The Involvement of Glutamate-mGluR5 Signaling in the Development of Vulvar Hypersensitivity

Provoked vulvodynia (PV) is the leading cause of vulvar pain and dyspareunia. The etiology of PV is multifactorial and remains poorly understood. PV is associated with a history of repeated vulvar inflammation and is often accompanied by sensory neuromodulation as a result of activation of the metabotropic glutamate receptor 5 (mGluR5) in the sensory nerve terminals. Therefore, this study aims to examine the role of glutamate-mGluR5 signaling during the initial inflammatory phase in chronic vulvar pain development in an animal model of PV.Thermal and mechanical vulvar sensitivity was assessed for three weeks following zymosan vulvar challenges. Anxiety-like behavior and locomotor activity were assessed at the end of the experiment. To investigate the role of glutamate mGluR5, the MTEP (mGluR5 antagonist) was injected into the vulva during vulvar inflammation. On the other hand, glutamate or CHPG (mGluR5 agonist) were injected in order to examine the effects of mGluR5 activation. RT-PCR was performed to assess changes in the transcription of genes related to neuroinflammation, neuromodulation, and neuroplasticity in the spinal cord (L6-S3). Zymosan-induced inflammation resulted in a significant thermal and mechanical vulvar hypersensitivity that persisted for over a month after the zymosan injection. However, local treatment with MTEP enhanced the vulvar mechanical and thermal hypersensitivity. On the other hand, activation of the mGluR5 via injection of glutamate or CHPG into the vulva leads to long-lasting vulvar mechanical and thermal hypersensitivity. The activation of the glutamate pathway was found to be accompanied by an increase in the transcription level of genes related to neuroinflammation and neuroplasticity in the sacral spine region. The present findings indicate that vulvar hypersensitivity is mediated by mGluR5 activation during inflammation. Hence, modulation of the mGluR5 pathway during the critical period of inflammation contributes to preventing chronic vulvar pain development. Conversely, activation of the mGluR5 pathway leads to long-lasting mechanical and thermal hypersensitivity.