Long-term potentiation (LTP) in hippocampus is a synaptic model of memory storage, while LTP at C-fiber synapses in spinal dorsal horn may underlie chronic pain produced by nerve injury and inflammation.It is, therefore, important to explore similarity and difference in the mechanisms of hippocampal LTP and spinal LTP.LTP in both regions is prevented by blockage of NMDA receptor.Intracellular protein kinases, such as PKA, PKC,CaMKⅡ and ERK are critically involved in LTP induction and early-phase maintenance in both hippocampus and in spinal dorsal horn.The drugs targeting at these molecules may not only inhibit chronic pain but also impair memory.The striking difference is that activation of microglia and subsequent over-expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), inhibits hippocampal LTP but facilitates the spinal LTP.Interestingly, both the inhibition of hippocampal LTP and facilitation of spinal LTP are mediated by activation of NF-κB, p38 MAPK and JNK.Recently we found that peripheral nerve injury, which induces spinal LTP and neuropathic pain, inhibited hippocampal LTP and impaired working memory by up-regulation of TNF-α.The number of dendrites and spines,and NMDA current decreased in hippocampal CA1 neurons but increased in projection neurons of spinal dorsal horn following peripheral nerve injury, and the morphological and functional changes were prevented by genetic deletion of TNFR1.The data suggested that over-expression of the pro-inflammatory cytokine in CNS might lead to chronic pain and memory deficit, simultaneously.Therefore, inhibition of TNF-α and its downstream molecules many relieve chronic pain and improve memory function as well.