title: Differential activation of MAPK in injured and uninjured DRG neurons following chronic constriction injury of the sciatic nerve in rats.
abstract: To investigate the intracellular signal transduction pathways involved in the pathophysiological mechanisms of neuropathic pain after partial nerve injury, we examined the activation of extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in the dorsal root ganglion (DRG) in the chronic constriction injury (CCI) model. The CCI induced an increase in the phosphorylation of ERK in predominantly injured medium-sized and large-sized DRG neurons and in satellite glial cells. Treatment with the MAPK kinase 1/2 inhibitor, U0126, suppressed CCI-induced mechanical allodynia and partially reversed the increase in neuropeptide Y (NPY) expression in damaged DRG neurons. In contrast, the CCI induced the activation of p38, mainly in uninjured small-to-medium-diameter DRG neurons and in satellite glial cells. The p38 inhibitor, SB203580, reversed the CCI-induced heat hyperalgesia and also the increase in brain-derived neurotrophic factor (BDNF) expression in intact DRG neurons. On the other hand, the nerve growth factor (NGF)-induced increase in BDNF expression in small-to-medium-diameter neurons was reversed by SB203580, whereas the anti-NGF-induced increase in NPY in medium-sized and large-sized neurons was partially blocked by U0126. Taken together, our results demonstrate that the activation of ERK and p38 and also the changes in NPY and BDNF expression may occur in different populations of DRG neurons after CCI, partially through alterations in the target-derived NGF. These changes in injured and intact primary afferents are likely to have a substantial role in pathological states, and MAPK pathways in nociceptors may be potential targets for the development of novel analgesics.
authors.affiliation: Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Obata
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Yi
authors.initials: Y
authors.lastname: Dai
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Mizushima
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Fukuoka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tokunaga
authors.forename: Koichi
authors.initials: K
authors.lastname: Noguchi
mesh_terms: D051700:Activating Transcription Factor 3; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001522:Behavior, Animal; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D003250:Constriction; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007839:Functional Laterality / Q000502:physiology; D005727:Ganglia, Spinal / Q000166:cytology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization; D008297:Male; D020932:Nerve Growth Factor / Q000276:immunology / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000201:enzymology*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051700:Activating Transcription Factor 3; D000906:Antibodies; C497108:Atf3 protein, rat; D019208:Brain-Derived Neurotrophic Factor; D002070:Butadienes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009478:Neuropeptide Y; D009570:Nitriles; D011725:Pyridines; D014157:Transcription Factors; C113580:U 0126; D020932:Nerve Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580