title: Targeting P(2)X(7) receptor for the treatment of central post-stroke pain in a rodent model.
abstract: Stroke is a leading cause of death and disability in industrialized countries. Approximately 8-14% of stroke survivors suffer from central post-stroke pain (CPSP) when hemorrhagic stroke occurs in lateral thalamic regions, which severely affects their quality of life. Because the mechanisms of CPSP are not well understood, effective treatments have not been developed. In the present study, we tested the hypothesis that persistent CPSP is caused by P(2)X(7)receptor activation after brain tissue damage and subsequent elevations in inflammatory cytokines. A thalamic hemorrhagic rat model was used, characterized by thermal and mechanical allodynia that develops in the subacute to chronic phases upon CPSP onset. We found a significant increase in P(2)X(7) expression in reactive microglia/macrophages in thalamic peri-lesion tissues at 5 weeks post-hemorrhage. Thalamic P(2)X(7) receptors were directly involved in pain transmission and hypersensitivity. The systemic targeting of P(2)X(7) receptors during the acute stage of hemorrhage rescued abnormal pain behaviors and neuronal activity in the thalamocingulate pathway by reducing reactive microglia/macrophage aggregation and associated inflammatory cytokines. After CPSP onset, the targeting of interleukin-1β reversed abnormal pain sensitivity. The aberrant spontaneous thalamocortical oscillations in rats with CPSP were modulated by blocking P(2)X(7) receptors. Taken together, our results suggest that targeting P(2)X(7) may be bi-effective in the treatment of CPSP, as both a pain blocker and immunosuppressant that inhibits inflammatory damage to brain tissue. P(2)X(7)receptors may serve as a potential target to prevent the occurrence of CPSP and may be beneficial for the recovery of patients from stroke.
authors.affiliation: Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, ROC.
authors.forename: Yung-Hui
authors.initials: YH
authors.lastname: Kuan
authors.affiliation: Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, ROC.
authors.forename: Hsi-Chien
authors.initials: HC
authors.lastname: Shih
authors.affiliation: Department of Neurology and Stroke Center, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan, ROC.
authors.forename: Sung-Chun
authors.initials: SC
authors.lastname: Tang
authors.affiliation: Department of Neurology and Stroke Center, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan, ROC.
authors.forename: Jiann-Shing
authors.initials: JS
authors.lastname: Jeng
authors.affiliation: Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, ROC. Electronic address: bmbai@gate.sinica.edu.tw.
authors.forename: Bai-Chuang
authors.initials: BC
authors.lastname: Shyu
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000378:metabolism; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006930:Hyperalgesia / Q000517:prevention & control; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage; D010146:Pain / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D058920:Purinergic P2X Receptor Antagonists / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D020521:Stroke / Q000150:complications*; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
chemical_list: D018696:Neuroprotective Agents; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7
keywords: Anterior cingulate cortex; Central pain; Medial thalamus; P(2)X(7) receptor; Stroke