title: Delayed activation of spinal microglia contributes to the maintenance of bone cancer pain in female Wistar rats via P2X7 receptor and IL-18.
abstract: Accumulating evidence suggests that activation of spinal microglia contributes to the development of inflammatory and neuropathic pain. However, the role of spinal microglia in the maintenance of chronic pain remains controversial. Bone cancer pain shares features of inflammatory and neuropathic pain, but the temporal activation of microglia and astrocytes in this model is not well defined. Here, we report an unconventional role of spinal microglia in the maintenance of advanced-phase bone cancer pain in a female rat model. Bone cancer elicited delayed and persistent microglial activation in the spinal dorsal horn on days 14 and 21, but not on day 7. In contrast, bone cancer induced rapid and persistent astrocytic activation on days 7-21. Spinal inhibition of microglia by minocycline at 14 d effectively reduced bone cancer-induced allodynia and hyperalgesia. However, pretreatment of minocycline in the first week did not affect the development of cancer pain. Bone cancer increased ATP levels in CSF, and upregulated P2X7 receptor, phosphorylated p38, and IL-18 in spinal microglia. Spinal inhibition of P2X7/p-38/IL-18 pathway reduced advanced-phase bone cancer pain and suppressed hyperactivity of spinal wide dynamic range (WDR) neurons. IL-18 induced allodynia and hyperalgesia after intrathecal injection, elicited mechanical hyperactivity of WDR neurons in vivo, and increased the frequency of mEPSCs in spinal lamina IIo nociceptive synapses in spinal cord slices. Together, our findings demonstrate a novel role of microglia in maintaining advanced phase cancer pain in females via producing the proinflammatory cytokine IL-18 to enhance synaptic transmission of spinal cord nociceptive neurons.
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, People's Republic of China, and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, People's Republic of China, and.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, People's Republic of China, and.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Li
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, People's Republic of China, and.
authors.forename: Hao
authors.initials: H
authors.lastname: Luo
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, People's Republic of China, and.
authors.forename: Xi-Yao
authors.initials: XY
authors.lastname: Gu
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, People's Republic of China, and.
authors.forename: Ning
authors.initials: N
authors.lastname: Lü
authors.affiliation: Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710 yuqiuzhang@fudan.edu.cn ru-rong.ji@duke.edu.
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, People's Republic of China, and yuqiuzhang@fudan.edu.cn ru-rong.ji@duke.edu.
authors.forename: Yu-Qiu
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D000255:Adenosine Triphosphate / Q000134:cerebrospinal fluid; D000818:Animals; D001859:Bone Neoplasms / Q000150:complications; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism* / Q000502:physiology; D055369:Miniature Postsynaptic Potentials; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D020671:Posterior Horn Cells / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020382:Interleukin-18; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D048051:p38 Mitogen-Activated Protein Kinases; D008911:Minocycline
keywords: IL-18; P2X7 receptor; bone cancer pain; female rats; microglia; neuron-glial interaction