Activation of NMDA Receptors in the Anterior Cingulate Cortex Enhances Anxiety‐Induced Behaviour and Antinociception, and Contributes to the Modulation of Pain‐Facilitatory Descending Pathways

ABSTRACT Background The anterior cingulate cortex (ACC) is known to modulate glutamate‐mediated fear‐related defensive behaviours and nociceptive responses. However, its role in acute anxiety‐related behaviours and associated antinociception remains unclear. This study aimed to investigate the involvement of the ACC in anxiety‐induced responses and its potential descending pathways influencing spinal nociceptive processing. Methods Male and female Wistar rats received microinjections of either vehicle or the NMDA receptor agonist N‐methyl‐D‐aspartic acid (NMDA; 1 nmol) into area 24b (Cg1) of the ACC. Rats were then tested in the elevated plus maze (EPM) or open field (OF) tests, followed by the tail‐flick test. In a separate experiment, anaesthetised rats were exposed to a thermal tail stimulus while undergoing electrophysiological recordings in the rostral ventromedial medulla (RVM) after ACC activation with NMDA. In some cases, NMDA administration was preceded by microinjections of vehicle or the NMDA receptor antagonist AP‐5 (1 nmol) into the dorsal periaqueductal grey (dPAG), a midbrain site involved in descending pain modulation. Results NMDA‐induced activation of ACC area 24b increased anxiety‐related behaviours and antinociception in males during both EPM and OF testing. In females, this effect was observed only in the EPM test. In anaesthetised rats, ACC activation facilitated spinal nociception, an effect abolished by dPAG NMDA receptor blockade, suggesting a relay through this midbrain region. Conclusions ACC activation enhances anxiety‐related behaviour. While it promotes pronociception under anaesthesia, it induces antinociceptive effects in awake animals exposed to anxiogenic contexts.