Neuropathic pain arises from an intricate network of interconnected pathophysiological mechanisms, yet the arsenal of effective therapeutic strategies remains frustratingly limited. Accumulating evidence has linked mitochondrial dysfunction to the progression of neuropathic pain. C1q‑tumor necrosis factor‑related protein‑3 (CTRP3), a newly identified adipokine with diverse cytoprotective capacities, has not been previously explored for its role in nociceptive processing. To explore the role of CTRP3 in pain hypersensitivity, pain‑related behavioral assessments were conducted using von Frey filaments and acetone drop method in male rats subjected to spared nerve injury (SNI). To unravel the underlying mechanisms, spinal cord tissues were subjected to western blotting, reverse transcription‑quantitative PCR, immunofluorescence staining, dihydroethidium staining, small interfering RNA (siRNA) technologies and biochemical assays for quantifying oxidative markers. The findings showed that SNI markedly reduced endogenous CTRP3 expression in spinal neurons. Intrathecal administration of recombinant CTRP3 (rCTRP3) alleviated mechanical allodynia and cold hyperalgesia in SNI‑induced rats. Additionally, rCTRP3 treatment enhanced PGC‑1α‑mediated mitochondrial biogenesis, ATF5‑triggered mitochondrial unfolded protein response (UPRmt), and mitigated spinal oxidative stress. Mechanistically, pharmacological inhibition of SIRT1 with EX‑527, or siRNA‑mediated silencing of PGC‑1α or ATF5, reversed the effects of CTRP3 on pain hypersensitivity, mitochondrial biogenesis, UPRmt and oxidative stress. The present study demonstrates that CTRP3 mitigates mechanical allodynia and cold hyperalgesia in male SNI rats by activating spinal SIRT1, thereby enhancing PGC‑1α‑mediated mitochondrial biogenesis and ATF5‑induced UPRmt. CTRP3 may therefore represent a novel therapeutic target for the management of neuropathic pain.

Neuropathic pain is a chronic pain disorder refractory to conventional analgesics. Iron-dependent neuronal ferroptosis has been implicated in its pathogenesis. G protein-coupled receptor 4 (GPR4), a proton-sensing receptor, is involved in inflammation and ferroptosis, but its role in neuropathic pain and spinal neuronal ferroptosis remains unclear. Neuropathic pain was induced in rats using the spared nerve injury (SNI) model, and GPR4 expression and its effects on pain behaviors, neuronal ferroptosis, and spinal inflammation were examined. GPR4 was inhibited by a selective antagonist or small interfering RNA (siRNA), while Ras homolog family member A (RhoA) and Yes-associated protein (YAP) were activated via intrathecal injection of specific agonists. Spinal GPR4 expression was significantly upregulated and neuronal ferroptosis was induced by SNI, as evidenced by increased iron accumulation, lipid peroxidation, and dysregulated ferroptosis-related protein expression. SNI-induced mechanical allodynia, cold hyperalgesia, neuronal ferroptosis, and spinal inflammation were attenuated by GPR4 inhibition or knockdown. Mechanistically, the spinal RhoA/YAP signaling pathway was activated by SNI, and this activation was reversed by GPR4 inhibition. Furthermore, the analgesic and anti-ferroptotic effects of GPR4 inhibition were abolished by RhoA or YAP activation. It is demonstrated that GPR4 regulates neuropathic pain, neuronal ferroptosis, and spinal inflammation via the spinal RhoA/YAP signaling pathway, suggesting that GPR4 inhibition may represent a promising novel therapeutic strategy for neuropathic pain.

Chronic pain poses a significant clinical challenge, often refractory to conventional therapies. Light-based interventions, including green, blue, and bright light therapies, laser photobiomodulation, and optogenetics, have emerged as promising non-pharmacological approaches for pain modulation. This review integrates recent advances from molecular to circuit-level mechanisms, highlighting how specific light wavelengths influence nociceptive pathways, neuroimmune interactions, and central pain circuits. We further examine translational progress in laser therapy and optogenetic neuromodulation, emphasizing therapeutic efficacy and circuit specificity. Together, these insights lay the foundation for next-generation precision neuromodulation strategies for chronic pain management.

BACKGROUND:Advanced cancer patients still suffer from devastating bone pain, with less efficacious treatments. The spinal microglia activation and neuroinflammation are the pivotal pathological processes of cancer-induced bone pain (CIBP). This study aims to explore whether c/EBPβ negatively regulates CD200R1 to induce microglia-medicated neuroinflammation in the spinal cord of CIBP mice. METHODS:The CIBP mice model was constructed by intrafemoral injection of Lewis lung cancer cells to investigate the role of CD200/CD200R1 signaling and their upstream molecule CCAAT/enhancer binding protein β (c/EBPβ) in CIBP. Mechanical allodynia and thermal hyperalgesia were evaluated by von Frey filaments and hot plate, respectively. Adeno-associated viruses were constructed to regulate the expression of CD200R1 and c/EBPβ. The protein level was assessed by western blotting, and microglia activation was detected by immunofluorescence. RESULTS:Our results showed that CD200/CD200R1 signaling was inhibited in the spinal cord of CIBP mice. Intrathecal injection of CD200R1 agonist CD200Fc effectively reversed the nociceptive behaviors in CIBP mice. Overexpression of CD200R1 could also effectively ameliorate the pain behaviors and spinal neuroinflammation in CIBP mice. Transcription factor c/EBPβ was upregulated in the spinal cord of CIBP mice. Knockdown of c/EBPβ effectively inhibited the microglia-mediated neuroinflammation by restoring CD200R1 protein levels, alleviating pain behavior in CIBP mice. CONCLUSION:c/EBPβ-mediated suppression of the CD200/CD200R1 signaling pathway represents one potential mechanism in promoting microglial activation and neuroinflammation in the spinal cord of CIBP mice, which provides a potential therapeutic target for CIBP management.

Collapsin Response Mediator Protein 2 (CRMP2) has emerged as a central node in the pathogenesis of chronic pain, functioning as a multimodal ‘molecular switch’ that regulates microtubule dynamics, ion channel trafficking, and synaptic plasticity. The dysregulation of CRMP2, particularly through aberrant post-translational modifications (PTMs) such as phosphorylation and SUMOylation, is a critical driver of both peripheral and central sensitization. This review systematically examines the structure, regulation, and multifaceted roles of CRMP2 in pain signaling pathways. We then critically evaluate a spectrum of CRMP2-targeted therapeutic strategies, including small-molecule inhibitors, peptide-based agents, and gene silencing, highlighting their promising preclinical efficacy and safety profiles. Despite challenges in targeting specificity and central nervous system delivery, we posit that innovations in delivery systems, precision medicine, and AI-assisted drug design will catalyze the clinical translation of CRMP2-based, non-opioid analgesics, offering a paradigm shift in chronic pain management.

BACKGROUND:Chronic pain and anxiety exhibit a high degree of comorbidity, in which these conditions can mutually exacerbate each other. The authors investigated whether glutamatergic neurons in the pedunculopontine tegmental nucleus (PPTg Glu ) and their projections to the central medial thalamic nucleus (CM) regulate nociceptive and anxiety-like behaviors in a complete Freund's adjuvant (CFA)-induced chronic pain model. METHODS:The authors used c-Fos staining, chemogenetics, and optogenetics to assess the role of PPTg Glu and the PPTg Glu -CM pathway in regulating nociceptive and anxiety-like behaviors. Rabies-mediated retrograde tracing was used to map the anatomical connection from PPTg Glu to glutamatergic neurons in the CM (CM Glu ). Optogenetics combined with electrophysiologic recordings was used to verify the functional connectivity of this pathway. RESULTS:Plantar injection of CFA induced anxiety-like behaviors. This behavioral comorbidity was associated with the activation of glutamatergic neurons in the PPTg, as indicated by c-Fos staining. Chemogenetic inhibition of the PPTg Glu alleviated both evoked and spontaneous nociceptive behaviors, as well as anxiety-like behaviors in CFA-treated mice. Conversely, optogenetic activation of these neurons was sufficient to elicit both evoked and spontaneous nociceptive behaviors, as well as anxiety-like behaviors in naïve mice. To identify the underlying circuit, the authors first employed both anterograde and retrograde tracing to map the anatomical connectivity between the PPTg and the CM. The authors then verified the functional connectivity of this specific PPTg Glu -CM Glu pathway using optogenetics combined with electrophysiologic recordings. Finally, pathway-specific manipulations demonstrated that chemogenetic inhibition of the PPTg Glu -CM pathway relieved nociceptive and anxiety-like behaviors, whereas optogenetic activation of this pathway was sufficient to induce these behaviors in naïve mice. CONCLUSIONS:The CM receives excitatory input from PPTg Glu , and this PPTg Glu -CM pathway modulates nociceptive and anxiety-like behaviors.

BACKGROUND:Glutamatergic neurons in the medial septum (MS) are identified to promote emergence from sevoflurane general anesthesia (GA), with the potential downstream neural circuit remaining to be explored. METHODS:Rabies virus (RV)-mediated monosynaptic retrograde tracing and anterograde tracing were first used to identify the projection from glutamatergic MS neurons (MSGlu) to glutamatergic neurons in the lateral hypothalamus (LH, LHGlu). In vivo fiber photometry, optogenetic bidirectionally manipulations, electroencephalogram/electromyogram (EEG/EMG), and behavioral tests were further employed to investigate the role of the circuit from MSGlu neurons to the LH (MSGlu-LH circuit) in regulating states of consciousness under two different states of sevoflurane GA: continuous, steady-state general anesthesia (CSSGA) and burst-suppression (BS) oscillations. RESULTS:The retrogradely labeled upstream neurons of LHGlu neurons were extensively detected in the MS, and most RV-infected neurons in the MS were co-labeled by Vesicular glutamate transporter 2 (Vglut2, mean ± standard error of the mean [SEM], 86.3% ± 1.5%, n = 4 mice). And the MSGlu-LHGlu circuit constitutes the highest proportion among the three downstream LH neuronal populations (presynaptic boutons co-localized ratio: glutamatergic, 77.0% ± 2.2%; γ-aminobutyric acid-ergic, 59.6% ± 0.9%; orexinergic, 28.5% ± 2.0%; n = 4 mice). The calcium activity of the MSGlu-LH circuit was inhibited concurrently as the process of loss of consciousness during 2.4% sevoflurane induction. Optogenetic activation of the MSGlu-LH circuit promoted behavioral arousal and increased β power of EEG (stimulation vs pre-stimulation, 16.8% ± 2.3% vs 9.7% ± 1.7%, P =.0065; n = 8 mice) during CSSGA. In contrast, during CSSGA, optogenetic inhibition of the MSGlu-LH projection deepened cortical inhibition, characterized by increased δ power and decreased power of β and γ (inhibition vs pre-inhibition, δ: 62.4% ± 4.5% vs 55.3% ± 4.2%, P =.0404; β: 6.7% ± 0.8% vs 9.4% ± 1.3%, P =.0069; γ: 3.3% ± 0.6% vs 4.8% ± 0.8%, P =.0076; n = 8 mice). Optogenetic bidirectionally manipulations of the MSGlu-LH circuit induced similar effects during BS: activation of this projection resulted in cortical activation with decreased burst-suppression ratio (BSR; median [25%-75% percentiles], stim vs pre, 59.0% [43.8%-64.5%] vs 77.5% [74.0%-84.3%], P =.0121; n = 8 mice), while inhibition of this projection led to cortical inhibition with increased BSR (inhib vs pre, 76.1% ± 7.0% vs 64.5% ± 8.4%, P =.0382; n = 8 mice). CONCLUSIONS:This study reveals that activation of the glutamatergic MS-LH circuit promotes emergence from sevoflurane GA.

Sleep-wake cycles and general anesthesia both involve reversible alterations in consciousness and share important neurobehavioral characteristics; however, their underlying mechanisms remain incompletely understood. As the principal inhibitory neuronal population in the central nervous system, GABAergic neurons play a key regulatory role in regulating transitions between states of consciousness. This review systematically synthesizes evidence from key brain regions—including the brainstem, basal forebrain, thalamus, hypothalamus, amygdala, and ventral striatum—to highlight the functional heterogeneity of GABAergic neuronal subpopulations involved in the regulation of sleep-wake cycles and anesthesia through “direct inhibition” and “disinhibition” mechanisms. We critically evaluate the shared circuit hypothesis of sleep and anesthesia and support a weaker version of this framework. Accordingly, we propose a three-tier classification system in which the neural circuits underlying sleep and anesthesia are categorized as fully shared, partially shared, or completely dissociated. These findings deepen our understanding of the neural mechanisms underlying transitions between states of consciousness and provide new theoretical targets for optimizing anesthetic management and developing therapeutic strategies for disorders of consciousness.

Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder primarily triggered by halogenated volatile anesthetics, succinylcholine, or cisatracurium. This report describes two cases exhibiting typical MH symptoms, including hyperthermia, hypercarbia, tachycardia, and acidosis, but with notable differences in the time of onset and symptom severity. The variable expression of MH may be influenced by multiple factors, such as the potency of the triggering agent, its dosage, the duration of exposure, and the "incomplete penetrance" of genetic variants. The novel RYR1 gene variants reported in this study may contribute to the Genomic Variant Database for this condition.

Celiac plexus block (CPB) is an established interventional technique for the management of severe upper abdominal pain, particularly in patients with chronic pancreatitis (CP) and pancreatic cancer (PC). Pain in these conditions is complex, involving visceral and neuropathic mechanisms and, in CP, additional contributions from neuropathic remodeling, central sensitization, and altered descending modulation play a role. CPB provides targeted neural blockade to disrupt nociceptive transmission from the upper abdominal viscera, thereby improving analgesia, reducing opioid requirements, and enhancing quality of life. This chapter emphasizes the role of CPB in treating pain resulting from CP and PC, with a specific focus on therapeutic timing, procedural approaches, technical considerations, efficacy, durability of pain relief, side effects, and recent advances. Current evidence suggests that CPB is highly effective in PC pain but provides only modest and short-lived benefit in CP, where it should be reserved for carefully selected refractory cases. Future directions include advanced imaging modalities, improved neurolytic agents, and integration of CPB into multimodal, mechanism-based strategies for comprehensive pain control.

Chronic pain is a significant global health burden often resistant to conventional analgesics. Evidence implicates that mitochondrial dysfunction is not only a cellular consequence of injury, but also a fundamental driver of pain chronification. This review synthesizes current insights into how mitochondrial impairment contributes to pain chronification across diverse pathological contexts. Bioenergetic failure marked by ATP depletion and electron transport chain defects plays a central role. This energy crisis converges with oxidative stress, calcium overload, and neuroinflammation to promote neuronal hyperexcitability. Meanwhile, impaired mitophagy, suppressed biogenesis, and abnormal dynamics all contribute to the disrupted mitochondrial quality control, which further perpetuates cellular stress. Crucially, the efficacy of multiple mitochondria-targeted therapeutic strategies was summarized in this review. Despite gaps in current research, we emphasize that developments in biomarker and exploration of neuro-glial immune interactions could advance mitochondria-based precision medicine for pain management.

Objective:This study aimed to evaluate the postoperative pain in patients with hypertrophic cardiomyopathy who underwent transapical beating-heart septal myectomy (TA-BSM) and to explore whether a thoracic paravertebral nerve block (TPVB) can effectively alleviate the postoperative pain resulting from this surgical procedure. Methods:Patients aged 18-75 years, classified as American Society of Anesthesiologists II-III, who underwent TA-BSM between April and September 2023, were included. A total of 197 patients were initially enrolled and evaluated in this study. Following the application of the inclusion and exclusion criteria, 136 participants were allocated to two cohorts: a control group (CON group) and a TPVB group, based on whether a TPVB was administered before the surgical intervention. Demographic data, perioperative characteristics, visual analog scale scores, analgesic strategy, and Quality of recovery-15 scores were evaluated. Results:After inverse probability of treatment weighting (IPTW) adjustment, the standardized mean difference in baseline characteristics between the two groups was <0.1. The incidence of moderate-to-severe pain on postoperative day 7 was 51.7% in the TPVB group compared to 71.1% in the CON group. The adjusted relative risk for moderate-to-severe pain was 0.748 [95% CI, 0.565 to 0.990] via IPTW analysis. The oral morphine equivalent administered via PCA during the initial 48 hours post-surgery was significantly lower in the TPVB group than in the CON group (225 vs 195; median difference, 34.5 [95% CI, 21 to 48]; P <0.001). Conclusion:Preoperative administration of a single TPVB before TA-BSM was associated with a reduced postoperative pain intensity, ranging from moderate to severe, and a subsequent decrease in opioid usage. TPVB may be a beneficial analgesic strategy for patients undergoing TA-BSM.

Real-time ultrasound can facilitate spinal anesthesia. However, it remains uncertain whether this technique prolongs the time for parturients entry into the operating room to skin incision compared with the landmark-guided method. We conducted a retrospective, propensity-score-matched study involving patients who received real-time and landmark-guided spinal anesthesia over a five-year period (2019-2024). Results showed a significantly time reduction from “door” to “skin incision” in the landmark-guided spinal anesthesia group compared to the real-time group (37.9 ± 13.7 minutes vs. 41.9 ± 18.3 minutes, P < 0.05). Both the age, body mass index and American Society of Anesthesiologists classification remained no significant correlation with the time reduction from “door” to “skin incision”.

Ischemic stroke remains one of the leading causes of death and long-term neurological disability worldwide. Increasing evidence indicates that ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, contributes substantially to ischemic brain injury. Ferritinophagy, driven by nuclear receptor coactivator 4 (NCOA4), is considered a pivotal process promoting ferroptosis after cerebral ischemia; however, the upstream mechanisms regulating this pathway are yet to be fully defined. In the present study, using both cell-based and murine models of ischemic brain injury, we found that NCOA4 undergoes SUMOylation and identified sentrin/SUMO-specific protease 2 (SENP2) as an important suppressor of this modification. Mechanistically, SENP2 binds to NCOA4 and removes its SUMO modification, which is associated with reduced HERC2-mediated ubiquitination, increased NCOA4 stability, enhanced ferritinophagy, and exacerbated neuronal ferroptosis following ischemic stroke. In contrast, disrupting the interaction between SENP2 and NCOA4 using a membrane-permeable Tat-NCOA4 peptide maintained NCOA4 SUMOylation, attenuated ferritinophagy-associated ferroptosis, reduced infarct size and cerebral edema, and improved neurological outcomes in mice subjected to transient middle cerebral artery occlusion. Moreover, administration of a high dose of Tat-NCOA4 to nonischemic mice did not produce observable toxicity under the experimental conditions. Collectively, these findings reveal a previously unrecognized mechanism by which NCOA4 SUMOylation regulates neuronal ferroptosis and suggest that targeting SENP2 or the SENP2–NCOA4 axis may represent a promising therapeutic direction for ischemic stroke.

General anesthesia (GA) induces reversible unconsciousness for surgery, yet mechanisms underlying bidirectional transitions of states of consciousness during GA remain largely unknown. Here, we focused on states of consciousness rather than contents of consciousness, which reflects the capacity for responsiveness to stimuli. Electroencephalography/electromyography was applied in both male and female mice to investigate states of consciousness during sevoflurane GA. We identified the population activity of glutamatergic neurons in the medial septum (MS) to change synchronously with altered states of consciousness during sevoflurane GA. Activation of glutamatergic MS neurons (MSVglut2) or their projections in the ventral tegmental area (VTA) facilitated behavioral emergence and cortical activation during sevoflurane GA, while their inhibition deepened cortical inhibition. Nevertheless, we further identified anesthetic state-dependent dual control of states of consciousness by monosynaptic innervations from MSVglut2 neurons to heterogeneous downstream VTA neurons. Specifically, optogenetic activation of MS-innervated glutamatergic VTA neurons promoted cortical activation during both continuous steady-state GA (CSSGA) and burst suppression (BS). With current stimulation protocol, optogenetic activation of MS-innervated dopaminergic VTA neurons promoted cortical activation mainly under CSSGA. Optogenetic activation of MS-innervated GABAergic VTA neurons enhanced cortical inhibition mainly under BS. Our findings reveal an anesthetic state-dependent mechanism where MSVglut2 neurons bidirectionally regulate states of consciousness through heterogeneous VTA neurons, providing insights to the complexity in the regulation of states of consciousness under GA.

Background The supramammillary nucleus (SuM), located in the caudal hypothalamus, includes wake-promoting glutamatergic neurones. Their potential role in regulating states of consciousness during general anaesthesia remains unknown. Methods We used in vivo fibre photometry, c-Fos staining, chemogenetic and optogenetic manipulations, and electroencephalography/electromyography to explore the roles of glutamatergic SuM neurones (SuMVglut2 neurones) at different phases of sevoflurane anaesthesia. Rabies-mediated retrograde and anterograde tract tracing were used to investigate the monosynaptic glutamatergic inputs from the medial septum (MS) to SuM. Their roles in sevoflurane anaesthesia were investigated by in vivo fibre photometry and optogenetic manipulations. Results The population activity of SuMVglut2 neurones decreased at loss of consciousness but increased during recovery of consciousness under sevoflurane anaesthesia. Their activity also decreased during suppression but increased during bursts in sevoflurane-induced burst-suppression oscillations. Activating SuMVglut2 neurones chemogenetically or optogenetically decreased sensitivity to sevoflurane, induced behavioural arousal and cortical activation during continuous steady-state anaesthesia, and stable burst-suppression oscillations under sevoflurane. In contrast, chemogenetic or optogenetic inhibition of SuMVglut2 neurones increased sensitivity to sevoflurane or intensified cortical inhibition during sevoflurane anaesthesia. Retrograde and anterograde tracing verified monosynaptic projections from MSVglut2 neurones to SuMVglut2 neurones. The activity of MSVglut2 SuM terminals increased during loss of consciousness but recovered during recovery of consciousness. Optogenetic activation or inhibition of MSVglut2 SuM terminals induced cortical activation or inhibition, respectively, during sevoflurane anaesthesia. Conclusions Activation of SuMVglut2 neurones or the glutamatergic septo-supramammillary circuit induces behavioural arousal and cortical activation during sevoflurane anaesthesia.

Resveratrol, a natural polyphenol with anti-inflammatory, antioxidant, and neuroprotective properties, shows great potential in managing chronic pain. This review explores its analgesic mechanisms, including the inhibition of neuroinflammation, enhancement of antioxidant activity, induction of autophagy, reduction of endoplasmic reticulum stress, modulation of the serotonin system, restoration of gut microbiota homeostasis, regulation of the neuroendocrine system, and promotion of mitochondrial biogenesis. While its analgesic potential is considerable, future research should prioritize enhancing its bioavailability, investigating drug interactions, and confirming long-term safety to develop more effective therapies for chronic pain.

BACKGROUND:Spinal muscular atrophy ( SMA ) is a rare genetic neuromuscular disorder characterized by progressive muscle atrophy and weakness. Nusinersen, the only US Food and Drug Administration-approved antisense oligonucleotide specifically for SMA management, is administered intrathecally. However, a substantial proportion of adult patients with SMA develop severe scoliosis, posing significant technical challenges for traditional lumbar puncture procedures. Real-time ultrasound guidance offers a potential solution for intrathecal nusinersen administration in these challenging cases. OBJECTIVES:We sought to evaluate the technical feasibility and safety profile of real-time, ultrasound-guided intrathecal delivery of nusinersen in adult patients with SMA and complex spinal anatomy, including those with scoliosis or vertebral hardware. STUDY DESIGN:Retrospective chart review. SETTING:This study was conducted at a single medical center. METHODS:The data were retrospectively collected from the medical records Of 26 adult patients with SMA who had challenging intrathecal access (scoliosis or vertebral hardware) and who underwent real-time ultrasound-guided intrathecal nusinersen administration. Real-time ultrasound-guided lumbar puncture was performed using either the paramedian sagittal oblique view translaminar approach or the coronal view transforaminal approach. Procedure time, technical success, and adverse events were noted. RESULTS:A total of 151 real-time, ultrasound-guided lumbar punctures were performed. All procedures were technically successful and well-tolerated. The mean procedure time for the paramedian sagittal oblique view translaminar approach was 10.5 ± 1.7 minutes for moderate scoliosis and 20.7 ± 9.3 minutes for severe scoliosis. The mean procedure time for the transforaminal approach, used when the paramedian sagittal oblique view translaminar approach was not feasible, was 22.5 ± 6.1 minutes. No severe adverse events were observed. LIMITATIONS:This was a retrospective, single-center study with a relatively small sample size. Generalizability may be limited. CONCLUSIONS:Real-time ultrasound-guided intrathecal administration of nusinersen is feasible and appears safe in adult patients with SMA and complex spinal anatomies. Further prospective, multi-center clinical trials are warranted to validate these findings and evaluate long-term safety and efficacy in a larger patient cohort.