences in brain regions between the two groups were obtained using two-sample t-tests. The association of abnormal brain regions with pain intensity and psychological tests were analyzed in parallel.

Results: Compared to classical frequency band, the number of brain regions with changes in DC values in the slow-5 frequency band is greater. The right angular gyrus was found in both the slow-5 frequency band and the classical frequency band, while the left putamen was only found in the slow-5 frequency band. The dDC values were changed in left hippocampus, and right putamen, which were all different from the brain regions that the static DC (sDC) value altered.

Conclusion: This study demonstrates that incorporating frequency and dynamic analysis in addition to traditional DC metrics can better understand the functional characteristics of the brain in CBP.

When conventional drug-based Western medicine proves ineffective, complementary and alternative medicine (CAM), including herbal medicine and acupuncture, often gains prominence. Phytochemicals, plant-derived compounds synthesized for self-protection against environmental stressors like ultraviolet radiation and insects, have also shown numerous physiological benefits in humans. Among these, flavonoid compounds-abundant in fruits and vegetables-have garnered significant research interest due to their reported biological activities, such as antioxidant, anti-inflammatory, and anticancer effects.　Recent in vitro studies have provided substantial evidence that flavonoids modulate the activity of various ion channels. These channels are crucial for the generation and conduction of activation and action potentials in excitable cells, including those involved in pain transmission. These findings strongly suggest that flavonoids could serve as novel therapeutic agents for pain relief, potentially replacing existing local anesthetics.This paper discusses recent in vivo neurophysiological findings which reveal the potential of flavonoids to substitute existing local anesthetics in nociceptive and inflammatory pain. We explore the possibility of developing new drugs with fewer side effects by focusing on the common chemical structure of flavonoids, addressing the shortcomings of current anesthetics, and outlining future prospects.

It is well known that pain and anxiety can enhance each other in both animals and humans. In case of chronic pain, patients often suffer anxiety and depression. Animal experiments provide important basic mechanisms for the interaction between chronic pain and anxiety. At cortical level, recent studies have consistently indicated that anterior cingulate cortex (ACC) and insular cortex (IC), two critical cortical regions for pain-related unpleasantness and suffering, are also involved in the process of emotional anxiety. At synaptic level, long-term potentiation (LTP), a key cellular mechanism for memory and chronic pain, has also been found to contribute to emotional anxiety in animal models of chronic pain. In a recent study published in Neuron [1] by the group of Prof. Xu, it has been found that at subcortical level, anterior and posterior paraventricular nucleus of the thalamus (PVT) contribute to pain and anxiety through distinct projections to the basolateral amygdala (BLA) and central amygdala (CeA). In this review, I will first introduce the recent work by Prof Xu, and then discuss possible mechanisms at different levels for pain and anxiety in the condition of chronic pain, including chronic visceral pain. Some of medicines used in the current treatment will be analyzed, and potential future treatment for pain and anxiety in chronic pain conditions will be discussed.

Introduction: It has well been documented that sex-related difference in the prevalence of migraine is widely accepted with more commonly seen in female patients. Although trigeminal ganglion (TG) neurons are the key players in the etiology of migraine, the underlying pathophysiology remains under debate so far.

Methods: Myelinated Ah-type TG neurons were identified by the waveform characters of action potential (AP) conjugated with pharmacological validation using whole-cell patch techniques.

Results: The results showed that AP duration and current derivative for repolarization were markedly increased by 3 μM Yoda1 along with the increased firing frequency of repetitive discharge that could be abolished by 3 μM GsMTx4. Although Yoda1 concentration-dependently increased the peaks of Ca2+ currents, the blocker for Ca2+ channel ω-Conotoxin did not alter the AP waveform characters and discharge profiles, whereas Yoda1-mediated changes in AP waveform trajectory and repetitive discharge could be completely reversed by1.0 μM Iberiotoxin, a selective KCa1.1 blocker, suggesting that Piezo1-induced Ca2+ influx can activate KCa1.1 via presumably channel coupling. Additionally, Ah-type TG neurons functionally expressed Nav1.9/Nav1.8 in all tested neurons and their peaks were significantly increased by 3 μM Yoda1 and completely blocked by 3 μM GsMTx4.

Conclusion: These datasets have demonstrated Piezo1-mediated neuroexcitation of female-specific subpopulation of myelinated Ah-type TG neurons due at least to the coupling between N-type Ca2+ channel and KCa1.1 and functional upregulation of Nav1.9, which uncovers an additional insights for higher incidence of migraine in woman.

Migraine is a very common and incapacitating condition. We chose to assess the therapeutic effect of Botulinum toxin injection on migraine and tension-type headache patients in an effort to measure salivary alpha amylase for these groups before and after treatment with Botulinum toxin injection because stress appears to be a significant provoking factor of this disorder.There were twenty patients with chronic tension-type headaches and twenty-five patients with chronic migraines among the forty-five individuals. Enzyme-linked immunosorbent assay (ELISA) kits were used to test the salivary biomarker (salivary cortisol and salivary alpha amylase). The PREEMPT (Onabotulinum toxinS AntIpOde for chronic migraiNe) treatment protocol, a systematic procedure for treating chronic migraines, was administered to the patients. Biomarkers measured during the study were analyzed as surrogate measures of stress to shed light on potential physiological action of the intervention. Context In patients with chronic migraine and tension-type headaches, the effect of Nabota (Botulinum toxin type A) on specific stress-related indicators was evaluated.The results demonstrated a statistically significant (p<0.05) rise in salivary cortisol and a statistically significant (p<0.05) decrease in salivary alpha amylase following Botulinum toxin intervention for both research groups (chronic migraine, chronic tension headaches).

Noxious chemicals like chlorine induce extreme distress, pain, and irritation in exposed individuals, yet methods to evaluate the pain-related behavioral response are absent. It is also unknown whether analgesics would alleviate pain and physical discomfort induced by such noxious chemicals. The grimace scale (GS), which evaluates facial expression features such as orbital tightening (OT), is a valuable indicator of pain and distress in animals. However, conventional GS approaches are labor-intensive, prone to subjectivity, and lack quantitative precision. In this study, we employed machine learning with DeepLabCut to annotate key facial landmarks in video recordings of chlorine-exposed rats. Focusing on the superior and inferior eyelid margins and the medial and lateral canthi, we quantified eyelid distance and palpebral fissure width as measures of OT. Rigorous inclusion and exclusion criteria for annotated images were established to ensure accuracy and reproducibility. The quantitative GS in rats subjected to chlorine exposure was validated. Significant reductions in eyelid distance and palpebral fissure width were observed upon chlorine exposure as compared to unexposed baseline control animals. Administration of the opioid analgesic buprenorphine significantly reduced the OT caused by chlorine. This study establishes a robust, quantitative method for assessing OT in chlorine-exposed rats using DeepLabCut, providing a scalable, objective tool for assessing pain induced by noxious chemicals in preclinical research. This study also suggests that opioids can alleviate pain and physical discomfort induced by inhalation of noxious chemicals, providing a new therapeutic strategy for managing the respiratory hazard of noxious chemicals.

Paclitaxel (PTX) is a drug commonly used in cancer chemotherapy despite its neurotoxicity. TRPA1 channels are essential mediators of sensory transduction and nociception. These cation channels are linked to PTX-induced neurotoxicity, which Li+ prevents. This study aimed to examine the effects of Li+ on PTX-induced neurotoxicity and on TRPA1 channels. We utilized the SH-SY5Y cell line to assess cell viability via the MTT assay. Intracellular Ca2+ concentration in Fura-2-loaded cells was measured using spectrofluorometry. TRPA1 channel activity was evaluated with whole-cell patch-clamp recordings. The effects of PTX, Li+, and TRPA1 agonists and antagonists were tested. Motor function, thermal response, and cognitive performance were assessed in adult Wistar rats with neuropathy induced by PTX. PTX (100 nM) significantly reduced cell viability, and Li+ (10 mM) alleviated this effect. AITC (300 µM), a TRPA1-selective agonist, decreased cell viability, with a more pronounced impact when PTX was present. A967079 (10 µM), a selective TRPA1 antagonist, significantly lessened the cytotoxicity caused by PTX. Li+ reduced the cytotoxic effects of TRPA1 activation both with and without PTX. PTX increased TRPA1 currents and amplified TRPA1-mediated intracellular Ca2+ increase, while Li+ neutralized both effects. Additionally, PTX causes sensorimotor and cognitive neuropathy, which was reversed by Li+ treatment. These findings suggest that Li+ may act as a neuroprotective agent, preventing neuronal damage caused by PTX via TRPA1 channel pathways.

Although 5-hydroxytryptamine (5-HT) contributes to pruritus associated with allergic contact dermatitis (ACD), the role of 5-HT derived from mast cells (MC) in chronic pruritus induced by squaric acid dibutyl ester (SADBE) and the expression and distribution of 5-HT2A receptor (HTR2A) in sensory neurons remain unclear. In this study, a SADBE-induced ACD mouse model was established to evaluate pruritus behavior, MC activation and 5-HTproduction. The mechanism was verified through pharmacological intervention (MC stabilizer cromolyn, HTR2A antagonist Ketanserin) and FcεRIα-KO mice. It was found that SADBE triggered time-dependent MC recruitment (peaking at Day 14-21) and Mc-derived 5-HT release, which were associated with persistent pruritus. The intervention of MC stabilizer cromolyn and FcεRIα-KO mice confirmed MC/ IgE-dependent 5-HT release, and inhibiting MC degranulation could reduce pruritus. Single-cell RNA sequencing and RNAscope in situ hybridization techniques revealed that HTR2A was mainly expressed in the NF3/PEP2/NP3 subsets of DRG neurons. The co-expression level of HTR2A and Nppb was relatively high, partially overlapping with TRPV1/TRPA1. HTR2A antagonists can relieve SADBE-induced pruritus. In conclusion, we have determined that the MC-5-HT-HTR2A axis is involved in chronic pruritus in SADBE-induced ACD, and targeting this axis provides a very promising therapeutic strategy.

The cellular and molecular mechanisms of acupuncture have been investigated across various tissues in multiple animal models. However, the dynamic cellular and molecular changes at human acupuncture points remain unexplored. The primary challenge preventing such a study is the practical difficulty of obtaining sufficient cells from acupoints. To address this, we developed a new needle manipulation technique that enables the collection of sufficient cell number from the acupuncture needle during the treatment. Using this approach and single-cell technology, we identified eight cell types at the acupoint BL23: inflammatory fibroblast, myofibroblast, skeletal muscle cell, endothelial cell, smooth muscle cell, adipocyte, macrophage and a novel cell type characterized by marker genes CNTNAP2 and CSMD1. Remarkably, this novel cell population was significantly enriched during the pain relief phase compared to the pain state, while the other seven cell types were significantly reduced following acupuncture analgesia. Transcriptomic analysis suggested that these novel cells are involved in synapse assembly and synaptic plasticity. This study presents the first characterization of cellular and transcriptional dynamics at the acupoint BL23, offering new insights into the mechanism underlying acupuncture-induced pain relief.

Purpose: To investigate evodiamine's analgesic effects and molecular mechanisms on chemotherapy-induced peripheral neuropathy (CIPN), focusing on the p38/MAPK-TRPV1 signaling axis and macrophage polarization in dorsal root ganglia (DRG).

Methods: A paclitaxel-induced CIPN rat model was established with behavioral assessments via von Frey and thermal hyperalgesia tests. TRPV1, TRPV4, and inflammatory cytokine expression were analyzed using qRT-PCR, ELISA, and Western blot. Macrophage infiltration and polarization were evaluated by flow cytometry and immunofluorescence. Mechanistic studies utilized macrophage-conditioned media from RAW264.7 cells and clodronate liposome-mediated macrophage depletion to establish causal relationships between macrophage polarization and nociceptive behavior.

Results: Evodiamine dose-dependently alleviated paclitaxel-induced mechanical and thermal allodynia both acutely and preventively. It selectively inhibited upregulation of TRPV1 without affecting TRPV4 and reduced pro-inflammatory cytokine levels (TNF-α, IL-1β, IL-6, MCP-1) in the DRG. Evodiamine significantly reduced F4/80+ macrophage infiltration and shifted macrophage polarization from a pro-inflammatory M1 phenotype (decreased MCP1, CD86) to an anti-inflammatory M2 phenotype (increased CD163, CD206). Notably, macrophage-conditioned medium experiments revealed that evodiamine indirectly modulates neuronal TRPV1 expression through macrophage-derived factors. Furthermore, evodiamine attenuated paclitaxel-induced p38 MAPK phosphorylation in DRG neurons, with selective p38 MAPK inhibition by SB203580 confirming this pathway's critical involvement in TRPV1 regulation and pain modulation.

Conclusion: Evodiamine alleviates CIPN through a novel neuroimmune mechanism involving M2 macrophage polarization and inhibition of the p38/MAPK-TRPV1 axis in DRG neurons. These findings establish macrophage polarization as a key therapeutic target and highlight evodiamine's potential as a natural therapeutic agent for CIPN management.