Impairment of long-term depression in the anterior cingulate cortex of mice with bone cancer pain.

The anterior cingulate cortex (ACC) has been shown to play an important role in pain-related perception and chronic pain. However, little is known about the molecular mechanisms involved. To address this issue, we analyzed excitatory synaptic transmission and long-term synaptic plasticity in layer II/III pyramidal neurons within the rostral ACC (rACC) from mice with bone cancer pain induced by intra-tibia implantation of osteolytic fibrosarcoma cells. Ex vivo whole-cell patch-clamp recordings from rACC neurons showed no significant alterations in presynaptic glutamate release probability and postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic responses in mice with bone cancer pain. However, mechanical allodynia occurred in conjunction with decreased N-methyl-d-aspartate (NMDA)/AMPA ratio of synaptic currents elicited in bilateral rACC neurons. In addition, the induction of NMDA receptor-dependent long-term depression (LTD) at rACC synapses was impaired in rACC neurons of tumor-bearing mice. Western blot analysis revealed a significant decrease in the levels of NR1, NR2A, and NR2B subunits of NMDA receptors in the rACC under bone cancer pain condition. No significant changes in overall mRNA levels for any of the NMDA receptor subunits or calpain activity were observed in the rACC of tumor-bearing mice. These results indicate that tumor-induced injury or remodeling of primary afferent sensory nerve fibers that innervate the tumor-bearing bone may cause a persistent decrease in NMDA receptor expression in rACC neurons, resulting in a loss of LTD induction, thereby leading to long-term alterations of rACC activity and creating exaggerated pain behaviors.