Background: Remifentanil-induced postoperative hyperalgesia (RIH) refers to a state of hyperalgesia or aggravated pre-existing pain after remifentanil exposure. There has been considerable interest in understanding and preventing RIH. However, the mechanisms responsible for RIH are still not completely understood. Toll-like receptor 4 (TLR4), a classic innate immune receptor, has been detected in sensory neurons and participates in various nociceptive conditions, whereas its role in RIH remains unclear. Transient receptor potential ankyrin 1 (TRPA1) always serves as a nociceptive channel, whereas its role in RIH has not yet been investigated. This study aimed to determine whether the TLR4 signaling pathway in sensory neurons engaged in the development of RIH and the possible involvement of TRPA1 during this process. Methods: A rat model of remifentanil-induced postoperative hyperalgesia (RIH) was established, which presented decreased paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). The mRNA and protein expression levels of TLR4, phosphorylated NF-κB, and TRPA1 in the dorsal root ganglion (DRG) from RIH model were analyzed by real-time PCR, western blot, and immunofluorescence. The TLR4 antagonist TAK-242 and the TRPA1 antagonist HC-030031 were applied to determine the role of sensory neuron TLR4 signaling and TRPA1 in RIH. Results: Compared with control, PWMT and PWTL were significantly decreased in RIH model. Moreover, the mRNA and protein expression of TLR4 and TRPA1 in DRG were upregulated after remifentanil exposure together with increased NF-κB phosphorylation. TLR4 antagonist TAK-242 mitigated mechanical pain in RIH together with downregulated expression of TLR4, phosphorylated NF-κB, and TRPA1 in DRG neurons. In addition, TRPA1 antagonist HC-030031 also alleviated mechanical pain and decreased TRPA1 expression in RIH without affecting TLR4 signaling in DRG. Conclusions: Our results suggested that activation of TLR4 signaling pathway engaged in the development of RIH by regulating TRPA1 in DRG neurons. Blocking TLR4 and TRPA1 might serve as a promising therapeutic strategy for RIH.

Purpose Perioperative anaphylaxis (POA) is an acute severe systemic hypersensitivity reaction characterized by life-threatening respiratory and circulatory collapse. In our previous study, we reported the epidemiology of suspected POA in China. In the present study, we aimed to elucidate the management and outcomes of these cases and further verify the risk factors for near-fatal and fatal outcomes. Patients and Methods This was a retrospective study of 447 cases of suspected life-threatening POA encountered at 112 tertiary hospitals in mainland China between September 2018 and August 2019. Patient characteristics, symptoms, duration of hypotension, treatments, and clinical outcomes were documented. Bivariate logistic regression was used to identify risk factors for near-fatal and fatal outcomes. Results Most cases of suspected POA (89.9%) were recognized and treated within 5 min. Epinephrine was administered as the initial treatment in 232 (51.9%) cases. Corticosteroids (26.6%), other vasoactive drugs (18.3%), and bronchodilators (1.6%) were also administered as the initial treatment instead of epinephrine. The initial dosage of epinephrine (median, 35 µg) was insufficient according to the anaphylaxis guidelines. On multivariable analysis, age ≥65 years (odds ratio [OR] 7.48; 95% confidence interval [CI]: 1.33–41.87, P =0.022), ASA physical status IV (OR 17.68; 95% CI: 4.53-68.94; P <0.001), and hypotension duration ≥15 min (OR 3.63; 95% CI: 1.11–11.87; P =0.033) were risk factors for fatal and near-fatal outcomes. Conclusion Most cases in this study were managed in a timely manner, but the epinephrine application should be optimized according to the guidelines. Age ≥65 years, ASA physical status IV, and long-term hypotension were risk factors for near-fatal and fatal outcomes.