Approximately 8-14% of stroke victims suffer central post-stroke pain (CPSP) and such a cause of pain affects a large number of people, many of whom are not referred for proper medical evaluation or treatment. Studies that addressed the detailed mechanisms of CPSP are not well established, thus resulting in presently inadequate therapies (Bowsher, 2001). CNS inflammation arises from initial insults of ischemic and traumatic brain injuries such as stroke may give rise to increased levels of extracellular nucleotides. These extracellular nucleotides and their metabolites may activate a variety of cell surface purinergic receptors, influence the inflammatory activities among responding cells. Many of these activities are mediated through P2X receptors, and in particular, through the activation of the subtype, P2X7 receptor (Wang X. et al., 2004). P2X7 receptors have been highly postulated to be associated with nociceptive transmission and chronic neuropathic pain. However, it still unclear is whether P2X7 receptors directly participate in pain signaling in the CPSP. Proliferation of microglia and glia cells in dorsal root ganglia was reported in neuropathic pain induced by spinal cord injury or peripheral injury. Over expression of brain-derived neurotrophic factor (BDNF) by proliferated microglia or glia cell in dorsal root ganglia after injury was a factor related to neuropathic pain (Zhang. et al., 2011). Expression of KCC2 and NKCC1 channels of mature neuron cell could be changed after the over expression of BDNF and intracellular chloride concentration would be in an unbalance state that could cause an abnormal excitation (Jolivalt et al., 2008). In the present study, we tested the hypothesis that persistent CPSP is caused by P2X7 receptor activation and BDNF over expression after thalamic tissue damage and subsequent elevations in inflammatory cytokines, such as IL-1β. A CPSP rat model was utilized to elucidate the characteristics of CPSP. Male Sprague-Dawley rats (300-400 g) were housed in an air-conditioned room with free access to food and water. All experiments were carried out in accordance with the guidelines of the Academia Sinica Institutional Animal Care and Utilization Committee. Type 4 collagenase (0.125U/0.5 μl) was injected into rats’ lateral thalamic area. Significant hyperalgesia to mechanical and thermal pain stimulation were developed beginning 1 week after surgical CPSP induction, which persisted for at least 5-6 weeks compared with their contralateral unaffected side. P2X7 receptors and inflammatory cytokines were found highly elevated in the thalamus under CPSP conditions. Induced CPSP rats with early treatment of P2X7 antagonist exhibited reduction of hyperalgesia and hyper neuronal excitability. Early treatment with P2X7 receptor antagonist also blocked the enrichment of microglia aggregation and elevated P2X7, TNF-α, IL-6, and I-L1β but not BDNF levels. Activity of medial thalamus was enhanced after repeated noxious stimuli in CPSP animal and this enhancement could be blocked by acute TrKB-FC (an extracellular scavenger of BDNF) infusion. Medial thalamic spontaneous oscillatory activities could be suppressed by GABAA receptor agonist in control rats but that was enhanced in CPSP rats. Compared to control group, the expression of BDNF in medial thalamus was increased in CPSP. But expressions of GABAA channel and KCC2 channel were decreased in CPSP group. Expressions of TrKB receptor and NKCC1 channel were not different between two groups. Our results suggested that differential mechanisms involved glutamatergic and GABAergic neurotransmission were mediated by P2X7 receptor activation and BDNF over expression respectively after CPSP development. Targeting P2X7 receptors and BDNF may be bi-effectively therapeutic as a treatment for CPSP, as a pain blocker and immunosuppressant that inhibits inflammatory damage to brain tissue which will be widely beneficial for the recovery of central pain of patients suffered from stroke.