Objective It is known that chronic pain affects various higher brain functions including perception, emotion, cognition, and memory.However, few studies have been performed to examine pain-induced synaptic plastic changes in the hippocampal formation (HF), an important region subserving affective-motivational component of pain.Our previous study has revealed a strong impact of peripheral persistent noeiception on synaptic connection, transmission and function in the HF of rats, in both temporal and spatial domains.However, the underlying signaling mechanisms for this pain-related spatial and temporal plasticity are still less understood.The present study attempted to examine potential different roles of the mitogen-activated protein kinase (MAPK) members in mediating this plastic phenomenon.Methods Inhibitors targeting extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK) were used respectively.Spatial and temporal components of entorhinal-hippocampal synaptic connections and efficacy of rats were recorded by using a newly developed 64-channels (8×8) multi-electrode array technique (Med64 system).Results (1) Pharmacological inhibition of the ERK-and JNK-mediated signaling pathway, at the plateau phase of the long-term potentiation (LTP), significantly decreased pain-enhanced LTP maintenance whereas similar blockade of p38 MAPK pathway dramatically further increased the potentiation.(2) Regarding the spatial magnification of pain, ERK and p38 MAPK seemed to play opposing roles, with the former positively involved and the latter negatively involved, without any detectable effect of the JNK signaling pathway.Conclusion Together, these results suggest differential roles of the specific members of the MAPK family in mediating pain-associated spatial and temporal plasticity in the HF, which are in good agreement with previous observations.