An experimental model for primary neuropathic corneal pain induced by long ciliary nerve ligation in rats.

ABSTRACT: Neuropathic corneal pain (NCP) is a new and ill-defined disease characterized by pain, discomfort, aching, burning sensation, irritation, dryness, and grittiness. However, the mechanism underlying NCP remain unclear. Here, we reported a novel rat model of primary NCP induced by long ciliary nerve (LCN) ligation. After sustained LCN ligation, the rats developed increased corneal mechanical and chemical sensitivity, spontaneous blinking, and photophobia, which were ameliorated by intraperitoneal injection of morphine or gabapentin. However, neither tear reduction nor corneal injury was observed in LCN-ligated rats. Furthermore, after LCN ligation, the rats displayed a significant reduction in corneal nerve density, as well as increased tortuosity and beading nerve ending. Long ciliary nerve ligation also notably elevated corneal responsiveness under resting or menthol-stimulated conditions. At a cellular level, we observed that LCN ligation increased calcitonin gene-related peptide (neuropeptide)-positive cells in the trigeminal ganglion (TG). At a molecular level, upregulated mRNA levels of ion channels Piezo2, TRPM8, and TRPV1, as well as inflammatory factors TNF-α, IL-1ß, and IL-6, were also detected in the TG after LCN ligation. Meanwhile, consecutive oral gabapentin attenuated LCN ligation-induced corneal hyperalgesia and increased levels of ion channels and inflammation factors in TG. This study provides a reliable primary NCP model induced by LCN ligation in rats using a simple, minimally invasive surgery technique, which may help shed light on the underlying cellular and molecular bases of NCP and aid in developing a new treatment for the disease.

Comparison of different weight-based scalars of remimazolam tosylate for anesthesia induction in obese patients: study protocol for a prospective, controlled trial.

BACKGROUND: The physiologic and anthropometric characteristics changes associated with obesity may result in the alternation of pharmacologic management. Remimazolam tosylate is a new type of ultra-short-acting benzodiazepine with stable context-sensitive half-time (CSHT) and no lipid accumulation after long-time infusion. Although remimazolam tosylate has potential advantages for the induction and maintenance of anesthesia in obese patients, the appropriate induction dosing scalars among obese patients are unknown. Therefore, we aim to compare the different weight-based scalars for dosing remimazolam tosylate of anesthesia induction among obese patients. METHODS/DESIGN: The study will be performed as a prospective, single-center, double-blind, controlled clinical trial. The study design is a comparison of remimazolam tosylate requirements based on total body weight (TBW) or lean body weight (LBW) to reach a Modified Observer's Assessment of Alertness and Sedation (MOAA/S) score of 0 among obese subjects (BMI ≥ 35 kg/m2). Another twenty normal-weight subjects (18.5 kg/m2 ≤ BMI < 25 kg/m2) will be enrolled as a control group, whose induction dose is scaled based on TBW. The infusion rate of remimazolam tosylate during induction is 12 mg/kg/h in all groups. DISCUSSION: Results of the present study will provide evidence of dose scalar of remimazolam tosylate to guide the clinical practice of anesthesia induction in obese patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR220005664. Registered on 9 February 2022, https://www.chictr.org.cn/showproj.aspx?proj=151150 .

Corticosterone mediates FKBP51 signaling and inflammation response in the trigeminal ganglion in chronic stress-induced corneal hyperalgesia mice.

Stress-induced hyperalgesia is a health-threatening condition that lacks effective therapeutic intervention, impairing the quality of life. Interestingly, a high prevalence of corneal pain symptoms was also found in patients experienced severe stressors. Excessive secretion corticosterone in rodents has been shown to contribute to the development of visceral and mechanical hyperalgesia under stressful conditions. The co-chaperone protein FK506-binding protein 5 (FKBP5) was reported to modulate steroid sensitivity and inhibition of FKBP51 possessed anxiolytic and anti-hyperalgesic in the stressed-mice model. However, whether corticosterone and FKBP5 play a role in chronic stress-induced corneal hyperalgesia remains unknown. The aim of this study was to evaluate the corneal sensitivity after exposure to chronic restraint stress (CRS) and investigate the potential role of corticosterone and FKBP5 mediated proinflammatory cytokines release in trigeminal ganglion (TG) in corneal hyperalgesia under chronic stressful situations. Firstly, mice displayed increased corneal sensitivity without changes in tear production and corneal injury after CRS for 4 hours/day for 14 days. Meanwhile, corticosterone deficiency via adrenalectomy could prevent CRS-induced corneal hyperalgesia, whereas chronic corticosterone feeding increased the corneal sensitivity accompanied by increasing proinflammatory cytokines levels of phospho-NF-κB (p-NF-κB), tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in the TG on d14. Notably, we found that FKBP51 was significantly upregulated in the TG in the stressed-mice. Intraperitoneal injection of FKBP51 inhibitor significantly alleviated CRS-induced corneal hyperalgesia, and reversed calcitonin gene related peptide (CGRP) increase and proinflammatory cytokines production in the TG. Moreover, FKBP51 inhibitor could also exert its anti-hyperalgesic effect on corneal pain through intra-TG injection. Our study proves that CRS can induce corneal hyperalgesia in mice and uncovers the role of corticosterone and FKBP51 in modulating corneal sensitivity, providing a novel treatment strategy for stress-induced corneal hyperalgesia. AVAILABILITY OF DATA AND MATERIALS: All data and additional file are available upon request from the corresponding author.

Improved skill for tracheal intubation using optical stylets through remote training model: a before and after interventional study.

BACKGROUND: Conducting on-site, hands-on training during the Coronavirus disease 2019 (COVID-19) pandemic has been challenging. We conducted a before and after interventional study to estimate the efficacy of a new remote hands-on training model for improving the trainees' tracheal intubation competency using optical stylets. METHODS: Residents or physicians in anesthesiology apartment who have not received the nominated training in tracheal intubation using optical stylets were enrolled. The 4-week training course contains theoretical knowledge along with preclinical and clinical training of optical stylets techniques. Competency of intubation using optical stylets on patients with normal airways was evaluated according to an assessment tool with a maximum score of 29 points based on video recording pre-post training performance. Pre-post questionnaires measured theoretical knowledge and self-efficacy. RESULTS: Twenty-two participants were included (8 females, 14 men, mean age of 33.5 years). The total score of intubation competency was significantly improved after training from 14.6±3.7 to 25.3±2.6 (P < 0.0001). The scores of three subitems (anatomical identification, hand-eye coordination, and optimized intubation condition) were all significantly increased after training (P < 0.0001). The total percentage of correct answers in the multiple-choice questionnaire increased from 58.2%±8.2% before training to 85.2%±7.2% shortly after training (P < 0.0001). In addition, the self-efficacy score was significantly increased from 2.5±1.2 to 4.4±0.6 (P < 0.0001). CONCLUSIONS: The new remote and progressively advanced hands-on training model improved the competency of intubation using optical stylets under the COVID-19 pandemic.

Pretreatment with Low-Dose Esketamine for Reduction of Propofol Injection Pain: A Randomized Controlled Trial.

Background: Propofol-induced injection pain is a common adverse effect during the induction of general anesthesia. The purpose of this study is to investigate the effect of low-dose esketamine in preventing propofol injection pain. Methods: In this double-blind, randomized, controlled trial, patients scheduled for elective ear surgery under general anesthesia received either normal saline (NS), or 40 mg lidocaine, or 0.15 mg/kg esketamine 30 seconds before manual injection of propofol. The primary outcome of this study was the incidence of propofol injection pain. The secondary outcomes included injection pain score, vital signs, total dosage of vasoactive drugs used within 5 minutes after induction, and adverse events related to drugs. Results: A total of 105 patients were included. Compared with the NS group (67%), pretreatment with esketamine and lidocaine significantly reduced the incidence of injection pain to 29% and 33%, respectively (both P < 0.05); however, no significant difference was found between the esketamine and lidocaine groups. The median of injection pain score was significantly lower in the esketamine and lidocaine groups (both median (interquartile range) = 0 (0-1)) than that in the NS group (1 (0-2); P < 0.05). In addition, compared with the NS and lidocaine groups, preinjection esketamine provided more stable hemodynamic parameters within 5 minutes after induction (P < 0.05). No statistical difference was found in adverse events among the three groups. Conclusions: Pretreatment with a low-dose esketamine can not only reduce the incidence of propofol injection pain but also provide a more stable circulation in patients after anesthesia induction. This convenient, well-tolerated, and economic treatment appears as an option to be routinely applied in clinic practice. Clinical Trial Registration. This trial is registered with https://www.chictr.org.cn/showproj.aspx?proj=136690 (the number for the trial registration isChiCTR2100052742).

Ultrasound-guided transversus thoracic muscle plane-pectoral nerve block for postoperative analgesia after modified radical mastectomy: a comparison with the thoracic paravertebral nerve block.

BACKGROUND: Modified radical mastectomy (MRM) is the most effective and common type of invasive surgery for breast cancer. However, it causes moderate to severe acute pain and even lasts for a long postoperative period. Transversus thoracic muscle plane-pectoral nerve block (TTP-PECS) is a novel and promising interfacial plane block which can provide analgesia for MRM while thoracic paravertebral nerve block (TPVB) is also widely used for this purpose. This study compared the postoperative analgesia between the ultrasound-guided TTP-PECS and TPVB in patients undergoing MRM. METHODS: In this randomized controlled trial, eighty female breast cancer patients undergoing unilateral MRM with sentinel lymph node dissection (SLND) and axillary dissection (ALND) were enrolled. Patients were randomized to receive either ultrasound-guided TTP-PECS (TTP-PECS group, n = 40) or TPVB (TPVB group, n = 40) with 0.5% ropivacaine 30 ml. Evaluated variables included 24 h postoperative total PCA fentanyl consumption, including PCA background consumption and PCA press consumption (per bolus dosage multiply by the effective pressing times), and intraoperative fentanyl consumption, as well as postoperative flurbiprofen axetil requirement, duration of analgesia, blocking area, pain intensity at rest and during activity, ability to reduce the inflammatory response, and the quality of recovery 40 (QoR-40) score of patients. RESULTS: Compared with the TPVB, the main blocking area was T2-T6 in the TTP-PECS group, which was more suitable for the MRM. TTP-PECS has a longer analgesia duration than TPVB; 24 h postoperative total PCA fentanyl consumption, especially the PCA press consumption, and the postoperative flurbiprofen axetil requirement were decreased in the TTP-PECS group than those in the TPVB group. Furthermore, the VAS scores at rest and during activity and inflammatory response were lower in the TTP-PECS group compared with the TPVB group at 12 h postoperatively. Finally, the total QoR-40 score, especially for the scores of pain; emotional state; and patient support were better in the TTP-PECS group. CONCLUSION: Compared with the TPVB, TTP-PECS can provide better postoperative analgesia in patients undergoing MRM, simultaneously reduce the inflammatory response, and prompt early recovery. These results suggest that TTP-PECS is an attractive alternative to TPVB for postoperative analgesia of modified radical mastectomy.

[D-Ala2, D-Leu5] Enkephalin Inhibits TLR4/NF-κB Signaling Pathway and Protects Rat Brains against Focal Ischemia-Reperfusion Injury.

BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury is the main cause of acute brain injury, which is a life-threatening disease due to the lack of effective treatments. [D-Ala2, D-Leu5] enkephalin (DADLE) is a synthetic delta-opioid receptor agonist that is reported to confer neuroprotective effect; however, the underlying mechanism is still being explored. The purpose of the present study is to determine whether DADLE administrated intracerebroventricularly could attenuate the cerebral I/R injury, to determine if this is through inhibiting the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway and therefore inhibiting neuroinflammation in an ischemic stroke model. METHODS: Rats were subjected to 120 minutes of ischemia by transient middle cerebral artery occlusion (MCAO). At 45 minutes after ischemia, DADLE or control vehicle (artificial cerebrospinal fluid, ACSF) was given to the rats intracerebroventricularly. Neurological deficit, cerebral infarct volume, and histopathological changes were assessed at 24 hours after reperfusion. Brain inflammation was assessed by measuring tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the ischemic penumbra by ELISA. The expression of TLR4 was determined by immunohistochemistry staining and western blotting. The expression of NF-κB was investigated by western blotting. RESULTS: Compared with the vehicle-treatment (ACSF), DADEL improved neurological deficit (9.6 ± 2.1 versus 13.8 ± 1.9), reduced cerebral infarct volume (18.74 ± 3.30% versus 10.57 ± 2.50%), and increased the number of normal neurons (29.72 ± 8.53% versus 51.37 ± 9.18%) after cerebral I/R injury in rats (all P < 0.05). Expressions of inflammatory molecules including TNF-α and IL-6 were highly expressed in the vehicle-treated rats, whereas treatment with DADLE downregulated these expressions (P < 0.05). Additionally, cerebral I/R injury significantly increased the TLR4 and NF-κB expression in vehicle-control group, which was markedly inhibited by DADLE (P < 0.05). CONCLUSIONS: DADLE, administrated intracerebroventricularly at 45 minutes after cerebral ischemia, significantly ameliorated I/R-induced brain damage in rats. This kind of neuroprotective effect appears to be related to the downregulation of TLR4-mediated inflammatory responses.

Effects of D­Ala2, D­Leu5­Enkephalin pre­ and post­conditioning in a rabbit model of spinal cord ischemia and reperfusion injury.

It has recently been revealed that during the aorta­clamped period, D­Ala2, D­Leu5­Enkephalin (DADLE) infusion can protect the spinal cord against ischemia and reperfusion (I/R) injury. However, the protective effects of DADLE administration prior to ischemia or at the time of early reperfusion have not yet been investigated. Drug pre­ or post­conditioning can serve as a more valuable clinical strategy. Therefore, the present study was designed to investigate the neuroprotective effect of DADLE infusion at different time intervals in order to determine the optimum time point for ischemic spinal cord protection. A total of 40 New Zealand white rabbits were randomly divided into 5 groups: Sham­operated (Sham), normal saline pre­conditioning (NS), DADLE per­conditioning (Dper), DADLE pre­conditioning (Dpre) and DADLE post­conditioning (Dpost). All animals were subjected to spinal cord ischemia for 30 min followed by 48 h reperfusion. Hind limb motor functions were assessed according to the Tarlov criterion when the animals regained consciousness, 6, 24 and 48 h after reperfusion. Histological analysis and the number of viable α­motor neurons were also used to assess the extent of spinal cord injury. Compared with the NS group, the Tarlov scores and the number of normal neurons were significantly higher in the Dper group (P<0.05), which were consistent with the results of a previous study. In addition, the paraplegia rate and loss of normal motor neurons were lower in the DADLE per­ and post­conditioning groups compared with the DADLE pre­conditioning; however, these were not statistically significant. DADLE 0.05 mg/kg administration at three time points all mitigated normal motor neuron injury in the anterior horn and decreased the paraplegia rates in rabbits. The therapeutic benefits appeared best in the post­conditioning group with DADLE, and worst in the pre­conditioning group.

The evolving role of neuro-immune interaction in brain repair after cerebral ischemic stroke.

Stroke is the world's leading cause of disability with limited brain repair treatments which effectively improve long-term neurological deficits. The neuroinflammatory responses persist into the late repair phase of stroke and participate in all brain repair elements, including neurogenesis, angiogenesis, synaptogenesis, remyelination and axonal sprouting, shedding new light on post-stroke brain recovery. Resident brain glial cells, such as astrocytes not only contribute to neuroinflammation after stroke, but also secrete a wide range of trophic factors that can promote post-stroke brain repair. Alternatively, activated microglia, monocytes, and neutrophils in the innate immune system, traditionally considered as major damaging factors after stroke, have been suggested to be extensively involved in brain repair after stroke. The adaptive immune system may also have its bright side during the late regenerative phase, affecting the immune suppressive regulatory T cells and B cells. This review summarizes the recent findings in the evolving role of neuroinflammation in multiple post-stroke brain repair mechanisms and poses unanswered questions that may generate new directions for future research and give rise to novel therapeutic targets to improve stroke recovery.

Antioxidative and Antiapoptotic Effects of Delta-Opioid Peptide [D-Ala2, D-Leu5] Enkephalin on Spinal Cord Ischemia-Reperfusion Injury in Rabbits.

Background: In our previous study, we found that regional administration of delta-opioid peptide [D-Ala2, D-Leu5] enkephalin (DADLE) could provide dose-dependent protection on spinal cord ischemia-reperfusion (I/R) injury in rabbits. However, the relative protective molecular mechanisms underlying this neuroprotection remain unclear. The purpose of this study was to investigate whether DADLE provided the protection in spinal cord I/R injury through its antioxidant property by decreasing malondialdehyde (MDA) and nitric oxide (NO) levels and increasing glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) levels and through its antiapoptotic capacity by inhibiting caspase-3 and p53 expression. Methods: The rabbits were divided into three groups. The animals in Group NS and Group DADLE were administered with normal saline (NS) or DADLE via aorta during 30 min of ischemia respectively, while the one in Group Sham received no intervention. During the period of reperfusion, the rabbit's blood samples were collected for enzyme-linked immunoabsorbent assay (ELISA) examinations of MDA, NO, GSH-Px and SOD. At 48 h after reperfusion, the lumbar spinal cords were harvested for immunohistochemical, real-time polymerase chain reaction (PCR) and western blot studies to detect the caspase-3 and p53 expressions. Results: The activities of serum MDA and NO showed significant reductions in the DADLE group as compared with the control group. By contrast, the levels of serum GSH-Px and SOD were significantly higher in the DADLE group than those in the NS group. In addition, caspase-3 and p53 expression were significantly increased in the NS group, while DADLE mitigated these changes. Conclusions: The protective effects of DADLE at the dosage of 0.05 mg/kg may be related to its antioxidant and antiapoptosis properties in the rabbit model of spinal cord I/R injury.

Protective effect of delta opioid receptor agonist (D-Ala2, D-Leu5) enkephalin on permanent focal cerebral ischemia in rats.

To investigate the effect of delta opioid receptor agonist (D-Ala, D-Leu) enkephalin (DADLE) on the permanent focal cerebral ischemia in rats. Thirty four male Sprague-Dawley rats were assigned randomly into three groups: sham group (group Sham, n=10), artificial cerebrospinal fluid group (group ACSF, n=12), and DADLE group (group DADLE, n=12). Permanent middle cerebral artery occlusion was performed to induce permanent focal cerebral ischemia in rats. Then, the animals in group DADLE and group ACSF were treated with DADLE or ACSF by an intracerebroventricular injection at 45 min after ischemia. Neurologic deficit scores were assessed according to the Garcia criterion at 24 h after ischemia. Infarct volume was determined using the 2,3,5-triphenyltetrazolium chloride staining method. The histological analysis was used to evaluate the extent of cerebral injury. Compared with the control group, the Garcia scores were significantly higher (P=0.000) and the infarct volumes (P=0.018) were significantly smaller in the DADLE treatment group at 24 h after ischemia. These neurologic changes were closely correlated with the outcome of the infarct volumes. In addition, the histological examination showed more intact neurons in rats treated with DADLE than those treated with ACSF at 24 h after ischemia (P=0.000). DADLE by intracerebroventricular administration at 45 min after ischemia can improve neurologic outcome and mitigate cortical neuronal injury induced by permanent focal cerebral ischemia in rats.