Molecular Pain最新文献

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.

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 by 1.0 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.

The insular cortex (IC), a critical hub for nociception, emotion, and cognition processing, has emerged as a key role in the descending modulation of spinal cord excitability. Although previous studies have suggested that IC may influence spinal nociceptive reflexes through direct or indirect top-down pathways, the specific effects of IC stimulation on spinal nociceptive transmission remain unclear. In this study, by combining in vivo whole-cell patch-clamp, behavioral and morphological approaches, we identified a direct projection from the IC to the contralateral dorsal spinal cord. To determine whether IC activation affect the spinal nociceptive reflex, we measured the spinal nociceptive tail-flick (TF) reflex during IC stimulation. We found that activating the IC by electric stimulation did not significantly alter the spinal TF reflex. Furthermore, in vivo whole-cell patch-clamp recordings from spinal dorsal horn neurons revealed that IC stimulation produced delayed inhibition of spontaneous excitatory transmission in some neurons, while exciting or having no significant effect on others. These results indicate that the top-down modulation from the IC to the spinal cord is not uniformly facilitatory, distinguishing it from the consistently facilitatory effects observed in the anterior cingulate cortex (ACC)-spinal cord projection.

The senescence-associated secretory phenotype (SASP) contributes to tissue degeneration and inflammation, yet its role in osteoarthritis (OA)-related pain remains poorly understood. We hypothesized that circulating SASP markers would be associated with distinct OA-pain phenotypes, defined by pain impact and radiographic OA (ROA) severity. A subset of middle-to-older-aged adults (45-85 years) from a larger multi-site study (n = 169) self-reported pain impact - defined as the extent to which pain interferes with daily functioning - and underwent knee radiography and blood collection. Hierarchical cluster analysis was used to empirically identify OA-pain phenotypes based on combined pain impact and Kellgren-Lawrence (KL) grade. Plasma levels of four SASP markers (GDF-15, activin-A, Osteopontin (OPN), and IL-15) were quantified from whole blood samples. Among 169 participants, 35.5% reported high-impact chronic knee pain and 27.8% exhibited moderate-to-severe radiographic OA. Cluster analysis identified distinct ROA-pain phenotypes. GDF-15 levels were significantly elevated in non-Hispanic White females with early ROA and high-impact pain, with race- and sex-dependent differences. Activin-A levels were higher in non-Hispanic Black participants without pain or ROA and varied by sex in early ROA/low-impact pain phenotypes. Osteopontin levels were elevated in males compared to females within the same phenotype group. IL-15 levels showed no association with ROA-pain phenotypes but were higher in males and positively correlated with age. SASP factors, particularly GDF-15, Activin-A, and Osteopontin, demonstrated race- and sex-dependent associations with OA-pain phenotypes. These findings underscore the importance of demographic context in OA pathophysiology and support further investigation into SASP factors as potential biomarkers and therapeutic targets for OA-related pain.

Inflammatory pain is a key component of acute traumatic pain and chronic rheumatic disease, which significantly reduces the quality of life of those who suffer from it and is often refractory to treatment. One contributor to the failure of current treatments is that the majority of pain testing has historically been performed in male subjects while the majority of pain patients are women. To better manage inflammatory pain, first the baseline sex differences in its experience must be assessed. Therefore, we evaluated C57BL/6J male and female mice for baseline sex differences in the formalin model of inflammatory pain, further investigating the observed significant sex differences through both assessing female mice at each phase of the estrous cycle and through examining the effects of gonadectomy (ovariectomy or castration) within the formalin model of inflammatory pain. Female mice in the metestrus or diestrus phase had decreased inflammatory pain relative to both male mice and female mice in the proestrus or estrus phase. Ovariectomy resulted in decreased pain, which was restored through treatment with estradiol (E2). Castration similarly reduced pain in male mice. Injection of the G-protein coupled estrogen receptor (GPER) agonist G1 resulted in significant antinociception in both female and male mice, in both mice that had received sham surgery or gonadectomy. These results establish baseline sex differences in the formalin model of inflammatory pain and support the need for further investigation into the interaction between estrogen, its receptors, and testosterone in the regulation of nociception.

This secondary data analysis aimed to determine the nature of the relationship between obstructive sleep apnea (OSA) risk, biological age acceleration, and nonspecific chronic low back pain (CLBP). In total, 199 adults aged 18-82 years who filled both STOPBANG and pain questionnaires subsetted for secondary analysis. Based on the STOPBANG questionnaire, 104 had a low OSA risk and 95 had an intermediate or high OSA risk. Dunedin Pace of Aging Computed from the Epigenome (DunedinPACE), Horvath's, Hannum's, PhenoAge, and GrimAge clocks were used to determine biological age and pace of biological aging. Individuals with low OSA risk reported increased DunedinPACE compared to those with intermediate/high OSA risk (p < 0.001). There was a significant correlation between the risk for OSA and biological age acceleration measured by PhenoAge as well as pace of biological aging (p < 0.05). Mediation analysis detected indirect effects of OSA risk on chronic pain outcomes through the pace of biological aging. Targeted interventions addressing OSA risk offers a promising therapeutic strategy. This could be particularly valuable for aging populations where both accelerated biological aging and chronic pain conditions are prevalent, offering a more holistic approach to improving nonspecific chronic pain outcomes through quality of sleep and restfulness.

Recent studies have shown that electroacupuncture (EA) can exert analgesic effects by modulating wide dynamic range (WDR) neurons in the spinal dorsal horn; however, how EA regulates WDR neurons to inhibit pain signals remains unclear. In this study, we identified a key brain region, rostral ventromedial medulla (RVM), involved in the modulation of spinal WDR neurons. Subsequently, we found evidence suggesting that GABAergic neurons in the RVM may mediate the transmission of nociceptive and non-nociceptive signals from the spinal cord, which underlies EA analgesia. The results demonstrated that the activation of RVM GABAergic neurons enhanced the excitability of WDR neurons, thereby facilitating the transmission of peripheral sensory signals within the spinal cord. Contralateral EA at 2 mA effectively suppressed WDR neuron activity and elevated pain thresholds in rats modeled with complete Freund's adjuvant (CFA). Notably, heightened activity of RVM GABAergic neurons mitigated the inhibitory effects of EA on WDR neurons and reduced EA-induced analgesia. These findings suggest that EA may attenuate WDR neuronal activity by modulating RVM GABAergic neurons, thereby inhibiting nociceptive transmission. This study highlights the potential involvement of RVM GABAergic neurons and identifies the efficacy of high-intensity, contralateral EA stimulation in producing analgesia.

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 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.

Paclitaxel (PTX) treatment induces a pathological pain state that is often associated with neuroinflammation in the central nervous system. The available interventions for PTX-induced pathological pain encounter adverse effects and limited efficacies. Recent studies have shown the significant effectiveness of Electroacupuncture (EA) in pain management as a simple and safe alternative medical treatment. Here, we evaluated the analgesic effect of EA on pain behaviors in PTX-treated rats and investigated its potential analgesic mechanisms. In this study, a pathological pain model was established in SD rats via intraperitoneal (i.p.) injection of PTX. EA or Sham EA treatments were applied every other day for PTX-treated rats. Pain behaviors of mechanical allodynia and thermal hyperalgesia in rats were measured, followed by analysis of the spinal cord tissue via using molecular biology methods. Here, we show that EA treatment is capable to alleviate PTX-induced mechanical allodynia and thermal hyperalgesia in rats. In addition, EA regulated the abnormal protein expression of astrocytes, microglia, neurons, TLR4-MyD88/TRIF signaling pathway and cytokines in the lumbar spinal cord of PTX-treated rats. Furthermore, we investigated the spinal co-expressions of TLR4 in astrocytes, microglia, and neurons respectively in rats and the regulatory effect of EA on TLR4 and cells mentioned above. In summary, EA shows analgesic properties as it ameliorates PTX-induced mechanical allodynia and thermal hyperalgesia probably by reducing central neuroinflammation. Therefore, we consider EA as a potential therapeutic candidate for the treatment of PTX-induced pathologic pain. Notably, this study provides the first morphological evidence that EA may concurrently influence TLR4-mediated neuroimmune interactions across multiple spinal cell types, suggesting a potential central mechanism distinct from previously reported peripheral actions.

Calcineurin inhibitors, including tacrolimus (FK506), are used as immunosuppressive agents and can cause unexplained calcineurin inhibitor-induced pain syndrome (CIPS). We investigated how FK506 affects the expression of Na_V1.7, a voltage-gated Na⁺ channel implicated in pain perception that is upregulated in dorsal root ganglion (DRG) neurons in several pain disorders. We generated a model of FK506-induced pain by administering FK506 to Na_V1.7-ChR2 mice, which exhibit light-responsive pain. To evaluate nociceptive responses, paw withdrawal threshold (PWT) was measured using the von Frey test. The optogenetic place aversion (OPA) and light irradiation paw withdrawal tests were also performed. On the 11th day of initial injection, DRGs were dissected from mice under anesthesia and analyzed for Na_V1.7 expression using quantitative reverse transcription PCR (RT-qPCR). PWT was also measured for mice that received the selective Na_V1.7 inhibitor or vehicle. PWT was lower in FK506-treated mice than in those administered the vehicle on the 8th and 12th days after initial FK506 injection (p < 0.05). Mechanical hypersensitivity was reversible and peaked at around 10 days after FK506 administration. OPA and light irradiation paw withdrawal test results corroborated the hypersensitivity to light-responsivity. Na_V1.7 mRNA levels in DRG were higher in FK506-treated mice than in those administered the vehicle on the 11th day (p < 0.05). A selective Na_V1.7 inhibitor reversed FK506-induced pain. Increased Na_V1.7 expression in DRG neurons may be responsible for FK506-induced peripheral neuropathy. Our findings suggest that endogenous calcineurin regulates Na_V1.7 expression. Thus, selective Na_V1.7 inhibition could be a potential therapeutic strategy for CIPS.