The Mechanism of Hyperalgesia and Anxiety Induced by Remifentanil: Phosphorylation of GluR1 Receptors in the Anterior Cingulate Cortex.

The anterior cingulate cortex (ACC) plays a key role in regulating mood in animals, especially anxiety, and is also a brain region that is indispensable to pain perception. Postoperative anxiety is closely related to the experience of pain. Remifentanil is a commonly used surgical analgesic. The mechanism of supraspinal hyperalgesia caused by remifentanil remains unclear. We used animal models to simulate postoperative hyperalgesia and studied the GluR1 AMPA receptor subunit in the ACC using western blots and immunocytochemistry. Behavioral tests were used to estimate anxiety levels. We found no significant change in GluR1 levels before and after hyperalgesia, whereas phosphorylation of GluR1Ser845 was significantly increased after hyperalgesia. Double staining for c-Fos, widely used as a marker of neural activation, and Arc, which facilitates GluR1 endocytosis, revealed that neural activation increased and the expression of Arc decreased after hyperalgesia. Local injection of a protein kinase A inhibitor (H89) in the ACC effectively blocked the phosphorylation of GluR1Ser845 and alleviated the hyperalgesia and anxiety shown in the behavioral tests. Double staining revealed no significant change in c-Fos or Arc levels after the administration of H89. Local injection of ibotenic acid caused damage to the ACC, following which remifentanil did not induce hyperalgesia or anxiety. These results lead us to conclude that the ACC is a critical hub for remifentanil-induced hyperalgesia (RIH) and RIH-related anxiety and that regulating the phosphorylation of GluR1Ser845 may modulate RIH and anxiety. Anxiety may be an influential factor contributing to individual differences in RIH occurrence.