Implication of system xc- in neuroinflammation during the onset and maintenance of neuropathic pain.

BACKGROUND: Despite the high prevalence of neuropathic pain, treating this neurological disease remains challenging, given the limited efficacy and numerous side effects associated with current therapies. The complexity in patient management is largely attributed to an incomplete understanding of the underlying pathological mechanisms. Central sensitization, that refers to the adaptation of the central nervous system to persistent inflammation and heightened excitatory transmission within pain pathways, stands as a significant contributor to persistent pain. Considering the role of the cystine/glutamate exchanger (also designated as system xc-) in modulating glutamate transmission and in supporting neuroinflammatory responses, we investigated the contribution of this exchanger in the development of neuropathic pain. METHODS: We examined the implication of system xc- by evaluating changes in the expression/activity of this exchanger in the dorsal spinal cord of mice after unilateral partial sciatic nerve ligation. In this surgical model of neuropathic pain, we also examined the consequence of the genetic suppression of system xc- (using mice lacking the system xc- specific subunit xCT) or its pharmacological manipulation (using the pharmacological inhibitor sulfasalazine) on the pain-associated behavioral responses. Finally, we assessed the glial activation and the inflammatory response in the spinal cord by measuring mRNA and protein levels of GFAP and selected M1 and M2 microglial markers. RESULTS: The sciatic nerve lesion was found to upregulate system xc- at the spinal level. The genetic deletion of xCT attenuated both the amplitude and the duration of the pain sensitization after nerve surgery, as evidenced by reduced responses to mechanical and thermal stimuli, and this was accompanied by reduced glial activation. Consistently, pharmacological inhibition of system xc- had an analgesic effect in lesioned mice. CONCLUSION: Together, these observations provide evidence for a role of system xc- in the biochemical processes underlying central sensitization. We propose that the reduced hypersensitivity observed in the transgenic mice lacking xCT or in sulfasalazine-treated mice is mediated by a reduced gliosis in the lumbar spinal cord and/or a shift in microglial M1/M2 polarization towards an anti-inflammatory phenotype in the absence of system xc-. These findings suggest that drugs targeting system xc- could contribute to prevent or reduce neuropathic pain.

Validation of a French-language version of TeamSTEPPS® T-TPQ and T-TAQ questionnaires.

Teamwork training and evaluation are essential to enhance safety and quality of care. The lack of the psychometric testing of the TeamSTEPPS® Teamwork Attitudes Questionnaire (T-TAQ) and Teamwork Perceptions Questionnaire (T-TPQ) across different language and cultural settings has questioned their widespread use because such attitudes and perceptions are highly subjective and context-bound. The present study aims to translate the T-TAQ and T-TPQ into the French language and validate the psychometric properties of the two questionnaires in a public health context. A forward-backward translation process, panel reviewing, and pilot testing in two rounds were followed to develop the French versions. Confirmatory factor analysis (CFA) and Cronbach's alpha were used to examine the factor structure and internal consistency, whereas two-way mixed Intraclass Correlation Coefficient (ICC) was performed to assess test-retest reliability. A total of 235 healthcare professionals in the French-speaking community of Belgium completed the T-TAQ and T-TPQ. After two to four weeks, 102 participants took part in the second round. Despite good fit indices as revealed by the CFA and Cronbach's alpha from 0.53 to 0.75 for the five dimensions of the T-TAQ and 0.76 to 0.79 for the T-TPQ, the squared correlations among the constructs were higher than the average variance extracted. Two-way mixed ICCs indicated fair to good test-retest reliability for all the five constructs of the two questionnaires, except the leadership scale of the T-TAQ. The French-language versions of the T-TAQ and T-TPQ were semantically equivalent and culturally relevant with adequate test-retest reliability as compared to the English versions. These two instruments might be used to capture the overall attitude toward teamwork and perceptions of team skills and behaviors. Yet, further research is advisable to refine the scales to establish the discriminant validity of the different dimensions and discriminative power of the instruments.