Enhancement of glutamatergic transmission in the cingulate cortex in response to mild noxious stimuli under a neuropathic pain‐like state

Abstract

Pain is evoked by noxious body stimulation or through negative emotional events and memories. There are several caveats to the simple proposition that pain and emotion are linked in the cingulate cortex (CG). In this study, we investigated whether mild noxious heat stimuli could affect the neuronal activity in the CG of rats with sciatic nerve ligation. We produced a partial sciatic nerve injury by tying a tight ligature in rats. Seven days after sciatic nerve ligation, rats received mild noxious heat stimuli. Mild noxious heat stimuli produced flinching behaviors in sciatic nerve-ligated rats, but not sham-operated rats. In addition, the mild noxious heat stimuli caused a significant increase in the release of glutamate in the CG of nerve-ligated rats compared with that of sham-operated rats. Furthermore, phosphorylated-NR1-positive cells in this area significantly increased after mild noxious heat stimuli under a neuropathic pain. Under this condition, there were no significant changes in the levels of immediate-early genes such as c-fos, c-jun, JunB, and Fra1 in the CG between nerve-ligated and sham-operated rats. However, mild noxious heat stimuli under a neuropathic pain-like state produced a marked increase in the phosphorylated-c-jun (p-c-jun) immunoreactivity, which is commonly used to map neurons in the brain that can be activated after N-methyl-D-aspartate receptor activation. These findings raise the possibility that mild noxious heat stimuli under a peripheral nerve injury may increase the release of glutamate and promote its related postneuronal activity in the CG.