CX3CR1 Mediates Nicotine Withdrawal-Induced Hyperalgesia via Microglial P38 MAPK Signaling.

Previously, we reported that nicotine withdrawal (NT) significantly increased pain sensitivity in rats. Recent reports suggest that fractalkine is involved in the spinal cord neuron-to-microglia activation via CX3CR1 signaling. However, its contribution to NT-induced hyperalgesia and the underlying mechanisms have yet to be elucidated. In the present study, a rat model of NT was used to test the changes in CX3CR1 expression in the spinal cord. We also evaluated the effect of the CX3CR1 neutralizing antibody on spinal microglial activity, the expression of phosphorylated p38-mitogen-activated protein kinase (p-p38-MAPK) and heat-induced pain responses. We established a NT model via subcutaneous injection of pure nicotine (3 mg/kg), three times daily for 7 days. The expression of CX3CR1 was studied by Western blot and immunofluorescence staining. Following NT, the rats received daily intrathecal injections of CX3CR1 neutralizing antibody for 3 days. The change in paw withdrawal latency (PWL) was observed. The activation of microglia and the expression of p-p38-MAPK were investigated by Western blot and immunofluorescence staining. The expression of CX3CR1 was significantly increased after NT and co-localized with IBA-1. NT rats treated with CX3CR1 neutralizing antibody showed significantly increased PWL on day 4 after NT. Furthermore, the activation of microglia and the expression of p-p38-MAPK in the spinal cord were suppressed. These results indicate that microglial CX3CR1/p38MAPK pathway is critical for the development of pain hypersensitivity after NT.

Efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil during fiberoptic bronchoscopy: A prospective, randomized, double-blind, non-inferiority trial.

Objective: Ciprofol is a novel 2,6-disubstituted phenol derivative that has improved pharmacokinetic and pharmacodynamic properties compared with propofol. This study was conducted to compare the efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil for patients undergoing fiberoptic bronchoscopy. Methods: Overall, 92 patients undergoing fiberoptic bronchoscopy were included in this prospective, randomized, double-blind, non-inferiority trial and were equally divided into two groups (n = 46 each). Fentanyl (50 µg) was given 2 min before the intravenous infusion of 0.3 mg/kg of ciprofol or 1.2 mg/kg of propofol over a time period of 30 s. During anesthesia maintenance, 0.05-0.2 µg/kg/min of remifentanil combined with one-third to one-fourth of the initial dose of ciprofol or propofol was repeated at 2-min intervals, as required, to maintain a Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale score <3. The primary outcome was the successful rate of fiberoptic bronchoscopy. Secondary outcomes included demographic characteristics, time metrics, hemodynamics, coughing severity, intubating conditions, lowest oxygen saturation, utilization of study drug doses, number of remedies (lidocaine and vasoactive drugs) used, satisfaction scores of both patients and the endoscopist, occurrence of intraoperative awareness, patients' willing to repeat fiberoptic bronchoscopy, and occurrence and severity of adverse events. Results: The successful completion rate of fiberoptic bronchoscopy was 91.30% (42 of 46; 95% confidence interval [CI]: 82.80%-99.80%) in the ciprofol-remifentanil group and 89.13% (41 of 46; 95% CI: 79.80%-98.50%) in the propofol-remifentanil group. Though the clinically acceptable intubating condition was improved in the ciprofol-remifentanil group, this difference has no clinical statistical difference (p > 0.05). No significant differences were noted between the two groups with respect to time metrics, consumption of fentanyl and remifentanil, or number of remedies (lidocaine and vasoactive drugs). Patients' willingness to repeat fiberoptic bronchoscopy and the satisfaction of both patients and endoscopist were significantly higher in the ciprofol-remifentanil than in the propofol-remifentanil group (p < 0.05). Compared with patients in the propofol-remifentanil group, patients in the ciprofol-remifentanil group had more stable hemodynamics. The lowest oxygen saturation was significantly higher in the ciprofol-remifentanil than in the propofol-remifentanil group (p < 0.05). The numbers of patients who experienced pain on injection in the ciprofol-remifentanil group was significantly lower than the number in the propofol-remifentanil group (p < 0.01). Severity of coughing, clinically acceptable severity of coughing, incidence of intraoperative awareness, and other adverse events were all similar between the two groups (p > 0.05). Only four patients experienced grade 2 adverse events (severe hypotension in one patient in the ciprofol-remifentanil group and three patients in the propofol-remifentanil group; p > 0.05); they were treated with noradrenaline. Conclusion: Ciprofol-remifentanil was non-inferior to propofol-remifentanil with regard to successful sedation for flexible bronchoscopy, when used with pre-intravenous administration of 50 µg of fentanyl. At the same time, patients' willingness to repeat flexible bronchoscopy and the satisfactions were all significantly improved.

Sesamol attenuates oxidative stress, apoptosis and inflammation in focal cerebral ischemia/reperfusion injury.

The aim of the present study was to evaluate the therapeutic potential of sesamol treatment on focal ischemia/reperfusion (I/R) injury in the rat brain. The results demonstrated that pretreatment with sesamol seven days prior to focal cerebral I/R injury had significant positive effects, including improvements in neurological deficits (P<0.05), and a reduction in malondialdehyde content and elevation of antioxidant levels (superoxide dismutase, glutathione and glutatione peroxidase; both P<0.05). Furthermore, levels of B cell lymphoma-2 (Bcl-2)-associated X protein and caspase-3 were significantly downregulated, whereas the level of Bcl-2 was effectively increased. Conversely, the mRNA expression of proinflammatory cytokines were significantly reduced in focal cerebral I/R injury rats upon sesamol intervention. Therefore, the beneficial effects of sesamol on cerebral I/R injury may be due to the reduction of oxidative stress, inhibition of apoptosis and inflammation. The findings of the present study suggest that sesamol supplementation may serve as potent adjuvant in the treatment of focal cerebral ischemia/reperfusion injury due to its neuroprotective effects.