Chronic stress increases the susceptibility to chronic vulvar pain following acute vulvar inflammation in a preclinical model of vulvodynia

Psychological distress and chronic stress were suggested to contribute to the pathophysiology of idiopathic pain conditions such as provoked vulvodynia (PV). The comorbidity of PV and mood disorder is quite common. Thus, vulvar pain can trigger anxiety, and mood disruption, whereas elevated anxiety and mood disruption play a critical role in pain maintenance. Yet, whether chronic stress can facilitate the development of chronic vulvar pain remains unclear. Here, we aimed to assess the effects of chronic stress on anxiety, depression-like behaviors, and the development of chronic vulvar pain after vulvar inflammation, which combines acute inflammation with chronic unpredictable stress (CUS) in female rats. Current result indicates that CUS leads to a reduction in vulvar mechanical thresholds and an increase in anxiety-like behavior, including reduced entries and time spent in the open arms of the EPM, reduced time in the center, increased distance moved in the OF, and reduced sucrose intake compared to the non-CUS group. Blood corticosterone levels and gene expression related to neuronal activation (cFOS) and GABA-synthesis (GAD67) were significantly increased in the amygdala and PAG in the CUS group compared to the non-CUS group. Following vulvar injection (saline/zymosan), there was a significant reduction in vulvar mechanical threshold in all groups: non-CUS/Saline, non-CUS/Zymosan, CUS/Saline, and CUS/Zymosan. However, mechanical thresholds returned to baseline in all groups except the CUS/Zymosan group, which exhibited prolonged vulvar hypersensitivity with no sign of recovery. Long-term behavioral assessments revealed reduced open-arm entries, altered locomotion, and decreased sucrose intake of the CUS groups compared to non-CUS groups. In conclusion, chronic stress enhances vulnerability to chronic vulvar pain following acute inflammation, alongside persistent anxiety and depression-like behaviors. These findings support a biopsychosocial model of PV, emphasizing the interplay between stress and inflammation in vulvar pain chronification.