Is endogenous d‐serine in the rostral anterior cingulate cortex necessary for pain‐related negative affect?

Functional activation of NMDA receptors requires co‐activation of glutamate‐ and glycine‐binding sites. d‐serine is considered to be an endogenous ligand for the glycine site of NMDA receptors. Using a combination of a rat formalin‐induced conditioned place avoidance (F‐CPA) behavioral model and whole‐cell patch‐clamp recording in rostral anterior cingulate cortex (rACC) slices, we examined the effects of d‐amino acid oxidase (DAAO), an endogenous d‐serine‐degrading enzyme, and 7‐chlorokynurenate (7Cl‐KYNA), an antagonist of the glycine site of NMDA receptors, on pain‐related aversion. Degradation of endogenous d‐serine with DAAO, or selective blockade of the glycine site of NMDA receptors by 7Cl‐KYNA, effectively inhibited NMDA‐evoked currents in rACC slices. Intra‐rACC injection of DAAO (0.1 U) and 7Cl‐KYNA (2 and 0.2 mm, 0.6 µL per side) 20 min before F‐CPA conditioning greatly attenuated F‐CPA scores, but did not affect formalin‐induced acute nociceptive behaviors and electric foot shock‐induced conditioned place avoidance. This study reveals for the first time that endogenous d‐serine plays a critical role in pain‐related aversion by activating the glycine site of NMDA receptors in the rACC. Furthermore, these results extend our hypothesis that activation of NMDA receptors in the rACC is necessary for the acquisition of specific pain‐related negative emotion. Thus a new and promising strategy for the prevention of chronic pain‐induced emotional disturbance might be raised.