title: Intensity-dependent activation of extracellular signal-regulated protein kinase 5 in sensory neurons contributes to pain hypersensitivity.
abstract: Alterations in the intracellular signal transduction pathway in primary afferents may contribute to pain hypersensitivity. Recently, we have reported that the phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) occurs in primary afferent neurons in response to noxious stimulation of the peripheral tissue, i.e., activity-dependent activation of ERK1/2 and p38 MAPK in dorsal root ganglion (DRG) neurons. In the present study, we investigated the phosphorylation of ERK5, also known as big MAPK1, in the DRG by noxious stimulation using immunohistochemistry. Capsaicin injection induced phosphorylated ERK5 (p-ERK5) in small-to-medium diameter sensory neurons with a peak at 2 min after capsaicin injection. Furthermore, we examined the p-ERK5 labeling in the DRG after noxious heat and cold stimuli and found a stimulus intensity-dependent increase in the number of activated neurons. Most of these p-ERK5-immunoreactive neurons were small- and medium-sized neurons, which coexpressed transient receptor potential (TRP) ion channel TRPV1 and TRPA1 after noxious heat and cold stimuli, respectively. In contrast, there was no change in ERK5 phosphorylation in the spinal dorsal horn. The i.t. administration of ERK5 antisense oligodeoxynucleotide reversed heat hyperalgesia, but not mechanical allodynia, produced by capsaicin injection. Taken together, these findings suggest that the in vivo activation of the ERK5 signaling pathway in sensory neurons by noxious stimulation may be, at least in part, correlated with functional activity and, further, involved in the development of pain hypersensitivity.
authors.affiliation: Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Mizushima
authors.forename: Koichi
authors.initials: K
authors.lastname: Obata
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Katsura
authors.forename: Jun
authors.initials: J
authors.lastname: Sakurai
authors.forename: Kimiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Yi
authors.initials: Y
authors.lastname: Dai
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Fukuoka
authors.forename: Takashi
authors.initials: T
authors.lastname: Mashimo
authors.forename: Koichi
authors.initials: K
authors.lastname: Noguchi
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002211:Capsaicin / Q000494:pharmacology; D003080:Cold Temperature; D004789:Enzyme Activation / Q000502:physiology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D048053:Mitogen-Activated Protein Kinase 6 / Q000096:biosynthesis / Q000378:metabolism*; D009475:Neurons, Afferent / Q000502:physiology*; D010766:Phosphorylation; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology; D016372:RNA, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D050916:TRPV Cation Channels / Q000187:drug effects / Q000502:physiology
chemical_list: D016372:RNA, Antisense; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D048053:Mitogen-Activated Protein Kinase 6; D002211:Capsaicin