Differential activation of extracellular signal-regulated protein kinase in primary afferent neurons regulates brain-derived neurotrophic factor expression after peripheral inflammation and nerve injury.
To investigate the intracellular signal transduction pathways involved in regulating the gene expression of brain-derived neurotrophic factor (BDNF) in primary afferent neurons, we examined the activation of extracellular signal-regulated protein kinase (ERK) in dorsal root ganglion (DRG) neurons after peripheral inflammation and sciatic nerve transection. Peripheral inflammation induced an increase in the phosphorylation of ERK, mainly in tyrosine kinase A-containing small-to-medium-diameter DRG neurons. The treatment of the mitogen-activated protein kinase (MAPK) kinase 1/2 inhibitor U0126 reversed the pain hypersensitivity and the increase in phosphorylated-ERK (p-ERK) and BDNF in DRG neurons induced by complete Freund's adjuvant. On the other hand, axotomy induced the activation of ERK mainly in medium-and large-sized DRG neurons and in satellite glial cells. U0126 suppressed the axotomy-induced autotomy behavior and reversed the increase in p-ERK and BDNF. The intrathecal application of nerve growth factor (NGF) induced an increase in the number of p-ERK-and BDNF-labeled cells, mainly small neurons, and the application of anti-NGF induced an increase in p-ERK and BDNF in some medium-to-large-diameter DRG neurons. The activation of MAPK in the primary afferents may occur in different populations of DRG neurons after peripheral inflammation and axotomy, respectively, through alterations in the target-derived NGF. These changes, including the changes in BDNF expression, might be involved in the pathophysiological changes in primary afferent neurons.
Obata
Koichi
K
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Yamanaka
Hiroki
H
Dai
Yi
Y
Tachibana
Toshiya
T
Fukuoka
Tetsuo
T
Tokunaga
Atsushi
A
Yoshikawa
Hideki
H
Noguchi
Koichi
K
D051700:Activating Transcription Factor 3; D000818:Animals; D019771:Axotomy; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D002070:Butadienes / Q000494:pharmacology; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000201:enzymology* / Q000293:injuries / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D016900:Neurofilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009475:Neurons, Afferent / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000201:enzymology / Q000293:injuries* / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism
D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; D019208:Brain-Derived Neurotrophic Factor; D002070:Butadienes; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D016900:Neurofilament Proteins; D009570:Nitriles; D014157:Transcription Factors; C113580:U 0126; C051774:neurofilament protein H; D020928:Mitogen-Activated Protein Kinases