Contributions Of The Ventrolateral Orbital Cortex To Pain-related Negative 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. More and more evidence indicates the patients with chronic pain in clinic suffer from much more the emotional disturbance than pain itself. Physiological arousal and hypersensitivity to painful stimuli cause unpleasant feelings to patients, such as fear, anxiety, anger, depression and even a suicidal tendency. These negative affective states in turn enhance pain perception. 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 negative emotion induced by chronic intractable pain.The ventrolateral orbital cortex (VLO), which comprised most area of prefrontal cortex, is an important component of this lobe. It receives projection form thalamus nucleus submedius (Sm) and densely descends its fibers to the ventrolateral part of the periaqueductal gray (PAG) and plays a critical role in pain modulation. Furthermore, VLO has strong bidirectional connections with other cortical and subcortical areas, such as the somatosensory cortex (SI, SII), anterior cingulate cortex (ACC), prepiriform cortex, insular cortex, amygdala and parabrachial nucleus, which are all implicated in emotion, cognition, memory, behavioral control and pain. Our recent studies indicated that ACC and amygdala are essential elements in pain-related negative emotion. Given that VLO is intensely connected with ACC and amygdala, it is reasonable to assume that VLO also takes part in affective pain.The cAMP response element binding protein (CREB) is a transcription factor that involved in the formation of long-term memory in hippocampus and the persistent pain-induced central sensitization of the spinal dorsal horn neurons. The immediately early gene (IEG) c-fos is the first identified CREB target gene and its protein product Fos is extensively used as a marker for the activation of neurons to study animal behaviors. Our previous studies have shown that F-CPA retrieval induced Fos expression in the ACC, insular cortex and amygdala, which are all implicated in emotion and pain. We wanted to prove that whether the activation of CREB and c-fos in the VLO play an important role in the acquisition of aversive pain learning.Using a rat formalin-induced conditioned place avoidance (F-CPA) model, which was considered as a direct reflection of negative emotion of pain, we observed the contributions of VLO to pain-related negative emotion and the expression level of pCREB (phosphorylated CREB) and Fos in the VLO following painful stimulus and F-CPA retrieval. The results revealed that (1) When unilateral intraplantar injection of 5 % formalin was paired with a particular compartment in the place conditioning apparatus, the rats spent significant less time in this compartment on the post-conditioning day compared with the pre-conditioning day, which means that CPA was produced. Electrolytic lesion of the bilateral VLO abolished the F-CPA. Compared with the sham VLO lesion group, the F-CPA scores of VLO lesion group significantly reduced; (2) Received Electric foot-shock (0.5 mA, 2 s), the rats can also produce CPA (S-CPA). Electrolytic lesion of the bilateral VLO didn't affect S-CPA. The difference in the S-CPA scores between VLO lesion and sham VLO lesion was not significant; (3) The bilateral VLO lesion fails to chang formalin-induced acute nociceptive behaviors; (4 )Unilateral intraplantar injection of 5 % formalin 50μl induced a persistent (>24 hrs) pCREB and an accompanying increase in Fos expression in the bilateral VLO; (5) Re-exposing rats to the nociceptive conditioning context for retrieval of pain experience produced upregulation of pCREB and Fos expression in the bilateral VLO also. These results suggest that the VLO is specially involved in pain-related negative emotion but not pain sensation and fear-related negative emotion. The activation of CREB and c-fos in VLO might be one of the intracellular molecular basis of acquization of pain-related aversion and retrieval of pain-related aversive memory.Collectly, VLO is necessary for acquisition of pain-related aversion. CREB and c-fos in the VLO plays an important role in the acquisition of aversive pain learning and the retrieval of pain experience in rats. Taking the present study together with the previous reports, supports the proposal that a neural network of the VLO with the ACC, amygdala and perhaps some other limbic structures contributes to the negative emotion of pain.