Exploring the role of ventrolateral periaqueductal gray in remifentanil-induced postoperative hyperalgesia

Remifentanil-induced postoperative hyperalgesia (RIH) delays recovery, prolongs hospitalization, and may contribute to chronic pain. The ventrolateral periaqueductal gray (vlPAG) is a critical area for processing pain and supporting opioid-based pain relief. Inside this region, glutamate (Glu) neurons and γ-aminobutyric acid (GABA) neurons work against each other to control pain signals. However, their specific roles and underlying mechanisms in RIH remain unclear. In this study, a RIH model was established by using incisional pain mice combined with continuous infusion of remifentanil. The results indicated that RIH mice showed a significant decrease in mechanical pain thresholds in both hind paws, and this hypersensitivity only occurred under the condition of remifentanil infusion combined with surgical trauma. The expression of immediate early protein (c-Fos) in the vlPAG was significantly upregulated; calcium signal recording showed that both vlPAG-Glu and vlPAG-GABA neurons were involved in the regulation of RIH. Chemical genetic activation of vlPAG-Glu or inhibition of vlPAG-GABA could alleviate hypersensitivity. Patch clamp results showed that vlPAG-Glu in RIH mice exhibited synchronous enhancement of postsynaptic function and intrinsic excitability, while vlPAG-GABA showed increased intrinsic excitability and reduced presynaptic inhibition. Therefore, these findings strongly suggest that RIH simultaneously excites vlPAG-Glu and vlPAG-GABA neurons, the final behavioral output depends on the relative balance of the activities of these two types of neurons. Artificial activation of vlPAG-Glu or inhibition of vlPAG-GABA can effectively alleviate hypersensitivity behavior. This study provides new ideas and theoretical basis for clinical intervention strategies for RIH.