Glial activation in the periaqueductal gray promotes descending facilitation of neuropathic pain through the p38 MAPK signaling pathway.
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.
['Ni|Hua-Dong|HD|', 'Yao|Ming|M|', 'Huang|Bing|B|', 'Xu|Long-Sheng|LS|', 'Zheng|Ying|Y|', 'Chu|Yu-Xia|YX|', 'Wang|Han-Qi|HQ|', 'Liu|Ming-Juan|MJ|', 'Xu|Shi-Jie|SJ|', 'Li|Hong-Bo|HB|']
D000818:Animals D000894:Anti-Inflammatory Agents, Non-Steroidal D002135:Calcium-Binding Proteins D004195:Disease Models, Animal D005904:Glial Fibrillary Acidic Protein D006930:Hyperalgesia D007093:Imidazoles D008297:Male D008840:Microfilament Proteins D009457:Neuroglia D010147:Pain Measurement D017288:Pain Threshold D010487:Periaqueductal Gray D010751:Phosphopyruvate Hydratase D011725:Pyridines D051381:Rats D017207:Rats, Sprague-Dawley D012585:Sciatica D015398:Signal Transduction D013997:Time Factors D048051:p38 Mitogen-Activated Protein Kinases
neuropathic pain MAPK microglia astrocytes mitogen-activated protein kinase