Acute Ongoing Nociception Delays Recovery of Consciousness from Sevoflurane Anesthesia via a Midbrain Circuit

Although anesthesia provides favorable conditions for surgical procedures, recent studies have revealed that the brain remains active in processing noxious signals even during anesthesia. However, whether and how these responses affect the anesthesia effect remains unclear. The ventrolateral periaqueductal gray (vlPAG), a crucial hub for pain regulation, also plays an essential role in controlling general anesthesia. Hence, it was hypothesized that the vlPAG may be involved in the regulation of general anesthesia by noxious stimuli. Here, we found that acute noxious stimuli, including capsaicin-induced inflammatory pain, acetic acid-induced visceral pain, and incision-induced surgical pain, significantly delayed recovery from sevoflurane anesthesia in male mice, whereas this effect was absent in the spared nerve injury-induced chronic pain. Pre-treatment with peripheral analgesics could prevent the delayed recovery induced by acute nociception. Furthermore, we found that acute noxious stimuli, induced by the injection of capsaicin under sevoflurane anesthesia, increased c-Fos expression and activity in the GABAergic neurons of the ventrolateral periaqueductal gray (vlPAG^GABA). Specific re-activation of capsaicin-activated vlPAG^GABA neurons mimicked the effect of capsaicin and its chemogenetic inhibition prevented the delayed recovery from anesthesia induced by capsaicin. Finally, we revealed that the vlPAG^GABA neurons regulated the recovery from anesthesia through the inhibition of ventral tegmental area dopaminergic neuronal activity, thus decreasing dopamine release and activation of dopamine D₁-like receptors in the brain. These findings reveal a novel, cell- and circuit-based mechanism for regulating anesthesia recovery by nociception and it is important to provide new insights for guiding the management of the anesthesia recovery period.Significance Statement There is evidence that the brain still processes pain signals during anesthesia. However, the significance and mechanisms of this phenomenon are poorly understood. Here, utilizing various pain models under anesthesia and integrating multiple techniques, the current study found that acute, but not chronic, ongoing noxious stimuli delayed the recovery from sevoflurane anesthesia. Furthermore, we identified the vlPAG^GABA-VTA circuit as a critical target for mediating this effect by inhibiting the VTA dopaminergic neurons, reducing dopamine release, and decreasing the activation of dopamine D₁-like receptors in the brain. This study presents the initial finding that the absence of pain perception under anesthesia does not equate to the absence of harm, offering a new perspective on guiding the administration of anesthesia medications.