Objective In recent years great progress has been made in the study of central sensitization of nociceptive neurons in the spinal cord, in which the glutamate NMDA receptor plays a pivotal role.Much less is known about sensitization in the supraspinal centers related to the pain modulation.The aim of this study was to test whether central sensitization can be induced in nociceptive neurons in the hypothalamic arcuate nucleus by peripheral inflammation, which is known to be one supraspinal component of the endogenous pain-modulating system.Methods Peripheral inflammation was induced by plantar injection of complete Freunds adjuvant (CFA) into the hind paw of rats.Single unit neuronal activity was recorded from the arcuate nucleus (ARC) in the slice of mediobasal hypothalamus as well as in anesthetized rats.Hyperalgesia following inflammation was measured by behavioral paw withdrawal responses.The function of NMDA receptor in ARC was detected by Western blot analysis.Different receptor antagonists and kinase inhibitors were used to analyze the underlying mechanisms of signal transduction involved.Results Behavioral measurement confirmed a definite hyperalgesia following peripheral inflammation.Central sensitization was found in ARC as evidenced by (1) significant increase in the frequency of spontaneous unit discharge of ARC neurons from brain slice of inflamed rats, as well as from anesthetized inflamed rats, as compared to the control rats; (2) enhancement of responses of ARC neurons to glutamate and NMDA application in slice of inflamed rats, and the responses of ARC neurons to non-noxious and noxious stimulation in anesthetized inflamed rats were enhanced as well.Up-regulated expression of phospho-NR1 and phospho-NR2B subunit, rather than NR1 and NR2B, was observed in ARC of inflamed rats.Intra-ARC microinjection of MK-801 (NMDA receptor antagonist), Ro25-6981 (NR2B subunit antagonist), CNQX (non-NMDA receptor antagonist) and PP2 (Src protein tyrosine kinase selective inhibitor) could diminish the increased frequency of neuronal discharge, the enhanced responses of ARC neurons and hyperalgesia of inflamed rats.Conclusion Central sensitization can be established in supraspinal ARC following peripheral inflammation, in which the phosphorylation of NMDA receptor, especially NR2B subunit plays an important role.