Wei Zhang

Macroautophagy/autophagy plays a crucial role in maintaining nervous system homeostasis but its role in chronic postoperative pain (CPOP) remains poorly understood. Here, we identify impaired autophagy and the accumulation of synaptic proteins in the anterior cingulate cortex (ACC) during the maintenance of CPOP after skin/muscle incision and retraction (SMIR). Lysosomal hydrolase levels are reduced upon SMIR, accompanied by a deficiency of the lysosomal trafficking protein transmembrane protein 251 (TMEM251, also named LYSET). TMEM251 overexpression alleviates impaired autophagy, accumulation of synaptic proteins within autophagy substrates, and maintenance of CPOP in SMIR mice. Conversely, TMEM251 knockdown induces autophagy impairment, accumulation of synaptic proteins, and chronic pain phenotypes in naive mice. Autophagy dysfunction is most pronounced in CaMKIIα-positive neurons in the ACC post-surgery, resulting in their activation, which is mitigated by TMEM251 overexpression. Chemogenetic activation of CaMKIIα neurons exacerbates autophagy impairment and CPOP, while their inhibition rescues SMIR-induced autophagy and pain phenotypes. Taken together, our study highlights the close relationship between impaired autophagy and neuronal activation in the promotion of chronic postoperative pain.

Spontaneous intracranial hypotension (SIH) is a rare clinical condition that may occur due to cerebrospinal fluid leakage. The purpose of this study was to compare the safety and efficacy of single catheter multisite epidural blood patch(CA-EBP) with standard procedures, including blinded and targeted epidural blood patch (EBP) for the treatment of SIH, and to investigate the effectiveness of dexamethasone as an adjuvant. Clinical data of 68 patients with postoperative SIH who underwent EBP between March 2022 and May 2024. In this prospective cohort trial, 68 patients were allocated to four groups: blind EBP, targeted EBP, CA-EBP, and CA-EBP + dexamethasone, based on the procedure received. Patients were assessed for pain using the visual analog scale (VAS), anxiety and depression using the Hospital Anxiety and Depression Scale (HADS), and quality of life using the Headache lmpact Test (HIT-6). Adverse events were documented to evaluate the safety of the procedure. A total of 68 patients were recruited for the study, comprising 41 females and 27 males, with a mean age of 40.76 years. The participants were distributed as follows: 9 in the blind EBP group, 17 in the targeted EBP group, 20 in the CA-EBP group, and 22 in the CA-EBP + dexamethasone group. After a single treatment, the severity of headaches significantly decreased in 5 (55.56%) patients in the blinded EBP group, 13 (76.47%) patients in the targeted EBP group, 19 (95.00%) patients in the CA-EBP group, and 20 (90.91%) patients in the CA-EBP + dexamethasone group. The most frequent complications in both groups were transient intracranial hypertension; however, no serious complications were reported. CA-EBP stands out as a safe and effective therapy for SIH. It notably alleviates pain, enhances quality of life, and surpasses standard EBP procedures. Moreover, dexamethasone, when used as an adjunct, proves effective in mitigating postoperative complications.

Introduction Several factors may lead to increased postoperative pain sensitivity, of which remifentanil-induced hyperalgesia (RIH) is one of the main factors. High-dose remifentanil exposure during anesthesia may induce RIH. Esketamine may prevent RIH by antagonizing N-methyl-d-aspartate (NMDA) receptors, thereby reducing the postoperative pain sensitivity. This study examined the effects of different esketamine doses on pain sensitivity in patients undergoing thyroidectomy and determined the optimal dose. Methods This study included 117 patients who received elective thyroidectomy. They were randomized into four groups: saline group (group C), esketamine 0.2 mg·kg⁻¹ group (group RK1), esketamine 0.4 mg·kg⁻¹ group (group RK2), and esketamine 0.6 mg·kg⁻¹ group (group RK3). Five minutes before anesthesia induction, the same volume of study drugs were injected respectively in groups C, RK1, RK2, and RK3. Remifentanil was pumped at the same rate of 0.3 µg·kg⁻¹·min⁻¹ during surgery to ensure uniformity. This study’s primary outcomes were the mechanical pain thresholds measured before surgery, as well as at 30 min, 6 h, 24 h, and 48 h after surgery. Hyperalgesia, rescue analgesia, numerical rating scale (NRS) score, and adverse reactions were recorded. Results Compared with baseline, the mechanical pain threshold was significantly decreased in group C [(94.67 ± 22.85) versus (112.00 ± 36.62) versus (161.33 ± 53.28) g, P < 0.001 at 30 min, P < 0.001 at 6 h] and group RK1 [(102.86 ± 24.17) versus (114.29 ± 41.05) versus (160.00 ± 54.98) g, P < 0.001 at 30 min, P < 0.001 at 6 h] around the surgical incision, and in group C [(112.00 ± 31.78) versus (170.67 ± 56.26) g, P < 0.001 at 30 min, (118.67 ± 34.42) versus (170.67 ± 56.26) g, P = 0.001 at 6 h] and group RK1 [(114.29 ± 45.17) versus (175.71 ± 54.80) g, P = 0.001 at 30 min, (121.43 ± 38.46) versus (175.71 ± 54.80) g, P = 0.002 at 6 h] on the forearm at 30 min and 6 h after surgery; compared with group C, the mechanical pain threshold was higher in group RK2 [(142.76 ± 50.06) versus (94.67 ± 22.85) g, P < 0.001 at 30 min, (145.52 ± 49.83) versus (112.00 ± 36.62) g, P < 0.001 at 6 h] and group RK3 [(140.00 ± 40.68) versus (94.67 ± 22.85) g, P < 0.001 at 30 min, (150.67 ± 56.50) versus (112.00 ± 36.62) g, P = 0.010 at 6 h] around the surgical incision, and in group RK2 [(149.66 ± 39.50) versus (112.00 ± 31.78) g, P = 0.006 at 30 min, (156.55 ± 47.23) versus (118.67 ± 34.42) g, P = 0.005 at 6 h] and group RK3 [(145.33 ± 51.18) versus (112.00 ± 31.78) g, P = 0.018 at 30 min, (154.67 ± 47.54) versus (118.67 ± 34.42) g, P = 0.008 at 6 h] on the forearm at 30 min and 6 h after surgery. Group RK3 had more glandular secretions than the other three groups (P = 0.042). Conclusions Intravenous injection of esketamine 0.4 mg·kg⁻¹ before anesthesia induction is a suitable dose to reduce pain sensitivity in patients undergoing thyroidectomy without increasing adverse reactions. However, future research needs to be extended to other populations. Trial Registration Registered at the Chinese Clinical Trials Registry http://www.chictr.org.cn/ (09/06/2022, ChiCTR-2200060741).

N6-methyladenosine (m⁶A) is the most abundant methylation modification on mRNA in mammals. Fat mass and obesity-related protein (FTO) is the main RNA m⁶A demethylase. FTO is involved in the occurrence and maintenance of neuropathic pain (NP). NP often induces mental disorders. We found that NP downregulated the expression of FTO in the anterior cingulate cortex (ACC), inhibited the expression of matrix metalloproteinase-9 (MMP-9) in the ACC, maladjusted the brain-derived neurotrophic factor precursor (proBDNF) and mature brain-derived neurotrophic factor (mBDNF) levels in the ACC, and induced anxiety- and depression-like behaviors in mice. Blocking the downregulation of FTO in the ACC induced by peripheral nerve injury could reverse the anxiety- and depression-like behaviors of mice. Contrarily, downregulation of simulated FTO induced anxiety- and depression-like behaviors in mice. After peripheral nerve injury, the binding of FTO to MMP-9 mRNA decreased and the enrichment of m⁶A on MMP-9 mRNA increased. In conclusion, downregulation of FTO in ACC by regulating MMP-9 mRNA methylation level contributes to the occurrence of anxiety- and depression-like behaviors in NP mice.

Objective: We developed and validated a sensitive and reliable UPLC-MS/MS method for simultaneous determination of dezocine (DEZ), midazolam (MDZ) and its metabolite 1-hydroxymidazolam (1-OH-MDZ) in beagle plasma and investigated the effect of dexmedetomidine (DEX) on the pharmacokinetics of DEZ, MDZ and 1-OH-MDZ in beagles. Materials and Methods: Diazepam was used as the internal standard (IS); the three analytes and IS were extracted by acetonitrile precipitation and separated on an Acquity UPLC BEH C18 column using acetonitrile-0.1% formic acid as mobile phase in gradient mode. In positive ion mode, the three analytes and IS were monitored by multiple reaction monitoring (MRM). Six beagles were designed as a double cycle self-control experiment with 0.15 mg/kg in the first cycle (Group A). After a 1-week washout period, the same six beagles were slowly injected intravenously with 2 μg/kg DEX in the second cycle (Group B), with continuous injection for 7 days. On the seventh day, 0.5 hr after intravenous injection of 2 μg/kg DEX, the six beagles were intramuscularly given with DEZ 0.33 mg/kg and MDZ 0.15 mg/kg. Results: Under the conditions of this experiment, this method exhibited a good linearity for each analyte. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect and stability have also met the requirements. Conclusion: The developed UPLC-MS/MS method for simultaneous determination of DEZ, MDZ and 1-OH-MDZ in beagles plasma was accurate, reproducible, specific, and suitable. DEX could inhibit the metabolism of DEZ and MDZ and increase the exposure of DEZ and MDZ in beagles. Therefore, the change of therapeutic effect and the occurrence of adverse reactions caused by drug–drug interaction should be paid attention to when the drugs were used in combination.

Introduction Infants can experience pain similar to adults, and improperly controlled pain stimuli could have a long-term adverse impact on their cognitive and neurological function development. The biggest challenge of achieving good infant pain control is obtaining objective pain assessment when direct communication is lacking. For years, computer scientists have developed many different facial expression-centred machine learning (ML) methods for automatic infant pain assessment. Many of these ML algorithms showed rather satisfactory performance and have demonstrated good potential to be further enhanced for implementation in real-world clinical settings. To date, there is no prior research that has systematically summarised and compared the performance of these ML algorithms. Our proposed meta-analysis will provide the first comprehensive evidence on this topic to guide further ML algorithm development and clinical implementation. Methods and analysis We will search four major public electronic medical and computer science databases including Web of Science, PubMed, Embase and IEEE Xplore Digital Library from January 2008 to present. All the articles will be imported into the Covidence platform for study eligibility screening and inclusion. Study-level extracted data will be stored in the Systematic Review Data Repository online platform. The primary outcome will be the prediction accuracy of the ML model. The secondary outcomes will be model utility measures including generalisability, interpretability and computational efficiency. All extracted outcome data will be imported into RevMan V.5.2.1 software and R V3.3.2 for analysis. Risk of bias will be summarised using the latest Prediction Model Study Risk of Bias Assessment Tool. Ethics and dissemination This systematic review and meta-analysis will only use study-level data from public databases, thus formal ethical approval is not required. The results will be disseminated in the form of an official publication in a peer-reviewed journal and/or presentation at relevant conferences. PROSPERO registration number CRD42019118784.

Previous studies have demonstrated that myeloid zinc finger 1 (MZF1) in the dorsal root ganglion (DRG) participates in neuropathic pain induced by chronic-constriction injury (CCI) via regulation of voltage-gated K⁺ channels (Kv). Emerging evidence indicates that transient receptor potential vanilloid 1 (TRPV1) is involved in the development and maintenance of neuropathic pain. Although it is known that the transcription of TRPV1 is regulated by Kruppel-like zinc-finger transcription factor 7 (Klf7)—and that the structure of TRPV1 is similar to that of Kv—few studies have systematically investigated the relationship between MZF1 and TRPV1 in neuropathic pain. In the present study, we demonstrated that CCI induced an increase in MZF1 and TRPV1 in lumbar-level 4/5 (L4/5) DRGs at 3 days post-CCI and that this increase was persistent until at least 14 days post-CCI. DRG microinjection of rAAV5-MZF1 into the DRGs of naïve rats resulted in a decrease in paw-withdrawal threshold (PWT) and paw-withdrawal latency (PWL) compared with that of the rAAV5-EGFP group, which started at four weeks and lasted until at least eight weeks after microinjection. Additionally, prior microinjection of MZF1 siRNA clearly ameliorated CCI-induced reduction in PWT and PWL at 3 days post-CCI and lasted until at least 7 days post-CCI. Correspondingly, microinjection of MZF1 siRNA subsequent to CCI alleviated the established mechanical allodynia and thermal hyperalgesia induced by CCI, which occurred at 3 days postinjection and lasted until at least 10 days postinjection. Microinjection of rAAV5-MZF1 increased the expression of TRPV1 in DRGs. Microinjection of MZF1 siRNA diminished the CCI-induced increase of TRPV1, but not P2X7R, in DRGs. These findings suggest that MZF1 may contribute to neuropathic pain via regulation of TRPV1 expression in DRGs.