Neural Mechanisms Underlying Anterior Cingulate Cortex Mediating Pain Aversive Emotion In Rats

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, which includes a sensory-discriminative and an affective-motivational component. During past decades, a great progress has been made on the study of the sensory-discriminative component of pain. However, the data on the pain-related affective aspect are quite limited, due to the lack of a behavioral index or available animal model relating to the affective component. A line of investigation indicated the patients with chronic pain in clinic suffer from much more the emotional disturbance, such as anxiety, fear, pessimism, than pain itself. Thus, clarify the mechanism of pain-related affective dimension is very important not only for deepening and expanding our understanding of pain but also for the cure and remission of chronic intractable negative emotion induced by pain.Anterior cingulate cortex is an important part of the limbic system. A great body of evidence indicates that ACC is related to emotion, memory and pain. Electrophysiological studies showed that some neurons within the ACC responded to either noxious stimulus per se or environmental cues that predict a painful stimulus. Positron emission tomography (PET) studies revealed that both noxious stimuli and pain-induced unpleasantness activated the ACC. Animal behavioral studies indicated that the ACC mediated the affective-like responses of tonic pain in hot-plate, formalin-induced conditioned place avoidance and laser-pain conditioning test. Our recent findings showed that following retrieval of formalin-induced conditioned place avoidance, Fos expression in the ACC was significantly increased. Clinically, surgical ablation of the ACC and surrounding cortical tissue obviously decreased pain-related unpleasantness/dysphoria without affecting the patient's ability to discriminate the intensity or localization of the noxious stimulus. Taken together, these studies suggest that the ACC is involved in processing both of pain sensation and pain emotion. The cAMP-responsive element binding protein (CREB) is a transcription factor that is involved in the formation of long-term memory and the persistent pain-induced central sensitization of the spinal dorsal horn neurons. Extracellular signal-regulated kinase (ERK) is a member of mitogen-activated protein kinase (MAPK) family that may be linked to mediate the activation of CREB. It is unknown whether CREB is a critical factor for pain-related affective states and whether MAPK/ERK signaling cascade mediate the activation of CREB during the induction of pain-related emotion.The present study was mainly to address the neurobiological mechanisms underlying the roles of ACC in pain aversive affection.1. Using fluorogold (FG) retrograde tract-tracing technique, the afferent projection of the ACC was traced. FG (3%, 0.2 μl) was injected into unilateral rACC or cACC. Seven days later, the rats were perfused. Forty-micrometer-thick sections were mounted on slides and observed under microscopy. The results showed that the distribution of the FG-labeled cells had no significant difference between rACC injection or cACC injection. FG-labeled cells were mainly distributed in the ipsilateral injection site. The ACC received afferent axons from many cortical and subcortical areas, including the midline and intralaminar thalamic nuclei, amygdala, secondary visual cortex, secondary auditory cortex, ectorhinal and perirhinal cortex. It is indicated that the ACC receives not only the nociceptive information from the thalamus but also the environmental information from visual, auditory, olfactory cortex. The results provided morphological evidence for an involvement of ACC in pain sensation and emotion.2. Combination of painful stimulus (injection of formalin into the rat's hindpaw) or unpainful stimulus (0.5 mA electric shock) with a place conditioning apparatus, we developed formalin-induced conditioned place avoidance (F-CPA) and electric foot-shock-induced conditioned pla...