Progress in study on animal models of trigeminal neuralgia. / ä¸‰å‰ç¥žç»ç—›åŠ¨ç‰©æ¨¡åž‹çš„ç ”ç©¶è¿›å±•.

Trigeminal neuralgia is a manifestation of orofacial neuropathic pain disorder, always deemed to be an insurmountable peak in the field of pain research and treatment. The pain is recurrent, abrupt in onset and termination similar to an electric shock or described as shooting. A poor quality of life has been attributed to trigeminal neuralgia, as the paroxysms of pain may be triggered by innocuous stimuli on the face or inside the oral cavity, such as talking, washing face, chewing and brushing teeth in daily life. The pathogenesis of trigeminal neuralgia has not been fully elucidated, although the microvascular compression in the trigeminal root entry zone is generally considered to be involved in the emergence and progression of the pain disorder. In addition, orofacial neuropathic pain restricted to one or more divisions of the trigeminal nerve might be secondary to peripheral nerve injury. Based on current hypotheses regarding the potential causes, a variety of animal models have been designed to simulate the pathogenesis of trigeminal neuralgia, including models of compression applied to the trigeminal nerve root or trigeminal ganglion, chronic peripheral nerve injury, peripheral inflammatory pain and center-induced pain. However, it has not yet been possible to determine which model can be perfectly employed to explain the mechanisms. The selection of appropriate animal models is of great significance for the study of trigeminal neuralgia. Therefore, it is necessary to discuss the characteristics of the animal models in terms of animal strains, materials, operation methods and behavior observation, in order to gain insight into the research progress in animal models of trigeminal neuralgia. In the future, animal models that closely resemble the features of human trigeminal neuralgia pathogenesis need to be developed, with the aim of making valuable contributions to the relevant basic and translational medical research.

Inhibition of the glutamatergic PVT-NAc projections attenuates local anesthetic-induced neurotoxic behaviors.

INTRODUCTION: Local anesthetic-induced neurotoxicity contributes to perioperative nerve damage; however, the underlying mechanisms remain unclear. Here, we investigated the role of the paraventricular thalamus (PVT)-nucleus accumbens (NAc) projections in neurotoxicity induced by ropivacaine, a local anesthetic agent. METHODS: Ropivacaine (58 mg/kg, intraperitoneal administration) was used to construct the local anesthetic systemic toxicity (LAST) mice model. We first identified neural projections from the PVT to the NAc through the expression of a retrograde tracer and virus. The inhibitory viruses (rAAV-EF1α-DIO-hm4D(Gi)-mCherry-WPREs: AAV2/retro and rAAV-CaMKII-CRE-WPRE-hGh: AAV2/9) were injected into the mice model to assess the effects of the specific inhibition of the PVT-NAc pathway on neurological behaviors in the presence of clozapine-N-oxide. The inhibition of the PVT-NAc pathway was evaluated by immunofluorescence staining of c-Fos-positive neurons and Ca2+ signals in CaMKIIa neurons. RESULTS: We successfully identified a circuit connecting the PVT and NAc in C57BL/6 mice. Ropivacaine administration induced the activation of the PVT-NAc pathway and seizures. Specific inhibition of NAc-projecting CaMKII neurons in the PVT was sufficient to inhibit the neuronal activity in the NAc, which subsequently decreased ropivacaine-induced neurotoxicity. CONCLUSION: These results reveal the presence of a dedicated PVT-NAc circuit that regulates local anesthetic-induced neurotoxicity and provide a potential mechanistic explanation for the treatment and prevention of LAST.

Causal relationship of gut microbiota and metabolites on cognitive performance: A mendelian randomization analysis.

Emerging evidence has indicated that the alterations in gut microbiota and metabolites are associated with cognitive performance. However, whether these associations imply a causal relationship remains to be definitively established. Here, we conducted two-sample mendelian randomization (MR) studies to explore the causal effects of gut microbiota and metabolites on cognitive performance, using large-scale genome-wide association studies (GWASs). We identified seven positive causalities between host genetic-driven gut microbiota and cognitive performance, including Class Clostridia (p = 0.0002), Order Clostridiales (p = 8.12E-05), Family Rhodospirillaceae (p = 0.042) and Ruminococcustorquesgroup (p = 0.030), Dialister (p = 0.027), Paraprevotella (p = 0.037) and RuminococcaceaeUCG003 (p = 0.007) at the genus level. Additionally, a total of four higher abundance of gut microbiota traits were identified to be negatively related to cognitive performance, including genus Blautia (p = 0.013), LachnospiraceaeFCS020group (p = 0.035), LachnospiraceaeNK4A136group (p = 0.034) and Roseburia (p = 0.00016). In terms of plasma metabolites, we discovered eight positive and six negative relationships between genetic liability in metabolites and cognitive performance (all p < 0.05). No evidence was detected across a series of sensitivity analyses, including pleiotropy and heterogeneity. Collectively, our MR analyses revealed that gut microbiota and metabolites were causally connected with cognitive performance, which holds significant potential for shedding light on the early detection and diagnosis of cognitive impairment, offering valuable insights into this area of research.

Advances of perioperative acute kidney injury in elderly patients undergoing non-cardiac surgery. / è€å¹´æ‚£è€ éžå¿ƒè„æ‰‹æœ¯å›´æ‰‹æœ¯æœŸæ€¥æ€§è‚¾æŸä¼¤çš„ç ”ç©¶è¿›å±•.

The risk of developing perioperative acute kidney injury (AKI) in elderly patients increases with age. The combined involvement of aging kidneys, coexisting multiple underlying chronic diseases, and increased exposure to potential renal stressors and nephrotoxic drugs or invasive procedures constitute susceptibility factors for AKI in elderly patients. The perioperative AKI in elderly patients undergoing noncardiac surgery has its own specific population characteristics, so it is necessary to further explore the characteristics of AKI in elderly patients in terms of epidemiology, clinical diagnosis, risk factors, and preventive and curative measures to provide meaningful clinical advice to improve prognosis, accelerate recovery, and reduce medical burden in elderly patients. Since AKI has the fastest-growing incidence in older patients and is associated with a worse prognosis, early detection, early diagnosis, and prevention of AKI are important for elderly patients in the perioperative period. Large, multicenter, randomized controlled clinical studies in elderly non-cardiac surgery patients with AKI can be conducted in the future, with the aim of providing the evidence to reduce of the incidence of AKI and to improve the prognosis of patients.

Prenatal anesthetic exposure and offspring neurodevelopmental outcomes-A narrative review.

While it is common for pregnant women to take anesthesia during surgery, the effects of prenatal anesthesia exposure (PAE) on the long-term neurodevelopment of the offspring remain to be clarified. Preclinical animal research has shown that in utero anesthetic exposure causes neurotoxicity in newborns, which is mainly characterized by histomorphological changes and altered learning and memory abilities. Regional birth cohort studies that are based on databases are currently the most convenient and popular types of clinical studies. Specialized questionnaires and scales are usually employed in these studies for the screening and diagnosis of neurodevelopmental disorders in the offspring. The time intervals between the intrauterine exposure and the onset of developmental outcomes often vary over several years and accommodate a large number of confounding factors, which have an even greater impact on the neurodevelopment of the offspring than prenatal anesthesia itself. This narrative review summarized the progress in prenatal anesthetic exposure and neurodevelopmental outcomes in the offspring from animal experimental research and clinical studies and provided a brief introduction to assess the neurodevelopment in children and potential confounding factors.

The correlation of intraoperative oliguria with acute kidney injury after noncardiac surgery: a systematic review and meta-analysis.

BACKGROUND: Acute kidney injury (AKI) occurs commonly after major surgery and is correlated with increased in-hospital morbidity and mortality. There is no consensus on whether intraoperative oliguria affects postoperative AKI. We conducted a meta-analysis to systematically assess the correlation of intraoperative oliguria with postoperative AKI. METHODS: PubMed, Embase, Web of Science, and Cochrane Library databases were searched to identify reports on the relationship between intraoperative oliguria and postoperative AKI. Quality was assessed using the Newcastle-Ottawa Scale. The primary outcomes were the unadjusted and multivariate-adjusted odds ratios (ORs) for intraoperative oliguria to correlate with postoperative AKI. The secondary outcomes included intraoperative urine output in the AKI and non-AKI groups, the demand for postoperative renal replacement therapy (RRT), in-hospital mortality, and length of hospital stay in the oliguria and non-oliguria groups. RESULTS: Nine eligible studies with 18 473 patients were included. The meta-analysis revealed that patients with intraoperative oliguria had a considerably greater risk of postoperative AKI (unadjusted OR: 2.03, 95% CI: 1.60-2.58, I2 =63%, P <0.00001; multivariate-adjusted OR: 2.00, 95% CI: 1.64-2.44, I2 =40%, P <0.00001). Further subgroup analysis did not find differences between different oliguria criteria or surgical types. Furthermore, the AKI group's pooled intraoperative urine output was less (mean differences: -0.16, 95% CI: -0.26 to -0.07, P <0.001). Intraoperative oliguria was associated with increased demand for postoperative RRT (risk ratios: 4.71, 95% CI: 2.83-7.84, P <0.001) and in-hospital mortality (risk ratios: 1.83, 95% CI: 1.24-2.69, P =0.002), but not with prolonged length of hospital stay (mean differences: 0.55, 95% CI: -0.27 to 1.38, P =0.19). CONCLUSIONS: Intraoperative oliguria was significantly associated with a higher incidence of postoperative AKI, as well as increased in-hospital mortality and demand for postoperative RRT, but not with prolonged hospitalization.

CircRalgapa1 facilitates morphine tolerance via miR-873a-5p/A20 axis in mice.

Morphine tolerance (MT) caused by long-term use of morphine is a major medical problem. The underlying molecular mechanisms of morphine tolerance remain unclear. Here, we establish the morphine tolerance model in mice and verify whether a novel circRNA, circRalgapa1 is involved in morphine tolerance and its specific molecular mechanism. We show that the expression of circRalgapa1 in the spinal cord is significantly down-expressed in the spinal cord of morphine-tolerant mice. CircRalgapa1 is mainly located in the neuronal cytoplasm and co-localizes with miR-873a-5p. Mechanically, circRalgapa1 acts as competing endogenous RNAs (ceRNAs) to regulate the inhibitory of miR-873a-5p on A20 (also known as tumor necrosis factor α-induced protein 3, TNFAIP3). Functionally, overexpression of circRalgapa1 by intrathecal injection of adeno-associated virus (AAV- circRalgapa1) attenuated the formation of morphine tolerance and partially reversed the development of morphine tolerance. Moreover, overexpression of miR-873a-5p blocked the effect of AAV-circRalgapa1 on alleviating morphine tolerance in mice. In conclusion, chronic morphine administration-mediated down-regulation of circRalgapa1 in the spinal cord contributes to morphine tolerance via miR-873a-5p/A20 axis in mice. Overexpression of circRalgapa1 may be a promising RNA-based therapy for morphine tolerance.

Noncoding RNAs: Novel Targets for Opioid Tolerance.

As a global health problem, chronic pain is one of the leading causes of disability, and it imposes a huge economic and public health burden on families and society. Opioids represent the cornerstone of analgesic drugs. However, opioid tolerance caused by long-term application of opioids is a major factor leading to drug withdrawal, serious side effects caused by dose increases, and even the death of patients, placing an increasing burden on individuals, medicine, and society. Despite efforts to develop methods to prevent and treat opioid tolerance, no effective treatment has yet been found. Therefore, understanding the mechanism underlying opioid tolerance is crucial for finding new prevention and treatment strategies. Noncoding RNAs (ncRNAs) are important parts of mammalian gene transcriptomes, and there are thousands of unique noncoding RNA sequences in cells. With the rapid development of high-throughput genome technology, research on ncRNAs has become a hot topic in biomedical research. In recent years, studies have shown that ncRNAs mediate physiological and pathological processes, including chromatin remodeling, transcription, posttranscriptional modification and signal transduction, which are key regulators of physiological processes in developmental and disease environments and have become biomarkers and potential therapeutic targets for various diseases. An increasing number of studies have found that ncRNAs are closely related to the development of opioid tolerance. In this review, we have summarized the evidence that ncRNAs play an important role in opioid tolerance and that ncRNAs may be novel targets for opioid tolerance.

Botulinum toxin type A counteracts neuropathic pain by countering the increase of GlyT2 expression in the spinal cord of CCI rats.

Botulinum toxin type A (BoNT/A) is a potent toxin, acts by cleaving synaptosome-associated-protein-25 (SNAP-25) to regulate the release of the neural transmitter and shows analgesic effect in neuropathic pain. However, the mechanisms of BoNT/A actions involved in nociceptions remain unclear. Glycine transporter 2 (GlyT2) is an isoform of glycine transporters, which plays an important role in the regulation of glycinergic neurotransmission. Inhibition of GlyTs could decrease pain sensation in neuropathic pain, the role of GlyT2 in the analgesic effect of BoNT/A has not been studied yet. In our present study, we demonstrated that the protein levels of GlyT2 and SNAP-25 were upregulated in the spinal cord after the development of chronic constriction injury (CCI)-induced neuropathic pain. Intraplantar application of BoNT/A (20 U/kg) attenuated mechanical allodynia induced by CCI and downregulated GlyT2 expression in the spinal cord. The application of BoNT/A s also decreased the expression of GlyT2 in pheochromocytoma (PC12) cells. Moreover, intrathecal application of lentivirus-mediated GlyT2 reversed the antinociceptive effect of BoNT/A in CCI rats. These findings indicate that GlyT2 contributes to the antinociceptive effect of BoNT/A and suggest a novel mechanism underlying BoNT/A's antinociception action.

Overexpression of GDNF in Spinal Cord Attenuates Morphine Analgesic Tolerance in Rats with Bone Cancer Pain.

Bone cancer pain (BCP) is one of the typical and distressing symptoms in cancer patients. Morphine is a widely used analgesic drug for BCP; however, long-term morphine administration will lead to analgesic tolerance. Our previous study indicated that spinal glial cell line-derived neurotrophic factor (GDNF) exerts analgesic effects in rats with BCP. In this study, BCP was established by inoculated Walker 256 carcinoma cells into rat tibias, while morphine tolerance (MT) was induced by intrathecally injecting morphine twice daily from the 9th to 15th postoperative day (POD) in BCP rats. The BCP rats developed mechanical and thermal hyperalgesia on POD 5 and it lasted to POD 15. The analgesic effect of morphine was decreased after repeat administration. Western blots and immunochemistry tests showed that GDNF was gradually decreased in the spinal cord after the development of MT in rats with BCP, and GDNF was colocalized with the µ opioid receptor (MOR) in the superficial laminate of the spinal cords. The overexpression of GDNF by lentivirus significantly attenuated MT, and restored the expression of MOR in the spinal cord. In summary, our results suggest that the reduction of GDNF expression participated in the development of MT in rats with BCP and could be a promising therapeutic option for BCP.

Identification and characterization of N6-methyladenosine circular RNAs in the spinal cord of morphine-tolerant rats.

Morphine tolerance (MT) is a tricky problem, the mechanism of it is currently unknown. Circular RNAs (circRNAs) serve significant functions in the biological processes (BPs) of the central nervous system. N6-methyladenosine (m6A), as a key post-transcriptional modification of RNA, can regulate the metabolism and functions of circRNAs. Here we explore the patterns of m6A-methylation of circRNAs in the spinal cord of morphine-tolerant rats. In brief, we constructed a morphine-tolerant rat model, performed m6A epitranscriptomic microarray using RNA samples collected from the spinal cords of morphine-tolerant rats and normal saline rats, and implemented the bioinformatics analysis. In the spinal cord of morphine-tolerant rats, 120 circRNAs with different m6A modifications were identified, 54 of which were hypermethylated and 66 of which were hypomethylated. Functional analysis of these m6A circRNAs found some important pathways involved in the pathogenesis of MT, such as the calcium signaling pathway. In the m6A circRNA-miRNA networks, several critical miRNAs that participated in the occurrence and development of MT were discovered to bind to these m6A circRNAs, such as miR-873a-5p, miR-103-1-5p, miR-107-5p. M6A modification of circRNAs may be involved in the pathogenesis of MT. These findings may lead to new insights into the epigenetic etiology and pathology of MT.

Dysregulation of Vesicular Glutamate Transporter VGluT2 via BDNF/TrkB Pathway Contributes to Morphine Tolerance in Mice.

Morphine is widely used in the treatment of moderate to severe pain. Long-term use of morphine leads to various adverse effects, such as tolerance and hyperalgesia. Vesicular glutamate transporter 2 (VGluT2) accumulates glutamate into synaptic vesicles and plays multiple roles in the central nervous system. However, the specific role of VGluT2 in morphine tolerance has not been fully elucidated. Here, we investigated the regulatory role of VGluT2 in morphine tolerance and assessed the potential role of the brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) pathway in VGluT2 mediated morphine antinociceptive tolerance in mice. In the present study, we found that VGluT2 is upregulated in the spinal cord after the development of morphine tolerance. Furthermore, inhibition of VGluT2 with its antagonist (Chicago sky blue 6 B, CSB6B) or knockdown of VGluT2 by lentivirus restored the analgesic effect of morphine, suppressed the activation of astrocytes and microglia, and decreased glial-derived pro-inflammatory cytokines. Overexpression of VGluT2 by lentivirus facilitated morphine tolerance and mechanical hyperalgesia. In addition, we found the expression of BDNF is correlated with VGluT2 expression in the spinal cord after chronic morphine administration. Intrathecal injection of the BDNF/TrkB pathway antagonist K252a attenuated the development of morphine tolerance and decreased the expression of VGluT2 in the spinal cord, which suggested the BDNF/TrkB pathway participates in the regulation of VGluT2 in morphine tolerance. This study elucidates the functional capability of VGluT2 in modulating morphine tolerance and identifies a novel mechanism and promising therapeutic target for morphine tolerance.

Effect of Intravenous Dexamethasone on Postoperative Pain in Patients Undergoing Total Knee Arthroplasty: A Systematic Review and Meta-Analysis.

BACKGROUND: Postoperative pain after total knee arthroplasty (TKA) is intense and remains an unsolved problem. Some studies show that perioperative, multimodal analgesia, including intravenous dexamethasone, can provide a better analgesic effect; however, the validity of studies has raised concerns and questions remain around the efficacy, dosing, and safety of dexamethasone in patients undergoing total knee arthroplasty. OBJECTIVES: The purpose of this systematic review and meta-analysis was to evaluate the impact of intravenous dexamethasone on postoperative pain among patients undergoing TKA. STUDY DESIGN: Systematic review and meta-analysis. SETTING: Web of Science, Embase, PubMed, and the Cochrane Central Register of Controlled Trials were searched to identify relevant randomized controlled trials. The last search was in August 2021. METHODS: The risk of bias of the included trials was assessed by the Cochrane Risk of Bias Tool. The primary outcome was postoperative visual analog scale (VAS) pain scores and secondary outcomes included cumulative equivalent intravenous morphine consumption, number of patients requiring rescue analgesic, length of hospital stay, and adverse events. We assessed the certainty of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Eleven studies with 1,671 patients were included. The pooled results indicated that patients receiving dexamethasone had lower VAS pain scores at rest (24 h, MD = -0.68, [95% CI: -0.87 to -0.49]; 48 h, MD = -0.33, [95% CI: -0.46 to -0.21]) and at movement (24 h, MD = -0.74, [95% CI: -1.10 to -0.37]; 48 h, MD = -0.46, [95% CI: -0.66 to -0.26]), required less morphine (24 h, MD = -2.84 mg, [95% CI: -5.13 to -0.54]; 48 h, MD= -4.16 mg, [95% CI: -5.55 to -2.78]) and rescue analgesics, and had shorter hospitalization. There was no increase in infection, gastrointestinal hemorrhage, wound healing problems, or blood glucose levels with dexamethasone. Subgroup analysis did not observe difference between single dose and repeat dose groups. LIMITATIONS: The perioperative multimodal analgesia measures were varied throughout the studies. The sample size was small for some outcomes and high heterogeneity was observed. CONCLUSIONS: Our results supported the addition of perioperative intravenous dexamethasone to multimodal analgesia in total knee arthroplasty to reduce postoperative pain, opioids consumption, and length of hospital stay. Current evidence did not support the superiority of repeated-dose dexamethasone over single-dose dexamethasone; thus, we recommended perioperative 8-10 mg intravenous dexamethasone to be used based on adequate basic analgesia; however, the results may have been affected by small sample sizes and heterogeneity.

LncRNA MRAK159688 facilitates morphine tolerance by promoting REST-mediated inhibition of mu opioid receptor in rats.

Morphine tolerance (MT) caused by the long-term use of morphine is a major medical problem. The molecular mechanism of morphine tolerance remains elusive. Here, we established a morphine tolerance model in rats and verified whether the long noncoding RNA (lncRNA) MRAK159688 is involved in morphine tolerance and its specific molecular mechanism. We show the significant upregulation of MRAK159688 expression in the spinal cord of morphine-tolerant rats. Overexpression of MRAK159688 by a lentivirus reduces the analgesic efficacy of morphine and induces pain behavior. Downregulation of MRAK159688 using a small interfering RNA (siRNA) attenuates the formation of morphine tolerance, partially reverses the development of morphine tolerance and alleviates morphine-induced hyperalgesia. MRAK159688 is located in the nucleus and cytoplasm of neurons, and it colocalizes with repressor element-1 silencing transcription factor (REST) in the nucleus. MRAK159688 potentiates the expression and function of REST, thereby inhibiting the expression of mu opioid receptor (MOR) and subsequently inducing morphine tolerance. Moreover, REST overexpression blocks the effects of MRAK159688 siRNA on relieving morphine tolerance. In general, chronic morphine administration-mediated upregulation of MRAK159688 in the spinal cord contributes to morphine tolerance and hyperalgesia by promoting REST-mediated inhibition of MOR. MRAK159688 downregulation may represent a novel RNA-based therapy for morphine tolerance.