title: Glial activation in the periaqueductal gray promotes descending facilitation of neuropathic pain through the p38 MAPK signaling pathway.
abstract: The midbrain ventrolateral periaqueductal gray (VL-PAG) is a key component that mediates pain modulation. Although spinal cord glial cells appear to play an important role in chronic pain development, the precise mechanisms involving descending facilitation pathways from the PAG following nerve injury are poorly understood. This study shows that cellular events that occur during glial activation in the VL-PAG may promote descending facilitation from the PAG during neuropathic pain. Chronic constriction nerve injury (CCI) was induced by ligature construction of the sciatic nerve in male Sprague-Dawley rats. Behavioral responses to noxious mechanical (paw withdrawal threshold; PWT) and thermal (paw withdrawal latency; PWL) stimuli were evaluated. After CCI, immunohistochemical and Western blot analysis of microglia and astrocytes in the VL-PAG showed morphological and quantitative changes indicative of activation in microglia and astrocytes. Intra-VL-PAG injection of microglial or astrocytic inhibitors attenuated PWT and PWL at days 7 and 14, respectively, following CCI. We also evaluated the effects of intra-VL-PAG administration of the phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) inhibitor SB 203580 at day 7 after CCI. This treatment abolished microglial activation and produced a significant time-dependent attenuation of PWT and PWL. Western blot analysis showed localized expression of p-p38 in the VL-PAG after CCI. P-p38 was expressed in labeled microglia of the VL-PAG but was not present in astrocytes and neurons on day 7 after CCI. These results demonstrate that CCI-induced neuropathic pain is associated with glial activation in the VL-PAG, which likely participates in descending pain facilitation through the p38 MAPK signaling pathway.
authors.affiliation: Department of Anesthesiology and Pain Medical Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, People's Republic of China.
authors.forename: Hua-Dong
authors.initials: HD
authors.lastname: Ni
authors.affiliation: Department of Anesthesiology and Pain Medical Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, People's Republic of China.|Department of Anesthesiology, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.affiliation: Department of Anesthesiology and Pain Medical Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, People's Republic of China.
authors.forename: Bing
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology and Pain Medical Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, People's Republic of China.
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology and Pain Medical Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Anesthesiology and Pain Medical Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, People's Republic of China.
authors.forename: Yu-Xia
authors.initials: YX
authors.lastname: Chu
authors.affiliation: Department of Anesthesiology, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Han-Qi
authors.initials: HQ
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology and Pain Medical Center, The First Affiliated Hospital of Jiaxing University, Jiaxing, People's Republic of China.
authors.forename: Ming-Juan
authors.initials: MJ
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Shi-Jie
authors.initials: SJ
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Li
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000473:pathology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010487:Periaqueductal Gray / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012585:Sciatica / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C100745:Aif1 protein, rat; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D007093:Imidazoles; D008840:Microfilament Proteins; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D010751:Phosphopyruvate Hydratase; C093642:SB 203580
keywords: MAPK; astrocytes; microglia; mitogen-activated protein kinase; neuropathic pain