Mechanism Of Central Disinhibition Facilitating Peripheral Inflammation Induced-Hyperalgesia In Rats

Chronic pain is one of the largest medical health problems. It affects approximately 20% of the adult population. While the management and treatment of acute pain is reasonably good, the needs of patients suffering chronic pain are largely unmet. Thus it is an urgent task for researchers to understand the role of central nervous system during chronic pain. Studies have shown that multiple brain regions in the central pain pathway endured long-term activity change during chronic pain, and the enhanced excitatory neurotransmission in these regions contributes to central sensitization. The change in central pain pathway is induced by increased input form peripheral nociceptors, and the change leads to long-term increased output of the neurons to noxious stimuli and stimuli which normally never produce pain.GABAergic transmission is the major fast inhibitory transmission in the central nervous system of adult mammals. As the GABA_A receptor is a chloride-permeable channel, its efficacy is largely determined by chloride gradient. Many studies shown that one of chloride transporters, Potassium-Chloride Co-Transporter (KCC2) endured decreased during many psychological diseases and abnormal synaptic activity, and the efficacy of GABAergic transmission decreased due to increased intracellular chloride concentration. Further more, synaptic activity change and psychological diseases also can lead to changes of GABA synthase, GABAergic interneuron, and GABA_Areceptors, as suggested by many studies. It is possible that decreased inhibitory transmission (disinhibition) is a general theme during abnormal brain activity. Recent advances suggest that peripheral nerve injury leads to disinhibition in central pain pathway; however, the mechanism of disinhibition is not fully investigated. In the present study, we investigated inhibitory transmission in brain regions involved in central pain pathway of rats suffering chronic pain induced be peripheral inflammation, and studied mechanism which lead to disinhibition.In the present study, we showed that:1. Reduced KCC2 Expression in Spinal Cord Dorsal Horn Neurons Contributes to Inflammatory Pain Hypersensitivity in Rats. In this part of study, we found the expression of KCC2 endured continuous decreased in the dorsal horn of spinal cord after peripheral inflammation, and the decrease contributed to hyperalgesia during chronic pain. The contralateral side to inflammation was also observed with decreased KCC2 expression. We further showed that KCC2 in the superficial layers of the dorsal horn suffered most. Further more, we found activation of BDNF-TrkB signaling pathway is necessary for KCC2 decrease. These results suggest that during peripheral inflammation, KCC2 expression also reduced, and such a decrease probably contributes to the maintenance of chronic pain. The role of BDNF-TrkB pathway on KCC2 expression also suggests that KCC2 expression is regulated by neuronal activity.2. Disinhibition in anterior cingulate cortex (ACC) contributes to hyperalgesia. We showed in this part of study that peripheral inflammation induced chronic pain increased excitatory transmission in ACC, and decreased inhibitory transmission. Using non-stationary fluctuation analysis, we found that activated GABA_Areceptor number in mIPSC event decreased after peripheral inflammation. Recording of paired-pulse IPSCs showed that the presynaptic mechanism of GABAergic transmission also altered, as the release probability increased. Thus our data suggest that reduced postsynaptic GABA_A receptor is more likely to contribute to disinhibition. We further confirmed this as the expression of GABA_a receptorβ2/3 subunits decreased while GABA synthase GAD65 increased. These results also suggest that a homeostasis regulation of GABAergic transmission also occurred during disinhibition. We further showed that disinhibition altered firing of ACC neurons, which might underlie the mechanism of spontaneous pain, observed in chronic pain patients. Behavioral study of chronic pain rats showed that disinhibition contributed to hyperalgesia.In this study we first time demonstrated during peripheral inflammation induced chronic pain KCC2 in the dorsal horn endured long-term decrease, which is induced by BDNF-TrkB signaling pathway activation. This suggests that reduced KCC2 in the dorsal horn could be a general theme in chronic pain. We also first time demonstrated that peripheral inflammation induced chronic pain would lead to disinhibition in anterior cingulate cortex. The disinhibition increased out put of ACC neurons, and facilitated hyperalgesia. Further more we also showed that homeostasis compensation of GABAergic transmission occur during inhibition.