Representation and control of remifentanil-induced hyperalgesia and pain-like hypersensitivity by distinct neural ensembles in the anterior cingulate cortex

Neurochem Int. 2026 Mar 2:106138. doi: 10.1016/j.neuint.2026.106138. Online ahead of print.

ABSTRACT

Remifentanil-induced hyperalgesia (RIH) is a common but severe clinical problem that occurs following intraoperative analgesia with remifentanil. However, it still remains unknown how RIH signals are encoded in the brain. Here, we uncover the critical role of the anterior cingulate cortex (ACC) in mediating RIH using chemogenetic approach. Chemogenetic manipulation of the excitatory neurons in the ACC was found to affect RIH bidirectionally. Furthermore, we reported that RIH and formalin-induced pain-like hypersensitivity (PLH) were represented and processed by separate neural ensembles in the ACC. Using a virus-mediated target-recombination-in-active population (TRAP) system, RIH- and PLH-activated neural ensembles in the ACC were labeled and manipulated respectively. Chemogenetic manipulation of RIH-activated neural ensembles in the ACC selectively affected RIH but not PLH. Conversely, chemogenetic manipulation of PLH-activated neurons in the ACC significantly affected PLH, whereas the intervention did not alter RIH. Moreover, RIH- and PLH-activated neural ensembles in the ACC were found to differ dramatically in histological locations and electrophysiological properties. These findings reveal the contribution of the ACC to the development of RIH and separate encoding of RIH and PLH by distinct neural ensembles in the ACC. Our study provides a novel perspective for the understanding of RIH information processing in the brain.

PMID:41780803 | DOI:10.1016/j.neuint.2026.106138