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Diclofenac etalhyaluronate (DF-HA) sustained diclofenac release with the effects of hyaluronic acid (HA), offering long-term analgesia in osteoarthritis. In this study, the effects of DF-HA on pain improvement and osteoarthritis were evaluated in a rat knee monoiodoacetate-induced osteoarthritis model compared to HA. Eight rats per group had been injected with monoiodoacetate (2.0 mg) or saline in the right knee for 4 weeks and were injected with either DF-HA (1.25 mg/kg; 0.5 mg), HA (0.5 mg), vehicle which was a substrate without DF-HA (50 μL), or saline and followed for 4 weeks. Mechanical plantar skin sensitivity was assessed weekly using the von Frey assay. Osteoarthritis changes were monitored with Larsen scores via CT imaging at every 2 weeks. The articular cartilage was analyzed using OARSI scores through H&E, Safranin-O staining at 8 weeks. The percentage of Iba-1 positive microglia in the spinal dorsal horn and of FG + CGRP-labeled cells among FG-positive cells in the dorsal root ganglion were evaluated by immunohistochemical staining. TNF-α and IL-6 mRNA expression levels in the knee synovium were evaluated by PCR. The DF-HA showed significantly improved pain hypersensitivity compared with the HA at 6-8 weeks. The percentage of Iba-1-positive microglia was significantly lower than that in the vehicle and the percentage of FG + CGRP/FG was significantly lower than that in the HA. OARSI scores did not differ among treatment groups, Larsen scores indicated lower in the DF-HA than in the vehicle. DF-HA was as effective as HA in joint protection and significantly improved inflammatory pain compared to HA., (© 2024 Orthopaedic Research Society.)

The appearance of contralateral effects after unilateral injury has been shown in various experimental pain models, as well as in clinics. They consist of a diversity of phenomena in contralateral peripheral nerves, sensory ganglia, or spinal cord: from structural changes and altered gene or protein expression to functional consequences such as the development of mirror-image pain (MP). Although MP is a well-documented phenomenon, the exact molecular mechanism underlying the induction and maintenance of mirror-like spread of pain is still an unresolved challenge. MP has generally been explained by central sensitization mechanisms leading to facilitation of pain impulse transfer through neural connections between the two sides of the central nervous system. On the contrary, the peripheral nervous system (PNS) was usually regarded unlikely to evoke such a symmetrical phenomenon. However, recent findings provided evidence that events in the PNS could play a significant role in MP induction. This manuscript provides an updated and comprehensive synthesis of the MP phenomenon and summarizes the available data on the mechanisms. A more detailed focus is placed on reported evidence for peripheral mechanisms behind the MP phenomenon, which were not reviewed up to now., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract: Microglia take on an altered morphology during chronic opioid treatment. This morphological change is broadly used to identify the activated microglial state associated with opioid side effects, including tolerance and opioid-induced hyperalgesia (OIH). Microglia display similar morphological responses in the spinal cord after peripheral nerve injury (PNI). Consistent with this observation, functional studies have suggested that microglia activated by opioids or PNI engage common molecular mechanisms to induce hypersensitivity. In this article, we conducted deep RNA sequencing (RNA-seq) and morphological analysis of spinal cord microglia in male mice to comprehensively interrogate transcriptional states and mechanistic commonality between multiple models of OIH and PNI. After PNI, we identify an early proliferative transcriptional event across models that precedes the upregulation of histological markers of microglial activation. However, we found no proliferative transcriptional response associated with opioid-induced microglial activation, consistent with histological data, indicating that the number of microglia remains stable during morphine treatment, whereas their morphological response differs from PNI models. Collectively, these results establish the diversity of pain-associated microglial transcriptomic responses and point towards the targeting of distinct insult-specific microglial responses to treat OIH, PNI, or other central nervous system pathologies., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Abstract: Preclinical research supports a critical role for nervous system glia in pain pathophysiology. This systematic review of human trials of potential glia-modulating drugs for the prevention or treatment of pain followed a predefined search strategy and protocol registration. We searched for English language, randomized, double-blind trials comparing putative glia-modulating drugs to placebo or other comparators. The primary outcomes included validated participant-reported measures of pain intensity or relief and, in studies of opioid administration, measures of opioid consumption and/or opioid-related adverse effects. Twenty-six trials (2132 participants) of glial modulators (12 minocycline, 11 pentoxifylline, and 3 ibudilast) were included. Because of clinical heterogeneity related to study drug, participant population, outcome measures, and trial design, no meta-analysis was possible. Only 6 trials reported a positive effect of the treatment (pentoxifylline-4 trials; minocycline-2 trials), whereas 11 trials reported mixed results and 9 trials reported no effect. This review does not provide convincing evidence of efficacy of current pharmacological targets of nervous system glial function for pain treatment or prevention. However, in light of ample preclinical evidence of the importance of neuroimmune signalling and glial functions in pain pathophysiology, continued strategic human research is anticipated to identify (1) drugs with maximal activity as selectively targeted glial modulators, (2) the necessary timing and duration of pharmacological glial modulation needed for pain prevention or treatment for specific injuries or pain conditions, and (3) the best design of future clinical trials of glial-targeted drugs for pain treatment and/or prevention., (Copyright © 2024 International Association for the Study of Pain.)

Abstract: Nociplastic pain, characterized by abnormal pain processing without an identifiable organic cause, affects a significant portion of the global population. Unfortunately, current pharmacological treatments for this condition often prove ineffective, prompting the need to explore new potential targets for inducing analgesic effects in patients with nociplastic pain. In this context, toll-like receptors (TLRs), known for their role in the immune response to infections, represent promising opportunities for pharmacological intervention because they play a relevant role in both the development and maintenance of pain. Although TLRs have been extensively studied in neuropathic and inflammatory pain, their specific contributions to nociplastic pain remain less clear, demanding further investigation. This review consolidates current evidence on the connection between TLRs and nociplastic pain, with a specific focus on prevalent conditions like fibromyalgia, stress-induced pain, sleep deprivation-related pain, and irritable bowel syndrome. In addition, we explore the association between nociplastic pain and psychiatric comorbidities, proposing that modulating TLRs can potentially alleviate both pain syndromes and related psychiatric disorders. Finally, we discuss the potential sex differences in TLR signaling, considering the higher prevalence of nociplastic pain among women. Altogether, this review aims to shed light on nociplastic pain, its underlying mechanisms, and its intriguing relationship with TLR signaling pathways, ultimately framing the potential therapeutic role of TLRs in addressing this challenging condition., (Copyright © 2024 International Association for the Study of Pain.)

Background: Post-traumatic headache (PTH) is a common comorbid symptom affecting at least one-third of patients with mild traumatic brain injury (mTBI). While neuroinflammation is known to contribute to the development of PTH, the cellular mechanisms in the trigeminal system crucial for understanding the pathogenesis of PTH remain unclear. Methods: A non-invasive repetitive mTBI (4 times with a 24-h interval) was induced in male mice and effect of mTBI was tested on either bregma or pre-bregma position on the head. Periorbital allodynia and spontaneous pain behavior were assessed using von Frey test and grimace score, respectively. Quantitative PCR was used to assess extent of mTBI pathology. RNA sequencing was performed to obtain transcriptomic profile of the trigeminal ganglion (TG), trigeminal nucleus caudalis (Sp5C) and periaqueductal gray (PAG) at 7 days post-TBI. Subsequently, quantitative PCR, in situ hybridization and immunohistochemistry were used to examine mRNA and protein expression of glia specific markers and pain associated molecules. Results: The repetitive impacts at the bregma, but not pre-bregma site led to periorbital hypersensitivity, which was correlated with enhanced inflammatory gene expression in multiple brain regions. RNA sequencing revealed mTBI induced distinct transcriptomic profiles in the peripheral TG and central Sp5C and PAG. Using gene set enrichment analysis, positive enrichment of non-neuronal cells in the TG and neuroinflammation in the Sp5C were identified to be essential in the pathogenesis of PTH. In situ assays also revealed that gliosis of satellite glial cells in the TG and astrocytes in the Sp5C were prominent days after injury. Furthermore, immunohistochemical study revealed a close interaction between activated microglia and reactive astrocytes correlating with increased calretinin interneurons in the Sp5C. Conclusions: Transcriptomics analysis indicated that non-neuronal cells in peripheral TG and successive in situ assays revealed that glia in the central Sp5C are crucial in modulating headache-like symptoms. Thus, selective targeting of glia cells can be a therapeutic strategy for PTH attributed to repetitive mTBI. [ABSTRACT FROM AUTHOR]

Background: Abnormal sensory perception, particularly pain insensitivity (PAI), is a typical symptom of autism spectrum disorder (ASD). Despite the role of myelin metabolism in the regulation of pain perception, the mechanisms underlying ASD-related PAI remain unclear. Methods: The pain-associated gene sphingosine-1-phosphate receptor 1 (S1PR1) was identified in ASD samples through bioinformatics analysis. Its expression in the dorsal root ganglion (DRG) tissues of BTBR ASD model mice was validated using RNA-seq, western blot, RT-qPCR, and immunofluorescence. Pain thresholds were assessed using the von Frey and Hargreaves tests. Patch-clamp techniques measured KCNQ/M channel activity and neuronal action potentials. The expression of S1PR1, KCNQ/M, mitogen-activated protein kinase (MAPK), and cyclic AMP/protein kinase A (cAMP/PKA) signaling proteins was analyzed before and after inhibiting the S1P-S1PR1-KCNQ/M pathway via western blot and RT-qPCR. Results: Through integrated transcriptomic analysis of ASD samples, we identified the upregulated gene S1PR1, which is associated with sphingolipid metabolism and linked to pain perception, and confirmed its role in the BTBR mouse model of ASD. This mechanism involves the regulation of KCNQ/M channels in DRG neurons. The enhanced activity of KCNQ/M channels and the decreased action potentials in small and medium DRG neurons were correlated with PAI in a BTBR mouse model of ASD. Inhibition of the S1P/S1PR1 pathway rescued baseline insensitivity to pain by suppressing KCNQ/M channels in DRG neurons, mediated through the MAPK and cAMP/PKA pathways. Investigating the modulation and underlying mechanisms of the non-opioid pathway involving S1PR1 will provide new insights into clinical targeted interventions for PAI in ASD. Conclusions: S1PR1 may contribute to PAI in the PNS in ASD. The mechanism involves KCNQ/M channels and the MAPK and cAMP/PKA signaling pathways. Targeting S1PR1 in the PNS could offer novel therapeutic strategies for the intervention of pain dysesthesias in individuals with ASD. [ABSTRACT FROM AUTHOR]

With the National Institutes of Health's mandate to consider sex as a biological variable (SABV), there has been a significant increase of studies utilizing both sexes. Historically, we have known that biological sex and hormones influence immunological processes and now studies focusing on interactions between the immune, endocrine, and nervous systems are revealing sex differences that influence pain behavior and various molecular and biochemical processes. Neuroendocrine-immune interactions represent a key integrative discipline that will reveal critical processes in each field as it pertains to novel mechanisms in sex differences and necessary therapeutics. Here we appraise preclinical and clinical literature to discuss these interactions and key pathways that drive cell- and sex-specific differences in immunity, pain, and physiology. Plain English summary: In the last decade, NIH-funded basic and clinical research studies have been mandated to include sex as a biological variable, and this has resulted in a boom of studies discovering sex differences. We know that females are more likely than males to develop chronic pain conditions and experience higher levels of pain for longer periods of time. Conditions that demonstrate this include migraine, arthritis, and peripheral neuropathy. Furthermore, these sex differences extend to surgical outcomes and are observable at the molecular, cellular, and systemic levels. Although pain perception pathways differ by sex, studies are also focusing on differences in the "conversation" between the immune system and the nervous system while addressing implications of sex hormones to gain a better understanding of the impact on pain, physiology, and behavior. Lifestyle factors such as diet and alcohol consumption also play a role in affecting the perception and impact of pain conditions. As this area of research continues to grow, the development and availability of sex-specific treatment options will grow and lead to improved patient outcomes and more effective pain management strategies. Highlights: Immune cell types and molecular pathways drive sex specific differences in inflammatory and neuropathic pain. TLR4 involvement in pain pathways show contextual sex-specific variations and its interaction with TRPV1 channels adds complexity to nociceptor physiology. Female mice tend to exhibit stronger TRPV1-mediated pain responses compared to males due to estrogen enhancement of TRPV1 expression levels. The interplay between nuclear receptors (PPARγ, PPARα) and prolactin receptors influences sex-specific neuroimmune interactions. In males, PPARα impacts immune responses and neuroinflammation. In females, PPARγ activity influences pain perception and PRL influences pain sensitivity. Personalized approaches are needed for pain management in males and females due to sex differences in pain perception and treatment outcomes driven by variations in hormone levels, adiposity, and neuroimmune mechanisms of inflammation. [ABSTRACT FROM AUTHOR]

Background: Ocular pain is a prevalent symptom of dry eye disease (DED), which often accompanies potential psychological issues. The study aimed to explore whether acupuncture could improve ocular pain, mental state, and dry eye parameters in patients with DED. Methods: The non-randomized pilot study included 48 patients divided into two groups: the acupuncture group (n=27) and the 0.3% sodium hyaluronate (SH) group (n=21). Participants in the acupuncture group underwent treatments on six bilateral acupuncture points (BL1, BL2, ST1, LI 20, SI1 and SI3) 3 times per week for 4 weeks. Patients in the SH group received 0.3% SH 4 times per day for 4 weeks. Ocular pain was assessed using the numerical rating scale (NRS), and mental state was evaluated through the self-rating anxiety scale (SAS) and self-rating depression scale (SDS). Ocular surface parameters, concentrations of inflammatory cytokines, and corneal nerve morphological indicators were measured at baseline, the first week, and the fourth week. Randomization procedures were not used in this study, and outcome assessors and statistical analysts were blinded. Results: Compared with baseline, both NRS scores (from 5.91 ± 1.52 to 1.94 ± 1.57) and ocular surface discomfort index (OSDI) scores (from 49.75 ± 14.92 to 29.64 ± 18.79) were decreased after 1 and 4 weeks of treatment in both groups (all p < 0.05). At 4 weeks, the acupuncture group showed significant improvements, including increased tear break-up time (TBUT) and corneal perception, decreased SAS and SDS scores, and reduced concentrations of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α concentration in tears (all p < 0.05). These changes were not observed in the SH group (all p > 0.05). Conclusion: Acupuncture treatment could improve ocular surface characteristics in patients with DED, and more importantly, it alleviates their ocular pain and depressive state. The anti-inflammatory effect of acupuncture may be involved in this process. Future research with larger, randomized controlled trials (RCTs) is necessary to confirm these findings and clarify the mechanisms involved. [ABSTRACT FROM AUTHOR]

BACKGROUND: The role of environmental factors in Alzheimer’s disease (AD) pathogenesis remains elusive. Mounting evidence suggests that acute and past exposure to the environmental toxicant lead (Pb) is associated with longitudinal decline in cognitive function, brain atrophy, and greater brain β-amyloid (Aβ) deposition. However, the nature of Pb-induced amyloid deposition and how it contributes to AD development remain unclear. OBJECTIVES: This study investigates the role of Pb in the pathogenesis of cerebral amyloid angiopathy (CAA) and whether plasminogen activator inhibitor-1 (PAI-1) contributes to this process in the APP/PS1 mouse model. METHODS: Female APP/PS1 mice at 8 wk of age were administered either 50 mg/kg Pb-acetate (PbAc) (i.e., 27 mg Pb/kg) or an equivalent molar concentration of sodium acetate (NaAc) via oral gavage once daily for 8 wk. Amyloid deposition and vascular amyloid were determined by immunostaining. In addition, Aβ perivascular drainage, vascular binding assay, and microglial endocytosis were examined to determine underlying mechanisms. Furthermore, magnetic resonance imaging demyelination imaging was performed in vivo measure the level of demyelination. Finally, Y-maze and Morris water maze tests were assessed to evaluate the cognitive function of mice. RESULTS: APP/PS1 mice (an AD mice model) exposed to PbAc demonstrated more vascular amyloid deposition less neocortical myelination, and lower cognitive function, as well as greater vascular binding to Aβ40, higher Aβ40/Aβ42 ratios, strikingly lower Aβ40 levels in the perivascular drainage, and microglial endocytosis. Importantly, exposure to a specific PAI-1 inhibitor, tiplaxtinin, which previously was reported to lower CAA pathology in mice, resulted in less CAA-related outcomes following PbAc exposure. DISCUSSION: Our findings suggest that PbAc induced CAA/AD pathogenesis via the PAI-1 signaling in the APP/PS1 mouse model, and the inhibition of PAI-1 could be a potential therapeutic target for PbAc-mediated CAA/AD disorders. [ABSTRACT FROM AUTHOR]

Objective: Neuropathic pain can be provoked by high mobility group box 1 (HMGB1) activation of toll-like receptor (TLR)4/nuclear factor (NF)-κB signaling in the dorsal root ganglion (DRG). Electroacupuncture (EA) has been reported to effectively alleviate neuropathic pain with few side effects, but its precise mechanism of action remains unknown. The aim of this study was to explore whether 2 Hz EA stimulation suppresses TLR4/NF-κB signaling in the DRG following spared nerve injury (SNI) in a rat model. Methods: In this experiment, SNI rats were given 2 Hz EA once every other day for a total of 21 days. Paw withdrawal threshold (PWT) was measured to assess SNI-induced mechanical hypersensitivity, and western blotting and immunofluorescence staining were used to determine the levels of pain-related signaling molecules and pro-inflammatory mediators in the DRG. Results: SNI up-regulated HMGB1, TLR4, myeloid differentiation factor-88 adaptor protein (MyD88) and NF-κB p65 protein expression in the DRG. In addition, immunofluorescence staining demonstrated that SNI induced higher levels of TLR4 and MyD88 in the DRG. We also demonstrated co-localization of TLR4 and MyD88 with both calcitonin gene-related peptide (CGRP) and isolectin GS-IB4 in the DRG of SNI rats, respectively. Meanwhile, 2 Hz EA stimulation effectively reversed the elevations of HMGB1, TLR4, MyD88 and NF-κB p65 induced by SNI in the DRG, which was coupled with amelioration of SNI-induced mechanical hypersensitivity. Conclusions: The results of this study suggested that inhibition of the TLR4/NF-κB signaling pathway in the DRG by 2 Hz EA might be exploited as a therapeutic option for neuropathic pain. [ABSTRACT FROM AUTHOR]

The management of inflammatory states typically involves non-steroidal anti-inflammatory drugs (NSAIDs) and opiates. Understanding the mechanisms underlying the processing of nociceptive information from potential alternatives such as some polysaccharides may enable new and meaningful therapeutic approaches. In this study, α-D-mannan isolated from the Kluyveromyces marxianus cell wall produced antinociceptive effects in models of inflammatory pain (formalin and complete Freund's adjuvant tests). Furthermore, α-D-mannan reduced paw edema and interleukin-6 (IL-6) production after carrageenan-induced inflammation. The polysaccharide α-D-mannan was characterized by gas chromatography-mass spectrometry, methylation analysis, and spectroscopic techniques. Moreover, the Doehlert experimental design was applied to find the optimal conditions for biomass production, with the best conditions being 10.8 g/L and 117 h for the glucose concentration and the fermentation time, respectively. These results indicate that α-D-mannan from K. marxianus exerts anti-inflammatory and antinociceptive effects in mice, possibly via a mechanism dependent on the inhibition of IL-6 production., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

HIV-related neuropathic pain (HRNP) is a neurodegeneration that gradually develops during the long-term course of acquired immune deficiency syndrome (AIDS) and manifests as abnormal sock/sleeve-like symmetrical pain and nociceptive hyperalgesia in the extremities, which seriously reduces patient quality of life. To date, the pathogenesis of HRNP is not completely clear. There is a lack of effective clinical treatment for HRNP and it is becoming a challenge and hot spot for medical research. In this study, we conducted a systematic review of the progress of HRNP research in recent years including (1) the etiology, classification and clinical symptoms of HRNP, (2) the establishment of HRNP pathological models, (3) the pathological mechanisms underlying HRNP from three aspects: molecules, signaling pathways and cells, (4) the therapeutic strategies for HRNP, and (5) the limitations of recent HRNP research and the future research directions and prospects of HRNP. This detailed review provides new and systematic insight into the pathological mechanism of HRNP, which establishes a theoretical basis for the future exploitation of novel target drugs. HIV infection, antiretroviral therapy and opioid abuse contribute to the etiology of HRNP with symmetrical pain in both hands and feet, allodynia and hyperalgesia. The pathogenesis involves changes in cytokine expression, activation of signaling pathways and neuronal cell states. The therapy for HRNP should be patient-centered, integrating pharmacologic and nonpharmacologic treatments into multimodal intervention., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Physical symptoms and aversion induced by opioid withdrawal strongly affect the management of opioid addiction. YTH N6-methyladenosine (m6A) RNA binding protein 1 (YTHDF1), an m6A-binding protein, from the periaqueductal gray (PAG) reportedly contributes to morphine tolerance and hyperalgesia. However, the role of YTHDF1 in morphine withdrawal remains unclear. Methods: A naloxone-precipitated morphine withdrawal model was established in C57/BL6 mice or transgenic mice. YTHDF1 was knocked down via adeno-associated virus transfection. Combined with the results of the single-cell RNA sequencing analysis, the changes in morphine withdrawal somatic signs and conditioned place aversion (CPA) scores were compared when YTHDF1 originating from different neurons in the ventrolateral periaqueductal gray (vlPAG) was knocked down. We further explored the role of inflammatory factors and transcription factors related to inflammatory response in morphine withdrawal. Results: Our results revealed that YTHDF1 expression was upregulated in the vlPAG of mice with morphine withdrawal and that the knockdown of vlPAG YTHDF1 attenuated morphine withdrawal-related somatic signs and aversion. The levels of NF-κB and p-NF-κB were reduced after the inhibition of YTHDF1 in the vlPAG. YTHDF1 from vlPAG inhibitory neurons, rather than excitatory neurons, facilitated morphine withdrawal responses. The inhibition of YTHDF1 in vlPAG somatostatin (Sst)-expressing neurons relieved somatic signs of morphine withdrawal and aversion, whereas the knockdown of YTHDF1 in cholecystokinin (Cck)-expressing or parvalbumin (PV)-expressing neurons did not change morphine withdrawal-induced responses. The activity of c-fos + neurons, the intensity of the calcium signal, the density of dendritic spines, and the frequency of mIPSCs in the vlPAG, which were increased in mice with morphine withdrawal, were decreased with the inhibition of YTHDF1 from vlPAG inhibitory neurons or Sst-expressing neurons. Knockdown of NF-κB in Sst-expressing neurons also alleviated morphine withdrawal-induced responses. Conclusions: YTHDF1 originating from Sst-expressing neurons in the vlPAG is crucial for the modulation of morphine withdrawal responses, and the underlying mechanism might be related to the regulation of the expression and phosphorylation of NF-κB. [ABSTRACT FROM AUTHOR]

Focus on the implications of common perioperative drugs for mitochondrial quality control and their subsequent impact on the overall physiological condition has been increasing. This review discusses the effects of perioperative drugs, such as intravenous and inhaled anesthetics, analgesics, local anesthetics on mitochondrial quality and their underlying mechanisms. These drugs influence mitochondrial properties, including morphology, dynamics, energy metabolism, and protein expression, thereby affecting the clinical outcomes of patients undergoing surgery. Such effects can be either protective or detrimental and are contingent upon multiple variables such as the specific drug used, dosage, application timing, and the patient's overall health status. Recognizing the effects of these perioperative drugs on mitochondrial quality control is crucial to selecting safer anesthetic protocols, reducing postoperative complications, enhancing postoperative recovery, and gaining insights into the development of innovative treatment methodologies and optimization of perioperative care. [ABSTRACT FROM AUTHOR]

Background: Surgery is the primary treatment for non-small cell lung cancer (NSCLC), but microscopic residual disease may be unavoidable. Preclinical studies have shown that volatile anesthetics might suppress host immunity and promote a pro-malignant environment that supports cancer cell proliferation, migration, and angiogenesis, whereas propofol may preserve cell-mediated immunity and inhibit tumor angiogenesis. However, clinical evidence that propofol-based total intravenous anesthesia (TIVA) can reduce tumor recurrence after curative resection remains inconsistent due to the retrospective observational nature of previous studies. Therefore, we will test the hypothesis that the recurrence-free survival (RFS) after curative resection of NSCLC is higher in patients who received TIVA than volatile anesthetics (GAS) in this multicenter randomized trial. Methods: This double-blind, randomized trial will enroll patients at 22 international sites, subject to study registration, institutional review board approval, and patient written informed consent. Eligible patients are adult patients undergoing lung resection surgery with curative intent for NSCLC. Exclusion criteria will be contraindications to study drugs, American Society of Anesthesiologists physical status IV or higher, or preexisting distant metastasis or malignant tumor in other organs. At each study site, enrolled subjects will be randomly allocated into the TIVA and GAS groups with a 1:1 ratio. This pragmatic trial does not standardize any aspect of patient care. However, potential confounders will be balanced between the study arms. The primary outcome will be RFS. Secondary outcomes will be overall survival and complications within postoperative 7 days. Enrollment of 5384 patients will provide 80% power to detect a 3% treatment effect (hazard ratio of 0.83) at alpha 0.05 for RFS at 3 years. Discussion: Confirmation of the study hypothesis would demonstrate that a relatively minor and low-cost alteration in anesthetic management has the potential to reduce cancer recurrence risk in NSCLC, an ultimately fatal complication. Rejection of the hypothesis would end the ongoing debate about the relationship between cancer recurrence and anesthetic management. Trial registration: The study protocol was prospectively registered at the Clinical trials (https://clinicaltrials.gov, NCT06330038, principal investigator: Hyun Joo Ahn; date of first public release: March 25, 2024) before the recruitment of the first participant. [ABSTRACT FROM AUTHOR]

Patients with degenerative cervical myelopathy (DCM) experience structural and functional brain reorganization. However, few studies have investigated the influence of sex on cerebral alterations. The present study investigates the role of sex on brain functional connectivity (FC) and global network topology in DCM and healthy controls (HCs). The resting-state functional MRI data was acquired for 100 patients (58 males vs. 42 females). ROI-to-ROI FC and network topological features were characterized for each patient and HC. Group differences in FC and network topological features were examined. Compared to healthy counterparts, DCM males exhibited higher FC between vision-related brain regions, and cerebellum, brainstem, and thalamus, but lower FC between the intracalcarine cortex and frontal and somatosensory cortices, while DCM females demonstrated higher FC between the thalamus and cerebellar and sensorimotor regions, but lower FC between sensorimotor and visual regions. DCM males displayed higher FC within the cerebellum and between the posterior cingulate cortex (PCC) and vision-related regions, while DCM females displayed higher FC between frontal regions and the PCC, cerebellum, and visual regions. Additionally, DCM males displayed significantly greater intra-network connectivity and efficiency compared to healthy counterparts. Results from the present study imply sex-specific supraspinal functional alterations occur in patients with DCM. [ABSTRACT FROM AUTHOR]

Introduction: Ultrasound-guided percutaneous cryoneurolysis provides analgesia using cold temperatures to reversibly ablate peripheral nerves. Cryoneurolysis probes pass a gas through a small internal annulus, rapidly lowering the pressure and temperature, forming an ice ball to envelope the target nerve. Analgesia is compromised if a nerve is inadequately frozen, and laboratory studies suggest that pain may be paradoxically induced with a magnitude and duration in proportion with the incomplete ablation. We therefore investigated the relative effects of various factors that may contribute to the size of the ice ball and the effective cryoneurolysis zone., Methods: A cryoprobe was inserted into a piece of meat, a gas was passed through for 2 min, and the resulting ice ball width (cross-section) and length (axis parallel to the probe) were measured using ultrasound, with the temperature evaluated in nine concentric locations concurrently., Results: The factor with the greatest influence on ice ball size was probe gauge: in all probe types, a change from 18 to 14 increased ice ball width, length, and volume by up to 70%, 113%, and 512% respectively, with minimum internal temperature decreasing as much as from -5 to -32 °C. In contrast, alternating the type of meat (chicken, beef, pork) and the shape of the probe tip (straight, coudé) affected ice ball dimensions to a negligible degree. The ice ball dimensions and the zone of adequate temperature drop were not always correlated, and, even within a visualized ice ball, the temperature was often inadequate to induce Wallerian degeneration., Conclusions: Percutaneous probe design can significantly influence the effective cryoneurolysis zone; visualizing a nerve fully encompassed in an ice ball does not guarantee adequate treatment to induce the desired Wallerian degeneration because ice forms at temperatures between 0 and -20 °C, whereas only temperatures below -20 °C induce Wallerian degeneration. The correlation between temperatures in isolated pieces of meat and perfused human tissue remains unknown, and further research to evaluate these findings in situ appears highly warranted., (© 2023. The Author(s).)

Although treatable with antiretroviral therapy, HIV infection persists in people living with HIV (PLWH). It is well known that the HIV virus finds refuge in places for which antiretroviral medications do not reach therapeutic levels, mainly the CNS. It is clear that as PLWH age, the likelihood of developing HIV-associated neurological deficits increases. At the biochemical level neurological dysfunction is the manifestation of altered cellular function and ineffective intercellular communication. In this review, we examine how intercellular signaling in the brain is disrupted in the context of HIV. Specifically, the concept of how the blood-brain barrier can be a convergence point for crosstalk, is explored. Crosstalk between the cells of the neurovascular unit (NVU) (endothelium, pericytes, astrocytes, microglia and neurons) is critical for maintaining proper brain function. In fact, the NVU allows for rapid matching of neuronal metabolic needs, regulation of blood-brain barrier (BBB) dynamics for nutrient transport and changes to the level of immunosurveillance. This review invites the reader to conceptually consider the BBB as a router or convergence point for NVU crosstalk, to facilitate a better understanding of the intricate signaling events that underpin the function of the NVU during HIV associated neuropathology. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) represents a complex pathology within the central nervous system (CNS), leading to severe sensory and motor impairments. It activates various signaling pathways, notably the mitogen‐activated protein kinase (MAPK) pathway. Present treatment approaches primarily focus on symptomatic relief, lacking efficacy in addressing the underlying pathophysiological mechanisms. Emerging research underscores the significance of the MAPK pathway in neuronal differentiation, growth, survival, axonal regeneration, and inflammatory responses post‐SCI. Modulating this pathway post‐injury has shown promise in attenuating inflammation, minimizing apoptosis, alleviating neuropathic pain, and fostering neural regeneration. Given its pivotal role, the MAPK pathway emerges as a potential therapeutic target in SCI management. This review synthesizes current knowledge on SCI pathology, delineates the MAPK pathway's characteristics, and explores its dual roles in SCI pathology and therapeutic interventions. Furthermore, it addresses the existing challenges in MAPK research in the context of SCI, proposing solutions to overcome these hurdles. Our aim is to offer a comprehensive reference for future research on the MAPK pathway and SCI, laying the groundwork for targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation and oxidative stress can aggravate the progression of Alzheimer's disease (AD). Centella asiatica has been traditionally consumed for memory and cognition. The triterpenes (asiaticoside, madecassoside, asiatic acid, madecassic acid) have been standardized in the ethanolic extract of Centella asiatica (SECA). The bioactivity of the triterpenes in different solvent polarities of SECA is still unknown. Objective: In this study, the antioxidative and anti-neuroinflammatory effects of SECA and its fractions were explored on lipopolysaccharides (LPS)-induced microglial cells. Methods: HPLC measured the four triterpenes in SECA and its fractions. SECA and its fractions were tested for cytotoxicity on microglial cells using MTT assay. NO, pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), ROS, and MDA (lipid peroxidation) produced by LPS-induced microglial cells were measured by colorimetric assays and ELISA. Nrf2 and HO-1 protein expressions were measured using western blotting. Results: The SECA and its fractions were non-toxic to BV2 microglial cells at tested concentrations. The levels of NO, TNF-α, IL-6, ROS, and lipid peroxidation in LPS-induced BV2 microglial cells were significantly reduced (p < 0.001) by SECA and its fractions. SECA and some of its fractions can activate the Nrf2/HO-1 signaling pathway by significantly enhancing (p < 0.05) the Nrf2 and HO-1 protein expressions. Conclusions: This study suggests that the inhibitory activity of SECA and its fractions on pro-inflammatory and oxidative stress events may be the result of the activation of antioxidant defense systems. The potential of SECA and its fractions in reducing neuroinflammation and oxidative stress can be further studied as a potential therapeutic strategy for AD. [ABSTRACT FROM AUTHOR]

Specific Aim: Provide an overview of the literature addressing major areas pertinent to pain in transgender persons and to identify areas of primary relevance for future research. Methods: A team of scholars that have previously published on different areas of related research met periodically though zoom conferencing between April 2021 and February 2023 to discuss relevant literature with the goal of providing an overview on the incidence, phenotype, and mechanisms of pain in transgender patients. Review sections were written after gathering information from systematic literature searches of published or publicly available electronic literature to be compiled for publication as part of a topical series on gender and pain in the Frontiers in Pain Research. Results: While transgender individuals represent a significant and increasingly visible component of the population, many researchers and clinicians are not well informed about the diversity in gender identity, physiology, hormonal status, and gender-affirming medical procedures utilized by transgender and other gender diverse patients. Transgender and cisgender people present with many of the same medical concerns, but research and treatment of these medical needs must reflect an appreciation of how differences in sex, gender, gender-affirming medical procedures, and minoritized status impact pain. Conclusions: While significant advances have occurred in our appreciation of pain, the review indicates the need to support more targeted research on treatment and prevention of pain in transgender individuals. This is particularly relevant both for gender-affirming medical interventions and related medical care. Of particular importance is the need for large longterm follow-up studies to ascertain best practices for such procedures. A multi-disciplinary approach with personalized interventions is of particular importance to move forward. [ABSTRACT FROM AUTHOR]

The tricarboxylic acid (TCA) cycle metabolite fumarate nonenzymatically reacts with the amino acid cysteine to form S-(2-succino) cysteine (2SC), referred to as protein succination. The immunometabolite itaconate accumulates during lipopolysaccharide (LPS) stimulation of macrophages and microglia. Itaconate nonenzymatically reacts with cysteine residues to generate 2,3-dicarboxypropylcysteine (2,3-DCP), referred to as protein dicarboxypropylation. Since fumarate and itaconate levels dynamically change in activated immune cells, the levels of both 2SC and 2,3-DCP reflect the abundance of these metabolites and their capacity to modify protein thiols. We generated ethyl esters of 2SC and 2,3-DCP from protein hydrolysates and used stable isotope dilution mass spectrometry to determine the abundance of these in LPS-stimulated Highly Aggressively Proliferating Immortalized (HAPI) microglia. To quantify the stoichiometry of the succination and dicarboxypropylation, reduced cysteines were alkylated with iodoacetic acid to form S-carboxymethylcysteine (CMC), which was then esterified. Itaconate-derived 2,3-DCP, but not fumarate-derived 2SC, increased in LPS-treated HAPI microglia. Stoichiometric measurements demonstrated that 2,3-DCP increased from 1.57% to 9.07% of total cysteines upon LPS stimulation. This methodology to simultaneously distinguish and quantify both 2SC and 2,3-DCP will have broad applications in the physiology of metabolic diseases. In addition, we find that available anti-2SC antibodies also detect the structurally similar 2,3-DCP, therefore "succinate moiety" may better describe the antigen recognized. [ABSTRACT FROM AUTHOR]

Vincristine, an alkaloid extracted from Catharanthus rosea, is a class of chemotherapy drugs that act by altering the function of the microtubules and by inhibiting mitosis. Despite its widespread application, a major adverse effect of vincristine that limits treatment duration is the occurrence of peripheral neuropathy (PN). PN presents with several symptoms including numbness, painful sensation, tingling, and muscle weakness. Vincristine-induced PN involves impaired calcium homeostasis, an increase of reactive oxygen species (ROS), and the upregulation of tumor necrosis factor-alpha (TNF-α), and interleukin 1 beta (IL-1β) expression. Several potential approaches to attenuate the vincristine-induced PN including the concomitant administration of chemicals with vincristine have been reported. These chemicals have a variety of pharmaceutical properties including anti-inflammation, antioxidant, and inhibition of calcium channels and calcineurin signaling pathways and increased expression of nerve growth factor (NGF). This review summarized several of these compounds and the mechanisms of action that could lead to effective options in improving vincristine-induced peripheral neuropathy (VIPN)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study aims to elucidate the key regulatory molecules, specifically messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and microRNAs (miRNAs) and their roles in the development and progression of spinal cord injury (SCI). Expression profiles (GSE45006, GSE19890, and GSE125630) for SCI were sourced from the Gene Expression Omnibus (GEO) database. By comparing rats with SCI at various time points against those without SCI, we identified differentially expressed mRNAs (DEmRNAs), lncRNAs (DElncRNAs), and miRNAs (DEmiRNAs). The GSE45006 dataset facilitated the production of DEmRNAs, which were then clustered using Mfuzz. Subsequently, we constructed a protein-protein interaction (PPI) network and anticipated interaction pairs between miRNA-mRNA and lncRNA-mRNA. These pairs were instrumental in forming a regulatory network involving lncRNA-miRNA-mRNA interactions. Additionally, we conducted functional enrichment studies on the DEmRNAs within these gene networks. A total of 2313 DEmRNAs were identified using the GSE45006 dataset, alongside 111 DEmiRNAs from GSE19890. From GSE125630, we extracted 154 DElncRNAs and 2322 DEmRNAs. Our analysis revealed 294 up-regulated DEmRNAs, grouped into the up-cluster, and 407 down-regulated DEmRNAs, forming the down-cluster. Key hub genes in the PPI network, such as Rhof, Vav1, Lyz2, Rab3a, Lyn, Cyfip1, Gns, and Nckap1l, were identified. Additionally, the study successfully constructed a competing endogenous RNA (ceRNA) network, revealing 55 unique lncRNA-miRNA-mRNA link pairs. Our research established a ceRNA network associated with SCI, identifying several critical lncRNA-miRNA-mRNA connection pairs integral to the disease's onset and progression. Notably, significant associations, including the AABR07041411.1-miR-125a-5p-Slc4a7 and the Smg1-rno-miR-331-3p-Tlr4 pairs, were observed to exert a significant influence within this biological context., Competing Interests: Declarations. Ethics Approval and Consent to Participate: All animal experiments were carried out in accordance with the guidelines and regulations approved by the Ethics Committee of The Second Hospital of Jilin University. All methods were carried out in accordance with relevant guidelines and regulations. All methods are reported in accordance with ARRIVE guidelines. Consent for Publication: Not applicable. Conflict of Interest: The author declares no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Approximately 50% of patients with chronic neuropathic pain experience cognitive impairment, which negatively impacts their quality of life. The cannabinoid type 2 receptor (CB2R) may be involved in hippocampal cognitive processes. However, its role in chronic neuropathic pain-induced cognitive impairment remains elusive. Spared nerve injury (SNI) was used to induce chronic neuropathic pain in rats, while the novel-object recognition test and the Y-maze test were employed to assess cognitive function. Immunofluorescence, western blotting, and stereotaxic hippocampal microinjection were utilized to elucidate the potential mechanisms. We observed a reduction in mechanical pain threshold and cognitive impairment in SNI rats. This was accompanied by a tendency for hippocampal microglia to adopt pro-inflammatory functions. Notably, no changes were detected in CB2R expression. However, downregulation of the endogenous ligands AEA and 2-AG was evident. Hippocampal microinjection of a CB2R agonist mitigated cognitive impairment in SNI rats, which correlated with a tendency for microglia to adopt anti-inflammatory functions. Additionally, SNI-induced activation of the p-ERK/NFκB pathway in the hippocampus. Activation of CB2R reversed this process by upregulating DUSP6 expression in microglia. The effects elicited by CB2R activation could be inhibited through the downregulation of microglial DUSP6 via hippocampal adeno-associated virus (AAV) microinjection. Conversely, overexpression of hippocampal DUSP6 using AAV ameliorated the cognitive deficits observed in SNI rats, which remained unaffected by the administration of a CB2R antagonist. Our findings demonstrate that activation of hippocampal CB2R can mitigate chronic neuropathic pain-induced cognitive impairment through the modulation of the DUSP6/ERK/NFκB pathway., (© 2024 Federation of American Societies for Experimental Biology.)

Neuropathic pain is a prevalent and debilitating condition experienced by the majority of individuals with spinal cord injury (SCI). The complex pathophysiology of neuropathic pain, involving continuous activation of microglia and astrocytes, reactive gliosis, and altered neuronal plasticity, poses significant challenges for effective treatment. This review focuses on the pivotal roles of microglia and astrocytes, the two major glial cell types in the central nervous system, in the development and maintenance of neuropathic pain after SCI. We highlight the extensive bidirectional interactions between these cells, mediated by the release of inflammatory mediators, neurotransmitters, and neurotrophic factors, which contribute to the amplification of pain signaling. Understanding the microglia-astrocyte crosstalk and its impact on neuronal function is crucial for developing novel therapeutic strategies targeting neuropathic pain. In addition, this review discusses the fundamental biology, post-injury pain roles, and therapeutic prospects of microglia and astrocytes in neuropathic pain after SCI and elucidates the specific signaling pathways involved. We also speculated that the extracellular matrix (ECM) can affect the glial cells as well. Furthermore, we also mentioned potential targeted therapies, challenges, and progress in clinical trials, as well as new biomarkers and therapeutic targets. Finally, other relevant cell interactions in neuropathic pain and the role of glial cells in other neuropathic pain conditions have been discussed. This review serves as a comprehensive resource for further investigations into the microglia-astrocyte interaction and the detailed mechanisms of neuropathic pain after SCI, with the aim of improving therapeutic efficacy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chronic post-thoracotomy pain (CPTP) is a major clinical problem that affects up to 35-55% of patients undergoing thoracic incisions. Evidence suggests that multiple cellular signaling pathways and neuro-inflammatory mediators may play an essential role in the pathogenesis of CPTP. In this comprehensive review, we present the current evidence on the cellular signaling pathways and inflammatory changes associated with the initiation and maintenance of CPTP, focusing on the potential application of these findings in the clinical setting. An electronic search of Medline, EMBASE, Cochrane, Google Scholar, and ClinicalTrials.gov was performed, and 3652 abstracts were identified. After an initial abstract screening, 131 studies underwent a full-text review, and nine papers were eventually included in this review. Studies were included if they assessed the cellular signaling pathways or inflammatory processes associated with the induction and/or maintenance of CPTP. All the identified studies were pre-clinical studies conducted on animal models. Our search identified seven cellular pathways (NK-1 receptor (NK-1), Glutaminase 1, Toll-like receptor 4 (TLR4), Resolvins, Ror-2, Sonic hedgehog signaling (Shh), and Wnt5a/Wnts) and six cytokines (IL-1β, IL-6, IL-8, IL-10, IFN-γ, and TNF-α) that were investigated in the context of CPTP. Multiple cellular signaling pathways and inflammatory cytokines may play an important role in the neuroinflammatory changes associated with the induction and maintenance of chronic post-thoracotomy pain in animal models. However, the clinical impact and therapeutic utility of these neuroinflammatory changes in routine clinical practice have yet to be demonstrated., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chemotherapy-induced peripheral neuropathy (CIPN) affects a significant majority of cancer patients, with up to 80% experiencing this severe and dose-limiting side effect while undergoing anti-cancer treatment. CIPN can be induced by a variety of drugs commonly employed in the management of both solid tumors and hematologic cancers. The inadequacies in comprehending the pharmacological interventions associated with CIPN and the subsequent signaling pathways have significantly contributed to the disappointing outcomes of several drugs in clinical trials. Recent investigations in pain research have demonstrated a growing inclination toward addressing neuro-inflammation as a strategy for managing chronic pain conditions. Notably, toll-like receptor-4 (TLR-4) has emerged as a key player in immune system activation and is undergoing extensive research. In this review, we emphasize the potential role of TLR-4 in neuropathic pain, highlighting its promise as a target for CIPN treatment. Furthermore, we explore and analyse the intricate interplay between TLR-4, diverse immune cells, downstream pathways, and receptors within the context of CIPN. A comprehensive exploration of these interactions provides valuable insights into the central role of TLR-4 in CIPN development, paving the way for potential ground-breaking therapeutic approaches to alleviate this debilitating condition., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The nervous and immune systems are the primary sensory interfaces of the body, allowing it to recognize, process, and respond to various stimuli from both the external and internal environment. These systems work in concert through various mechanisms of neuro-immune crosstalk to detect threats, provide defense against pathogens, and maintain or restore homeostasis, but can also contribute to the development of diseases. Among peripheral sensory neurons (PSNs), nociceptive PSNs are of particular interest. They possess a remarkable capability to detect noxious stimuli in the periphery and transmit this information to the brain, resulting in the perception of pain and the activation of adaptive responses. Pain is an early symptom of cancer, often leading to its diagnosis, but it is also a major source of distress for patients as the disease progresses. In this review, we aim to provide an overview of the mechanisms within tumors that are likely to induce cancer pain, exploring a range of factors from etiological elements to cellular and molecular mediators. In addition to transmitting sensory information to the central nervous system, PSNs are also capable, when activated, to produce and release neuropeptides (e.g., CGRP and SP) from their peripheral terminals. These neuropeptides have been shown to modulate immunity in cases of inflammation, infection, and cancer. PSNs, often found within solid tumors, are likely to play a significant role in the tumor microenvironment, potentially influencing both tumor growth and anti-tumor immune responses. In this review, we discuss the current state of knowledge about the degree of sensory innervation in tumors. We also seek to understand whether and how PSNs may influence the tumor growth and associated antitumor immunity in different mouse models of cancer. Finally, we discuss the extent to which the tumor is able to influence the development and functions of the PSNs that innervate it. [ABSTRACT FROM AUTHOR]

Abstract: The peripheral inflammatory response is an attractive therapeutic target for pain treatment. Neutrophils are the first circulating inflammatory cells recruited to sites of injury, but their contribution to pain outcomes is unclear. We performed a systematic review and meta-analysis of original preclinical studies, which evaluated the effect of preemptive neutrophil depletion on pain outcomes (PROSPERO registration number: CRD42022364004). Literature search (PubMed, January 19, 2023) identified 49 articles, which were meta-analyzed using a random-effects model. The risk of bias was evaluated using SYRCLE's tool. The pooled effect considering all studies showed that neutrophil depletion induced a consistent pain reduction. Inflammatory, joint, neuropathic, and visceral pain showed significant pain alleviation by neutrophil depletion with medium-large effect sizes. However, muscle and postoperative pain were not significantly alleviated by neutrophil depletion. Further analysis showed a differential contribution of neutrophils to pain outcomes. Neutrophils had a higher impact on mechanical hyperalgesia, followed by nociceptive behaviors and mechanical allodynia, with a smaller contribution to thermal hyperalgesia. Interspecies (mice or rats) differences were not appreciated. Analyses regarding intervention unveiled a lower pain reduction for some commonly used methods for neutrophil depletion, such as injection of antineutrophil serum or an anti-Gr-1 antibody, than for other agents such as administration of an anti-Ly6G antibody, fucoidan, vinblastine, CXCR1/2 inhibitors, and etanercept. In conclusion, the contribution of neutrophils to pain depends on pain etiology (experimental model), pain outcome, and the neutrophil depletion strategy. Further research is needed to improve our understanding on the mechanisms of these differences., (Copyright © 2024 International Association for the Study of Pain.)

Complete Freund's adjuvant (CFA) is used as a standard adjuvant for the induction of experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model in multiple sclerosis studies. Still, CFA induces glial activation and neuroinflammation on its own and provokes pain. In addition, as CFA contains Mycobacteria, an immune response against bacterial antigens is induced in parallel to the response against central nervous system antigens. Thus, CFA can be considered as a confounding factor in multiple sclerosis-related studies performed on EAE. Here, we discuss the effects of CFA in EAE in detail and present EAE variants induced in experimental animals without the use of CFA. We put forward CFA-free EAE variants as valuable tools for studying multiple sclerosis pathogenesis and therapeutic approaches. [ABSTRACT FROM AUTHOR]

Spinal cord injury is a severe neurological trauma that can frequently lead to neuropathic pain. During the initial stages following spinal cord injury, inflammation plays a critical role; however, excessive inflammation can exacerbate pain. Regulatory T cells (Treg cells) have a crucial function in regulating inflammation and alleviating neuropathic pain. Treg cells release suppressor cytokines and modulate the function of other immune cells to suppress the inflammatory response. Simultaneously, inflammation impedes Treg cell activity, further intensifying neuropathic pain. Therefore, suppressing the inflammatory response while enhancing Treg cell regulatory function may provide novel therapeutic avenues for treating neuropathic pain resulting from spinal cord injury. This review comprehensively describes the mechanisms underlying the inflammatory response and Treg cell regulation subsequent to spinal cord injury, with a specific focus on exploring the potential mechanisms through which Treg cells regulate neuropathic pain following spinal cord injury. The insights gained from this review aim to provide new concepts and a rationale for the therapeutic prospects and direction of cell therapy in spinal cord injury-related conditions. [ABSTRACT FROM AUTHOR]

Rationale: The endocannabinoid system (ECS) belongs to the G protein-coupled receptor family of cell membranes and is associated with neuropsychiatric conditions, and neurodegenerative diseases. Cannabinoid 2 receptors (CB2) are expressed in the central nervous system (CNS) on microglia and subgroups of neurons and are involved in various behavioural processes via immunological and neural regulation., Objective: The objective of this paper is to summarize and explore the impact of CB2 receptors on neuronal modulation, their involvement in various neurological disorders, and their influence on mood, behavior, and cognitive function., Results: The activation of CB2 appears to protect the brain and its functions from damage under neuroinflammatory actions, making it an attractive target in a variety of neurological conditions such as Parkinson's disease (PD), multiple sclerosis (MS), Alzheimer's disease (AD), and Huntington's disease (HD). During inflammation, there is an overexpression of CB2 receptors, and CB2 agonists show a strong anti-inflammatory effect. These results have sparked interest in the CB2 receptors as a potential target for neurodegenerative and neuroinflammatory disease treatment., Conclusion: In conclusion, CB2 receptors signalling shows promise for developing targeted interventions that could positively affect both immune and neuronal functions, ultimately influencing behavioral outcomes in both health and disease., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Spinal cord injury (SCI) remained one of the challenges to treat due to its complicated mechanisms. Photobiomodulation therapy (PBMT) accelerates neuronal regeneration. Cerium oxide nanoparticles (CeONPs) also eliminate free radicals in the environment. The present study aims to introduce a combined treatment method of making PCL scaffolds as microenvironments, seeded with CeONPs and the PBMT technique for SCI treatment. Methods: The surgical hemi-section was used to induce SCI. Immediately after the SCI induction, the scaffold (Sc) was loaded with CeONPs implanted. PBMT began 30 min after SCI induction and lasted for up to 4 weeks. Fifty-six male rats were randomly divided into seven groups. Glial fibrillary acidic protein (GFAP) (an astrocyte marker), Connexin 43 (Con43) (a member of the gap junction), and gap junctions (GJ) (a marker for the transfer of ions and small molecules) expressions were evaluated. The behavioral evaluation was performed by BBB, Acetone, Von Frey, and radiant heat tests. Result: The SC + Nano + PBMT group exhibited the most remarkable recovery outcomes. Thermal hyperalgesia responses were mitigated, with the combined approach displaying the most effective relief. Mechanical allodynia and cold allodynia responses were also attenuated by treatments, demonstrating potential pain management benefits. Conclusion: These findings highlight the potential of PBMT, combined with CeONPs-loaded scaffolds, in promoting functional motor recovery and alleviating pain-related responses following SCI. The study underscores the intricate interplay between various interventions and their cumulative effects, informing future research directions for enhancing neural repair and pain management strategies in SCI contexts. [ABSTRACT FROM AUTHOR]